Human Molecular Genetics

This Article Abstract FREE Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in ISI Web of Science Similar articles in PubMed Alert me to new issues of the journal Add to My Personal Archive Download to citation manager Search for citing articles in: ISI Web of Science (101) Request Permissions Google Scholar Articles by Stamm, S. Search for Related Content PubMed PubMed Citation Articles by Stamm, S. Social Bookmarking          What's this?

Human Molecular Genetics, 2002, Vol. 11, No. 20 2409-2416
© 2002 Oxford University Press

Signals and their transduction pathways regulating alternative splicing: a new dimension of the human genome

Stefan Stamm^*

Institute of Biochemistry, Fahrstraße 17, 91054 Erlangen, Germany

Received July 5, 2002; Accepted July 31, 2002

	ABSTRACT

TOP ABSTRACT SELECTION OF SPLICE SITES SPLICING AND DISEASE SIGNALS THAT CHANGE THE... CONCLUSIONS REFERENCES

 
The human genome project demonstrated that alternative splicing of genes is more the rule than the exception. Missplicing events are an important cause and indication of human disease. Changing alternative splicing patterns in response to an external stimulus seems to be a physiological process performed by many cells. Organisms regulate alternative splice site selection by changing the concentration and activity of splicing regulatory proteins. This is achieved by de novo protein synthesis, by regulation of the intracellular localization and by phosphorylation.

Most eukaryotic genes contain intervening sequences (introns) that interrupt the exonic sequences, which are joined in the pre-mRNA splicing process. A large number of exons are used alternatively; for example, the cell either includes an exon in the mature mRNA or omits this sequence as an intron. The sequencing of mammalian genomes demonstrated the importance of alternative splicing. In humans, a detailed analysis was performed for chromosome 22 and 19 (1). Of the 245 genes present on chromosome 22, 59% are alternatively spliced, and the 544 genes of chromosome 19 result in 1859 different messages. The comparison of expressed sequence tags (ESTs) with the human genome sequence indicates that 47% of human genes might be alternatively spliced (2). Since alternative splicing events usually result in multiple protein isoforms from a gene, this mechanism contributes to the surprising finding that only 23 000–40 000 genes (1,3) create a larger proteome, estimated to be >90 000 proteins (4).

The importance of alternative splicing is further illustrated by the increasing number of human diseases that have been attributed to missplicing events. The usage of alternative exons can be controlled by cells, for example in a developmental, tissue-specific or pathology-specific stage. As shown in this review, cells use known phosphorylation pathways, as well as relocalization and synthesis of splicing factors, to change their alternative splicing patterns. The emerging picture of signal transduction pathways regulating pre-mRNA alternative splicing will contribute to the development of therapies against diseases caused by missplicing.

	SELECTION OF SPLICE SITES

TOP ABSTRACT SELECTION OF SPLICE SITES SPLICING AND DISEASE SIGNALS THAT CHANGE THE... CONCLUSIONS REFERENCES

 
The joining of exons is performed by the spliceosome, a macromolecular complex comprising five small ribonucleoprotein particles (snRNPs) and a total of at least 45 proteins (5). The catalytic events of this process have been determined in great detail, and have recently been reviewed (6,7). However, how the weakly conserved splice sites are recognized and often alternatively controlled remains unclear (8,9). The borders of an exon are defined by the 5' and 3' splice sites as well as the branch-point. Owing to the degenerate nature of these cis elements, additional elements known as silencers or enhancers are needed to define an exon (10). Proteins binding to these sequence elements can be subdivided into two major groups: heterogeneous ribonucleoproteins (hnRNPs) (11) and SR/SR-like proteins (12). Usually these proteins contain RNA-binding motifs and protein : protein interaction domains. Although the binding of each individual protein to cis elements on the RNA is weak, a high specificity is achieved through interactions of multiple RNA elements with proteins that can interact with other RNA-binding proteins. As a result, exons are recognized with a remarkable fidelity through combinatorial control of different proteins (9). Since the concentrations of these proteins differ between tissues (13) or cell types (14–16), exons can be recognized alternatively in a tissue-specific manner, indicating a cellular code for splice site selection. In a given tissue, the activity of splicing regulatory proteins can change during development (17,18), which explains the frequently observed change (19) of splicing patterns during development. The combination of the regulatory proteins also seems to vary between individuals of the same species, which explains the different alternative splicing of the same allele. This results in a different penetrance of a disease-causing gene (20,21) and indicates that alternative splice site selection could be a potential genetic modifier of human disease (22).

Although splicing can be biochemically separated from other gene expression events, it is clear that pre-mRNA splicing is tightly coupled to transcription (23), polyadenylation (24), editing (25), RNA surveillance (11) and transport (26). Most of these processes share common proteins, and in an intact cell mRNA is most likely created by ‘gene expression’ (27) or ‘RNA factories’ (28). As a result of this interdependence, splice site selection can be influenced in vivo by indirect effects, for example promoter activity (29).

	SPLICING AND DISEASE

TOP ABSTRACT SELECTION OF SPLICE SITES SPLICING AND DISEASE SIGNALS THAT CHANGE THE... CONCLUSIONS REFERENCES

 
Changes in splice site selection are increasingly recognized as the cause or the consequence of human pathologies (reviewed in 30–32). Observed changes in splice site usage can result from mutations in regulatory elements or variations in the composition, concentration or localization of regulatory proteins. Mutations in splice sites account for at least 15% of point mutations causing disease in humans (33,34). Mutations in exonic elements can alter gene expression by changing splice site usage. Several of these mutations are translationally silent, which clearly demonstrates aberrant pre-mRNA processing as the most likely cause of disease (35). The nuclear concentration of regulatory proteins is changed in several diseases. For example, in mammary gland tumorigenesis (36) and ovarian cancer (37), the amount and ratios of SR proteins are altered. In brain ischemia, which is caused by stroke, SR proteins are translocated from the nucleus to the cytoplasma (38).

Proximal spinal muscular atrophy (SMA) provides a good example that illustrates changes of alternative splicing patterns in a human disease. SMA is a neurodegenerative disorder with progressive paralysis caused by the loss of -motor neurons in the spinal cord. It is the second most common autosomal recessive disorder and the most frequent genetic cause of infantile death (39). The gene responsible for the disease is SMN1 (survival of motor neurons), and the disease is caused by loss of (96.4%), or mutations in (3.6%), the SMN1 gene (40). SMN2 is a nearly identical copy of the SMN1 gene, but cannot compensate for the absence of SMN1 because it is processed differently. Owing to a single nucleotide difference in exon 7, this exon is skipped in SMN2. Therefore the proteins generated by the two genes differ in their C terminus, which is most likely crucial for the function. The exon enhancer containing the single nucleotide difference has been characterized (41,42) and found to be of the purine-rich GAR type. Systematic searches for trans-acting factors identified SRp30c and transformer2ß, members of the SR-(related) family of proteins (43,44). In co-transfection experiments, an increase in the concentration of both factors result in stimulation of exon 7 usage. In a mouse model, administration of high doses of sodium butyrate increases both SR-protein levels and exon 7 usage and enhances survival of the animals (45). In a cell culture system, aclarubicin, an anticancer drug used in chemotherapy, was also shown to increase exon 7 usage (46). To date, the link between the two substances and a change in splice site selection remains unclear. The SMN model illustrates the following general points: (i) diseases caused by splicing defects are common; (ii) a point mutation is sufficient to cause a phenotype; (iii) alternative exon usage is regulated by several factors in vivo; and, importantly, (iv) alternative exon usage can be changed by proper cell treatment or stimulation.

	SIGNALS THAT CHANGE THE SELECTION OF SPLICE SITES

TOP ABSTRACT SELECTION OF SPLICE SITES SPLICING AND DISEASE SIGNALS THAT CHANGE THE... CONCLUSIONS REFERENCES

 
Changes in splice site selection not only occur as a result of a disease, but are a normal adaptation of a cell. Studies in recent years showed that numerous stimuli, such as growth factors, cytokines, hormones and depolarization, result in a change in splice site selection. Most of the systems investigated play a role in the immune or nervous system, which reflects the high abundance of alternative splicing in these organs (2,47,48). For some systems, parts of the signal transduction pathways have been worked out, but for most of the signals these pathways remain to be determined. The paradigms applied can be roughly subgrouped into three categories: stimulation of a receptor, cellular stress and neuronal activity (Table 1). Several studies performed in intact animals with physiological stimulation protocols resulted in an alteration of splice site selection. For example, when mice are forced to swim, this stressful experience is enough to change the alternative splicing pattern of the acetylcholine esterase pre-mRNA (49). Another example is the expression of a Praja1 splice variant after pavlovian fear memory training (50). Nutritional status, especially the amount of polyunsaturated fatty acids, regulates the alternative splice variants of glucose-6-phosphate dehydrogenase (51,52). These examples show that changes in alternative splicing patterns are part of a physiological adaptation. The changes seen in models of pathology, such as stroke (38) and cocaine (53) and ethanol (54) abuse, are most likely a more pronounced manifestation of the adaptations that occur under normal physiological conditions.

View this table: [in this window] [in a new window]   Table 1. Stimuli that change alternative splicing patterns

 
Currently, three major mechanisms are known that change alternative splice site usage in response to a stimulus: synthesis, phosphorylation, and a change in localization of splicing regulatory proteins. Treatment of T cells with phorbol ester stimulates the Ras-pathway by activating PKC, which changes the splicing pattern of CD45. This change in splice site selection is blocked when protein synthesis is inhibited (55). In other systems, a change in splice site selection does not require protein synthesis and is mediated solely by phosphorylation. For example, changes in splicing patterns of CD44 (56) and a plasma membrane Ca²⁺-ATPase (57) occur without protein synthesis. Expression of SR protein kinases or their inhibition can change splice site selection in vivo, suggesting that phosphorylation of SR proteins is a common regulatory principle (58,59). The application of several models of cellular stress results in a change of the intracellular localization of splicing regulatory proteins. A subset of SR proteins shuttles between the nucleus and the cytosol (60). When cells are stressed by osmotic shock or ultraviolet irradiation, some SR proteins and hnRNP A leave the nucleus and accumulate in the cytosol. As a result, splice site selection in a reporter gene is changed (61). When cells are subjected to heat shock, the SR proteins SRp30c and SF2/ASF accumulate in stress-induced nuclear bodies in the nucleus. Again this change is accompanied by a change in splice site selection (62).

Regulation of PKC isoforms by insulin
The regulation of protein kinase C (PKC) ßII alternative splicing provides a good example how a hormonal signal changes splice site selection (Fig. 1A). Application of insulin to myotubes results in the incorporation of the PKCßII exon within 30 minutes of stimulation (63). Activation of the insulin receptor by insulin recruits a p85/p110 phosphatidylinositol 3-kinase (PI-3K) to the activated insulin receptor complex. As a result, phosphatidylinositol 3,4,5-trisphosphate is formed. This substance activates several protein serine–threonine kinases. One or several of these kinases phosphorylate predominantly the SR protein SRp40. SRp40 acts on a purine-rich RNA element that was first identified in the intron adjacent to regulated fibronectin EIIIB exon (64). In the PKCß pre-mRNA, this element is located in the intron downstream of the ßII exon, which parallels the situation in fibronectin. Similar to the fibronectin EIIIB system, an increase in SRp40 concentration results in inclusion of the downstream exon (65). However, the exact link between an increase in SRp40 activity and its phosphorylation remains to be determined. One possibility is that specifically SRp40 is recruited from speckles, intranuclear storage sites of numerous factors involved in pre-mRNA processing.

View larger version (38K): [in this window] [in a new window]   Figure 1. Examples of signal transduction pathways that regulate alternative splice site selection. The stimuli are shown in gray boxes on the left. Receptors or ion channels are shown in brown. The cytosol is shown in gray and the nucleus in sand color. Kinases are shown in dark blue and splicing regulatory proteins in yellow. Adapter molecules are shown in green. Constitutive exons are shown as black boxes and introns as lines. The alternative exons are shown as white boxes. Regulatory RNA elements are shown in red. The name of the gene is shown in a white box. For simplicity, only one of the alternative mRNA isoforms is shown. (A) Regulation of PKC splicing by insulin. Binding of insulin activates PI3-K via binding to the insulin receptor substrate (IRS). PI3-K forms phosphatidylinositol 3,4,5-trisphosphate, which activates an unknown protein serine–threonine kinase that ultimately phosphorylates SRp40, which acts on an intronic element that leads to exon ßII inclusion. (B) Regulation of CD44 after T-cell stimulation. Stimulation of the T-cell receptor activates Ras via Grb2 (growth hormone-binding protein 2) and Sos (‘son of severless’) binding. Ras activates Raf, which phosphorylates MEK1, which phosphorylates ERK. Phosphorylated ERK translocates into the nucleus and releases repressors on two silencing elements of the alternative exon v5. This exon is subsequently included. (C) Regulation of the BK STREX exon by neuronal activity. Neuronal activity opens voltage-gated calcium channels. The rise in intracellular calcium activates CaMKIV, which phosphorylates unknown proteins that bind to an intronic element at the 3' splice site of the STREX exon. De-repression of this element results in an inclusion of the STREX exon. (D) Regulation of the ICH-1 gene by ischemia. Ischemia evokes a rise in the intracellular calcium levels by opening plasma membrane calcium channels and releasing calcium stored in the endoplasmatic reticulum (white structure). The rise in calcium concentration probably activates a calcium-dependent kinase, which ultimately leads to a translocation of SR proteins from the nucleus to the cytosol. The alternative exon of the ICH-1 gene is repressed by the SR proteins SC35 and SF2, possibly by indirect interaction with a pyrimidine-rich repressing element downstream of the alternative exon. The decrease in nuclear SR protein concentration results in inclusion of the exon.

 
Regulation of CD44 by the Ras/Raf/MEK/ERK pathway
The change of CD44 isoforms in response to T-cell activation is another example of how phosphorylation cascades can regulate splice site selection (Fig. 1B). CD44 is a transmembrane protein that can form multiple isoforms due to alternative splicing of internal cassette exons. The expression of different CD44 isoforms is characteristic of malignant tumors. Systematic overexpression and inhibition of components of the mitogen-activated protein kinase (MAPK; also known as extracellular signal-regulated kinase, ERK) pathway in T cells, showed that activation of the T-cell receptor switches on Ras, which activates the serine–threonine kinase Raf. Raf acts on a MAPK/ERK kinase (MEK; also known as MAPK kinase, MKK)—in the T-cell model most likely MEK1. Finally, MEK1 activates ERK by phosphorylation. Activated ERK translocates into the nucleus and acts on a factor that silences the 5' and middle part of the alternative exon v5. As a result, exon v5 inclusion is stimulated after T-cell receptor activation (66). How ERK influences CD44 exon v5 splicing is still unclear. However, co-transfection and binding studies implicate hnRNP A as part of the regulated exonic enhancer (67). The regulation of exon v5 does not require protein synthesis, demonstrating that signal-induced phosphorylation of regulatory splice factors is the regulatory principle. Interestingly, the Raf/MEK/ERK pathway is activated by a mutant constitutive active form of Ras, which is found in many tumor cells. Therefore, activation of this pathway could account for the changes in alternative splicing seen in cancer.

Change of alternative splicing as a response to neuronal activity
A change of alternative splice site selection after neuronal stimulation has been observed in several systems. In most of these cases, the subsequent change of protein isoforms is part of an adaptation to neuronal activity, and will likely be used to memorize the stimulus (49,50,53,68,69). The analysis of the STREX (stress axis) exon of the large-conductance Ca²⁺ and voltage-activated potassium (BK) channel revealed the existence of a Ca²⁺/calmodulin-dependent protein kinase (CaMK) response element (CaRRE) (Fig. 1C). This pyrimidine-rich element is located in the 3' splice site of the regulated STREX exon and is responsible for STREX repression after neuronal stimulation. The element is specific for CaMKIV, since it does not respond to CaMKI or II. It can be transferred to other ion channels, where it mediates CaMKIV-specific exon regulation. It is therefore possible that this element orchestrates a coordinated response to the rise in intracellular calcium that follows neuronal activity (69). However, the factors binding to this element and their interaction with CaMK remain to be determined.

Change of intracellular localization of splicing factors after stress
When cells are stressed by pH change, osmotic or temperature shock, they often respond with a change in splice site selection. Several studies showed a remarkable specific response of cellular splice site selection to these unspecific stimuli (Table 1). The lack of oxygen in an ischemic event is another cellular stress that evokes a response in affected neurons (Fig. 1D). When the brain area that lacked circulation and oxygen for several minutes was examined, it became apparent that several, but not all, splicing regulatory proteins translocate from the nucleus to the cytosol. Concomitant with this translocation is a change in alternative splice site selection (38) of the interleukin-1ß converting enzyme homologue 1 (ICH-1, caspase 2) gene. Its alternative exon 9 is repressed by SC35 and SF2/ASF (70). Since both proteins leave the nucleus after the ischemic event, this translocation could be responsible for the change in splice site selection. The molecular mechanism is still unclear. A negative regulatory element in the intron downstream of exon 9 has been identified and shown to bind to polypyrimidine track-binding protein. It is assumed that SC35 and SF2/ASF act indirectly on this element, for example by sequestration (71). Studies in primary neuronal cultures show that a similar translocation effect can be evoked by increasing the intracellular calcium concentration (38). As some of the regulatory proteins that accumulate in the cytosol are hyperphosphorylated, it is likely that a calcium-dependent kinase is involved in this regulation. More than two pathways seem to be responsible for the stress-mediated translocation of regulatory proteins, since in the ischemia model no activation of the MKK-p38 pathway is observed, which is induced by osmotic shock or UV light that leads to an accumulation of splicing factors in the cytosol of fibroblasts (61).

	CONCLUSIONS

TOP ABSTRACT SELECTION OF SPLICE SITES SPLICING AND DISEASE SIGNALS THAT CHANGE THE... CONCLUSIONS REFERENCES

 
The examples compiled here show that alternative splice site selection can be altered by the cell in response to a signal received. Since the formation of protein complexes on the pre-mRNA is responsible for splice site selection, the cell can regulate alternative splicing by altering the composition of these proteins. This can be achieved by altering the interaction of splicing regulatory proteins with RNA or other proteins through phosphorylation or by changing the concentration of these proteins by de novo protein synthesis, phosphorylation-dependent release from nuclear storage pools or alteration in the intracellular localization. Several model systems show that phosphorylation of splicing regulatory proteins is at least in part controlled by the established phosphorylation signaling pathways. However, many gaps still remain to be filled.

Given the prevalence of missplicing in human disease, the elucidation of the signaling pathways is an important goal. Because of the combinatorial nature of splice site selection, a combination of bioinformatic (72) and array approaches (73,74) will be needed to work out exactly the signal transduction pathways and their target exons.

	ACKNOWLEDGEMENT

 
This work was supported by the Deutsche Forschungsgemeinschaft (Sta399/7-1 and SFB473 C8).

	FOOTNOTES

 
^* To whom correspondence should be addressed. Tel: +49 91318524622; Fax: +49 91318524605; Email: stefan{at}stamms-lab.net

	REFERENCES

TOP ABSTRACT SELECTION OF SPLICE SITES SPLICING AND DISEASE SIGNALS THAT CHANGE THE... CONCLUSIONS REFERENCES

 
1 Lander, E.S., Linton, L.M., Birren, B., Nusbaum, C., Zody, M.C., Baldwin, J., Devon, K., Dewar, K., Doyle, M., FitzHugh, W. et al. (2001) Initial sequencing and analysis of the human genome. Nature, 409, 860–921.[Medline]

2 Modrek, B., Resch, A., Grasso, C. and Lee, C. (2001) Genome-wide detection of alternative splicing in expressed sequences of human genes. Nucleic Acids Res., 29, 2850–2859.[Abstract/Free Full Text]

3 Venter, J.C., Adams, M.D., Myers, E.W., Li, P.W., Mural, R.J., Sutton, G.G., Smith, H.O., Yandell, M., Evans, C.A., Holt, R.A. et al. (2001) The sequence of the human genome. Science, 291, 1304–1351.[Abstract/Free Full Text]

4 Harrison, P.M., Kumar, A., Lang, N., Snyder, M. and Gerstein, M. (2002) A question of size: the eukaryotic proteome and the problems in defining it. Nucleic Acids Res., 30, 1083–1090.[Abstract/Free Full Text]

5 Neubauer, G., King, A., Rappsilber, J., Calvio, C., Watson, M., Ajuh, P., Sleeman, J., Lamond, A. and Mann, M. (1998) Mass spectometry and EST-database searching allows characterization of the multiprotein spliceosome complex. Nat. Genet., 20, 46–50.[Web of Science][Medline]

6 Will, C.L. and Luhrmann, R. (2001) Spliceosomal UsnRNP biogenesis, structure and function. Curr. Opin. Cell Biol., 13, 290–301.[Web of Science][Medline]

7 Hastings, M.L. and Krainer, A.R. (2001) Pre-mRNA splicing in the new millennium. Curr. Opin. Cell Biol., 13, 302–309.[Web of Science][Medline]

8 Caceres, J.F. and Kornblihtt, A.R. (2002) Alternative splicing: multiple control mechanisms and involvement in human disease. Trends Genet., 18, 186–193.[Web of Science][Medline]

9 Smith, C.W. and Valcarcel, J. (2000) Alternative pre-mRNA splicing: the logic of combinatorial control. Trends Biochem. Sci., 25, 381–388.[Web of Science][Medline]

10 Blencowe, B.J. (2000) Exonic splicing enhancers: mechanism of action, diversity and role in human genetic diseases. Trends Biochem. Sci., 25, 106–110.[Web of Science][Medline]

11 Dreyfuss, G., Kim, V.N. and Kataoka, N. (2002) Messenger-RNA-binding proteins and the messages they carry. Nat. Rev. Mol. Cell Biol., 3, 195–205.[Web of Science][Medline]

12 Graveley, B.R. (2000) Sorting out the complexity of SR protein function. RNA, 6, 1197–1211.[Web of Science][Medline]

13 Hanamura, A., Caceres, J.F., Mayeda, A., Franza, B.R. and Krainer, A.R. (1998) Regulated tissue-specific expression of antagonistic pre-mRNA splicing factors. RNA, 4, 430–444.[Abstract]

14 Jensen, K.B., Dredge, B.K., Stefani, G., Zhong, R., Buckanovich, R.J., Okano, H.J., Yang, Y.Y. and Darnell, R.B. (2000) Nova-1 regulates neuron-specific alternative splicing and is essential for neuronal viability. Neuron, 25, 359–371.[Web of Science][Medline]

15 Markovtsov, V., Nikolic, J.M., Goldman, J.A., Turck, C.W., Chou, M.Y. and Black, D.L. (2000) Cooperative assembly of an hnRNP complex induced by a tissue-specific homolog of polypyrimidine tract binding protein. Mol. Cell Biol., 20, 7463–7479.[Abstract/Free Full Text]

16 Komatsu, M., Kominami, E., Arahata, K. and Tsukahara, T. (1999) Cloning and characterization of two neural-salient serine/arginine-rich (NSSR) proteins involved in the regulation of alternative splicing in neurons. Genes to Cells, 4, 593–606.[Abstract]

17 Sanford, J.R. and Bruzik, J.P. (1999) Developmental regulation of SR protein phosphorylation and activity. Genes Dev., 13, 1513–1518.[Abstract/Free Full Text]

18 Mahe, D., Fischer, N., Decimo, D. and Fuchs, J.P. (2000) Spatiotemporal regulation of hnRNP M and 2H9 gene expression during mouse embryonic development. Biochim. Biophys. Acta, 1492, 414–424.[Medline]

19 Stamm, S., Zhu, J., Nakai, K., Stoilov, P., Stoss, O. and Zhang, M.Q. (2000) An alternative-exon database and its statistical analysis. DNA Cell Biol., 19, 739–756.[Web of Science][Medline]

20 Rave-Harel, N., Kerem, E., Nissim-Rafinia, M., Madjar, I., Goshen, R., Augarten, A., Rahat, A., Hurwitz, A., Darvasi, A. and Kerem, B. (1997) The molecular basis of partial penetrance of splicing mutations in cystic fibrosis. Am. J. Hum. Genet., 60, 87–94.[Web of Science][Medline]

21 Slaugenhaupt, S.A., Blumenfeld, A., Gill, S.P., Leyne, M., Mull, J., Cuajungco, M.P., Liebert, C.B., Chadwick, B., Idelson, M., Reznik, L. et al. (2001) Tissue-specific expression of a splicing mutation in the IKBKAP gene causes familial dysautonomia. Am. J. Hum. Genet., 68, 598–605.[Web of Science][Medline]

22 Nissim-Rafinia, M. and Kerem, B. (2002) Splicing regulation as a potential genetic modifier. Trends Genet., 18, 123–127.[Web of Science][Medline]

23 Cramer, P., Srebrow, A., Kadener, S., Werbajh, S., de la Mata, M., Melen, G., Nogues, G. and Kornblihtt, A.R. (2001) Coordination between transcription and pre-mRNA processing. FEBS Lett., 498, 179–182.[Web of Science][Medline]

24 Minvielle-Sebastia, L. and Keller, W. (1999) mRNA polyadenylation and its coupling to other RNA processing reactions and to transcription. Curr. Opin. Cell Biol., 11, 352–357.[Web of Science][Medline]

25 Rueter, S.M., Dawson, T.R. and Emeson, R.B. (1999) Regulation of alternative splicing by RNA editing. Nature, 399, 75–80.[Medline]

26 Reed, R. and Hurt, E. (2002) A conserved mRNA export machinery coupled to pre-mRNA splicing. Cell, 108, 523–531.[Web of Science][Medline]

27 Maniatis, T. and Reed, R. (2002) An extensive network of coupling among gene expression machines. Nature, 416, 499–506.[Medline]

28 Bentley, D. (2002) The mRNA assembly line: transcription and processing machines in the same factory. Curr. Opin. Cell Biol., 14, 336–342.[Web of Science][Medline]

29 Cramer, P., Pesce, C.G., Baralle, F.E. and Kornblihtt, A.R. (1997) Functional association between promoter structure and transcript alternative splicing. Proc. Natl Acad. Sci. USA, 94, 11456–11460.[Abstract/Free Full Text]

30 Philips, A.V. and Cooper, T.A. (2000) RNA processing and human disease. Cell. Mol. Life Sci., 57, 235–249.[Web of Science][Medline]

31 Stoss, O., Stoilov, P., Daoud, R., Hartmann, A.M., Olbrich, M. and Stamm, S. (2000) Misregulation of pre-mRNA splicing that causes human diseases. Gene Ther. Mol. Biol., 5, 9–28.

32 Stoilov, P., Meshorer, E., Gencheva, M., Glick, D., Soreq, H. and Stamm, S. (2002) Defects in pre-mRNA processing as causes of and predisposition to diseases. DNA Cell Biol., in press.

33 Nakai, K. and Sakamoto, H. (1994) Construction of a novel database containing aberrant splicing mutations of mammalian genes. Gene, 141, 171–177.[Web of Science][Medline]

34 Krawczak, M., Reiss, J. and Cooper, D.N. (1992) The mutational spectrum of single base-pair substitutions in mRNA splice junctions of human genes: causes and consequences. Hum. Genet., 90, 41–54.[Web of Science][Medline]

35 Cartegni, L., Chew, S.L. and Krainer, A.R. (2002) Listening to silence and understanding nonsense: exonic mutations that affect splicing. Nat. Rev. Genet., 3, 285–298.[Web of Science][Medline]

36 Stickeler, E., Kittrell, F., Medina, D. and Berget, S.M. (1999) Stage-specific changes in SR splicing factors and alternative splicing in mammary tumorigenesis. Oncogene, 18, 3574–3582.[Web of Science][Medline]

37 Scorilas, A., Kyriakopoulou, L., Katsaros, D. and Diamandis, E.P. (2001) Cloning of a gene (SR-A1), encoding for a new member of the human Ser/Arg-rich family of pre-mRNA splicing factors: overexpression in aggressive ovarian cancer. Br. J. Cancer, 85, 190–198.[Web of Science][Medline]

38 Daoud, R., Mies, G., Smialowska, A., Oláh, L., Hossmann, K. and Stamm, S. (2002) Ischemia induces a translocation of the splicing factor tra2-ß1 and changes alternative splicing patterns in the brain. J. Neurosci., 22, 5889–5899.[Abstract/Free Full Text]

39 Pearn, J. (1980) Classification of spinal muscular atrophies. Lancet, 1, 919–922.[Web of Science][Medline]

40 Wirth, B. (2000) An update of the mutation spectrum of the survival motor neuron gene (SMN1) in autosomal recessive spinal muscular atrophy (SMA). Hum. Mutat., 15, 228–237.[Web of Science][Medline]

41 Lorson, C.L., Hahnen, E., Androphy, E.J. and Wirth, B. (1999) A single nucleotide in the SMN gene regulates splicing and is responsible for spinal muscular atrophy. Proc. Natl Acad. Sci. USA, 96, 6307–6311.[Abstract/Free Full Text]

42 DiDonato, C.J., Lorson, C.L., De Repentigny, Y., Simard, L., Chartrand, C., Androphy, E.J. and Kothary, R. (2001) Regulation of murine survival motor neuron (Smn) protein levels by modifying Smn exon 7 splicing. Hum. Mol. Genet., 10, 2727–2736.[Abstract/Free Full Text]

43 Young, P.J., DiDonato, C.J., Hu, D., Kothary, R., Androphy, E.J. and Lorson, C.L. (2002) SRp30c-dependent stimulation of survival motor neuron (SMN) exon 7 inclusion is facilitated by a direct interaction with hTra2ß1. Hum. Mol. Genet., 11, 577–587.[Abstract/Free Full Text]

44 Hofmann, Y., Lorson, C.L., Stamm, S., Androphy, E.J. and Wirth, B. (2000) Htra2-ß1 stimulates an exonic splicing enhancer and can restore full-length SMN expression to survival motor neuron 2 (SMN2). Proc. Natl Acad. Sci. USA, 97, 9618–9623.[Abstract/Free Full Text]

45 Chang, J.G., Hsieh-Li, H.M., Jong, Y.J., Wang, N.M., Tsai, C.H. and Li, H. (2001) Treatment of spinal muscular atrophy by sodium butyrate. Proc. Natl Acad. Sci. USA, 98, 9808–9813.[Abstract/Free Full Text]

46 Andreassi, C., Jarecki, J., Zhou, J., Coovert, D.D., Monani, U.R., Chen, X., Whitney, M., Pollok, B., Zhang, M., Androphy, E. et al. (2001) Aclarubicin treatment restores SMN levels to cells derived from type I spinal muscular atrophy patients. Hum. Mol. Genet., 10, 2841–2849.[Abstract/Free Full Text]

47 Grabowski, P.L. and Black, D.L. (2001) Alternative RNA splicing in the nervous system. Prog. Neurobiol., 65, 289–308.[Web of Science][Medline]

48 Stamm, S. and Thanaraj, T.A. (2002) Prediction and statistical analysis of alternatively spliced exons. Prog. Mol. Sub. Biol., in press.

49 Kaufer, D., Friedman, A., Seidman, S. and Soreq, H. (1998) Acute stress facilitates long-lasting changes in cholinergic gene expression. Nature, 393, 373–377.[Medline]

50 Stork, O., Stork, S., Pape, H.C. and Obata, K. (2001) Identification of genes expressed in the amygdala during the formation of fear memory. Learn. Mem., 8, 209–219.[Abstract/Free Full Text]

51 Amir-Ahmady, B. and Salati, L.M. (2001) Regulation of the processing of glucose-6-phosphate dehydrogenase mRNA by nutritional status. J. Biol. Chem., 276, 10514–10523.[Abstract/Free Full Text]

52 Tao, H., Szeszel-Fedorowicz, W., Amir-Ahmady, B., Gibson, M.A., Stabile, L.P. and Salati, L.M. (2002) Inhibition of the splicing of glucose-6-phosphate dehydrogenase pre-mRNA by polyunsaturated fatty acids. J. Biol. Chem., 277, 31270–31278.[Abstract/Free Full Text]

53 Berke, J.D., Sgambato, V., Zhu, P.P., Lavoie, B., Vincent, M., Krause, M. and Hyman, S.E. (2001) Dopamine and glutamate induce distinct striatal splice forms of Ania-6, an RNA polymerase II-associated cyclin. Neuron, 32, 277–287.[Web of Science][Medline]

54 Petrie, J., Sapp, D.W., Tyndale, R.F., Park, M.K., Fanselow, M. and Olsen, R.W. (2001) Altered GABA_A receptor subunit and splice variant expression in rats treated with chronic intermittent ethanol. Alcohol Clin. Exp. Res., 25, 819–828.[Web of Science][Medline]

55 Lynch, K.W. and Weiss, A. (2000) A Model system for activation-induced alternative splicing of CD45 pre-mRNA in T cells implicates protein kinase C and Ras. Mol. Cell. Biol., 20, 70–80.[Abstract/Free Full Text]

56 König, H., Ponta, H. and Herrlich, P. (1998) Coupling of signal transduction to alternative pre-mRNA splicing by a composite splice regulator. EMBO J., 17, 2904–2913.[Web of Science][Medline]

57 Zacharias, D.A. and Strehler, E.E. (1996) Change in plasma membrane Ca²⁺-ATPase splice-variant expression in response to a rise in intracellular Ca²⁺. Curr. Biol., 6, 1642–1652.[Web of Science][Medline]

58 Hartmann, A.M., Rujescu, D., Giannakouros, T., Nikolakaki, E., Goedert, M., Mandelkow, E.M., Gao, Q.S., Andreadis, A. and Stamm, S. (2001) Regulation of alternative splicing of human tau exon 10 by phosphorylation of splicing factors. Mol. Cell. Neurosci., 18, 80–90.[Web of Science][Medline]

59 Pilch, B., Allemand, E., Facompre, M., Bailly, C., Riou, J.F., Soret, J. and Tazi, J. (2001) Specific inhibition of serine- and arginine-rich splicing factors phosphorylation, spliceosome assembly, and splicing by the antitumor drug NB-506. Cancer Res., 61, 6876–6884.[Abstract/Free Full Text]

60 Caceres, J.F., Screaton, G.R. and Krainer, A.R. (1998) A specific subset of SR proteins shuttles continously between the nucleus and the cytoplasm. Genes Dev., 12, 55–66.[Abstract/Free Full Text]

61 van der Houven van Oordt, W., Diaz-Meco, M.T., Lozano, J., Krainer, A.R., Moscat, J. and Caceres, J.F. (2000) The MKK(3/6)-p38-signaling cascade alters the subcellular distribution of hnRNP A1 and modulates alternative splicing regulation. J. Cell Biol., 149, 307–316.[Abstract/Free Full Text]

62 Denegri, M., Chiodi, I., Corioni, M., Cobianchi, F., Riva, S. and Biamonti, G. (2001) Stress-induced nuclear bodies are sites of accumulation of pre-mRNA processing factors. Mol. Biol. Cell., 12, 3502–3514.[Abstract/Free Full Text]

63 Chalfant, C.E., Watson, J.E., Bisnauth, L.D., Kang, J.B., Patel, N., Obeid, L.M., Eichler, D.C. and Cooper, D.R. (1998) Insulin regulates protein kinase CßII expression through enhanced exon inclusion in L6 skeletal muscle cells. A novel mechanism of insulin- and insulin-like growth factor-I-induced 5' splice site selection. J. Biol. Chem., 273, 910–916.[Abstract/Free Full Text]

64 Du, K., Peng, Y., Greenbaum, L.E., Haber, B.A. and Taub, R. (1997) HRS/SRp40-mediated inclusion of the fibronectin EIIIB exon, a possible cause of increased EIIIB expression in proliferating liver. Mol. Cell Biol., 17, 4096–4104.[Abstract]

65 Patel, N.A., Chalfant, C.E., Watson, J.E., Wyatt, J.R., Dean, N.M., Eichler, D.C. and Cooper, D.R. (2001) Insulin regulates alternative splicing of protein kinase CßII through a phosphatidylinositol 3-kinase-dependent pathway involving the nuclear serine/arginine-rich splicing factor, SRp40, in skeletal muscle cells. J. Biol. Chem., 276, 22648–22654.[Abstract/Free Full Text]

66 Weg-Remers, S., Ponta, H., Herrlich, P. and Konig, H. (2001) Regulation of alternative pre-mRNA splicing by the ERK MAP-kinase pathway. EMBO J., 20, 4194–4203.[Web of Science][Medline]

67 Matter, N., Marx, M., Weg-Remers, S., Ponta, H., Herrlich, P. and Konig, H. (2000) Heterogeneous ribonucleoprotein A1 is part of an exon-specific splice-silencing complex controlled by oncogenic signaling pathways. J. Biol. Chem., 275, 35353–35360.[Abstract/Free Full Text]

68 Daoud, R., Da Penha Berzaghi, M., Siedler, F., Hubener, M. and Stamm, S. (1999) Activity-dependent regulation of alternative splicing patterns in the rat brain. Eur. J. Neurosci., 11, 788–802.[Web of Science][Medline]

69 Xie, J. and Black, D.L. (2001) A CaMK IV responsive RNA element mediates depolarization-induced alternative splicing of ion channels. Nature, 410, 936–939.[Medline]

70 Jiang, H.-H., Zhang, W.-J., Rao, Y. and Wu, J.Y. (1998) Regulation of Ich-1 pre-mRNA alternative splicing and apoptosis by mammalian splicing factors. Proc. Natl Acad. Sci. USA, 95, 9155–9160.[Abstract/Free Full Text]

71 Cote, J., Dupuis, S. and Wu, J.Y. (2001) Polypyrimidine track-binding protein binding downstream of caspase-2 alternative exon 9 represses its inclusion. J. Biol. Chem., 276, 8535–8543.[Abstract/Free Full Text]

72 Modrek, B. and Lee, C. (2002) A genomic view of alternative splicing. Nat. Genet., 30, 13–19.[Web of Science][Medline]

73 Clark, T.A., Sugnet, C.W. and Ares, M., Jr (2002) Genomewide analysis of mRNA processing in yeast using splicing-specific microarrays. Science, 296, 907–910.[Abstract/Free Full Text]

74 Yeakley, J.M., Fan, J.B., Doucet, D., Luo, L., Wickham, E., Ye, Z., Chee, M.S. and Fu, X.D. (2002) Profiling alternative splicing on fiber-optic arrays. Nat. Biotechnol., 20, 353–358.[Web of Science][Medline]

75 Lemaire, R., Winne, A., Sarkissian, M. and Lafayatis, R. (1999) SF2 and SRp55 regulation of CD45 exon 4 skipping during T cell activation. Eur. J. Immunol., 29, 823–837.[Web of Science][Medline]

76 Shifrin, V.I. and Neel, B.G. (1993) Growth factor-inducible alternative splicing of nontransmembrane phosphotyrosine phosphatase PTP-1B pre-mRNA. J. Biol. Chem., 268, 25376–25384.[Abstract/Free Full Text]

77 Ishizuka, T., Kajita, K., Yamada, K., Miura, A., Kanoh, Y., Ishizawa, M., Wada, H., Itaya, S., Yamamoto, M., Yasuda, K. et al. (1996) Insulin regulated PKC isoform mRNA in rat adipocytes. Diabetes Res. Clin. Pract., 33, 159–167.[Web of Science][Medline]

78 Sell, S.M., Reese, D. and Ossowski, V.M. (1994) Insulin-inducible changes in insulin receptor mRNA splice variants. J. Biol. Chem., 269, 30769–30772.[Abstract/Free Full Text]

79 Scotet, E. and Houssaint, E. (1998) Exon III splicing switch of fibroblast growth factor (FGF) receptor-2 and -3 can be induced by FGF-1 or FGF-2. Oncogene, 17, 67–76.[Web of Science][Medline]

80 Mackay, C.R., Terpe, H.J., Stauder, R., Marston, W.L., Stark, H. and Gunthert, U. (1994) Expression and modulation of CD44 variant isoforms in humans. J. Cell Biol., 124, 71–82.[Abstract/Free Full Text]

81 Eissa, N.T., Strauss, A.J., Haggerty, C.M., Choo, E.K., Chu, S.C. and Moss, J. (1996) Alternative splicing of human inducible nitric-oxide synthase messenger-RNA—tissue-specific regulation and induction by cytokines J. Biol. Chem., 271, 27184–27187.[Abstract/Free Full Text]

82 McKay, N.G., Hunter, D.J., Haites, N.E. and Power, D.A. (1994) Regulation of alternative splicing of the fibronectin IIICS domain by cytokines. Biochem. Biophys. Res. Commun., 199, 1005–1011.[Web of Science][Medline]

83 Wang, A.D., Cohen, S., Palmer, E. and Sheppard, D. (1991) Polarized regulation of fibronectin secretion and alternative splicing by transforming growth factor ß. J. Biol. Chem., 266, 15598–15601.[Abstract/Free Full Text]

84 Balza, E., Borsi, L., Allemanni, G. and Zardi, L. (1988) Transforming growth factor ß regulates the levels of different fibronectin isoforms in normal human cultured fibroblasts. FEBS Lett., 228, 42–44.[Web of Science][Medline]

85 Kosaki, A. and Webster, N.J. (1993) Effect of dexamethasone on the alternative splicing of the insulin receptor mRNA and insulin action in HepG2 hepatoma cells. J. Biol. Chem., 268, 21990–21996.[Abstract/Free Full Text]

86 Xie, J. and McCobb, D.P. (1998) Control of alternative splicing of potassium channels by stress hormones. Science, 280, 443–446.[Abstract/Free Full Text]

87 Metheny, L.J. and Skuse, G.R. (1996) NF1 mRNA isoform expression in PC12 cells: modulation by extrinsic factors. Exp. Cell Res., 228, 44–49.[Web of Science][Medline]

88 Smith, M.A., Fanger, G.R., O'Connor, L.T., Bridle, P. and Maue, R.A. (1997) Selective regulation of agrin mRNA induction and alternative splicing in PC12 cells by Ras-dependent actions of nerve growth factor. J. Biol. Chem., 272, 15675–15681.[Abstract/Free Full Text]

89 Helme-Guizon, A., Davis, S., Israel, M., Lesbats, B., Mallet, J., Laroche, S. and Hicks, A. (1998) Increase in syntaxin 1B and glutamate release in mossy fibre terminals following induction of LTP in the dentate gyrus: a candidate molecular mechanism underlying transsynaptic plasticity. Eur. J. Neurosci., 10, 2231–2237.[Web of Science][Medline]

90 Rodger, J., Davis, S., Laroche, S., Mallet, J. and Hicks, A. (1998) Induction of long-term potentiation in vivo regulates alternative splicing to alter syntaxin 3 isoform expression in rat dentate gyrus. J. Neurochem., 71, 666–675.[Web of Science][Medline]

91 Kamphuis, W., Monyer, H., De Rijk, T.C. and Lopes da Silva, F.H. (1992) Hippocampal kindling increases the expression of glutamate receptor-A Flip and -B Flip mRNA in dentate granule cells. Neurosci. Lett., 148, 51–54.[Web of Science][Medline]

92 Bottai, D., Guzowski, J.F., Schwarz, M.K., Kang, S.H., Xiao, B., Lanahan, A., Worley, P.F. and Seeburg, P.H. (2002) Synaptic activity-induced conversion of intronic to exonic sequence in Homer 1 immediate early gene expression. J. Neurosci., 22, 167–175.[Abstract/Free Full Text]

93 Hayakawa, M., Endo, H., Hamamoto, T. and Kagawa, Y. (1998) Acidic stimulation induces a negative regulatory factor that affects alternative exon selection in vitro in human ATP synthase -subunit pre-mRNA. Biochem. Biophys. Res. Commun., 251, 603–608.[Web of Science][Medline]

94 Borsi, L., Balza, E., Gaggero, B., Allemanni, G. and Zardi, L. (1995) The alternative splicing pattern of the tenascin-C pre-mRNA is controlled by the extracellular pH. J. Biol. Chem., 270, 6243–6245.[Abstract/Free Full Text]

95 Meshorer, E., Erb, C., Gazit, R., Pavlovsky, L., Kaufer, D., Friedman, A., Glick, D., Ben-Arie, N. and Soreq, H. (2002) Alternative splicing and neuritic mRNA translocation under long-term neuronal hypersensitivity. Science, 295, 508–512.[Abstract/Free Full Text]

96 Ars, E., Serra, E., de la Luna, S., Estivill, X. and Lazaro, C. (2000) Cold shock induces the insertion of a cryptic exon in the neurofibromatosis type 1 (NF1) mRNA. Nucleic Acids Res., 28, 1307–1312.[Abstract/Free Full Text]

97 Shen, J., Beall, C.J. and Hirsh, J. (1993) Tissue-specific alternative splicing of the Drosophila dopa decarboxylase gene is affected by heat shock. Mol. Cell Biol., 13, 4549–4555.[Abstract/Free Full Text]

98 Kimura, K., Asami, K. and Yamamoto, M. (1997) Effect of heat shock treatment on the production of variant testosterone-repressed prostate message-2 (TRPM-2) mRNA in culture cells. Cell. Biochem. Funct., 15, 251–257.[Web of Science][Medline]

99 Takechi, H., Hosokawa, N., Hirayoshi, K. and Nagata, K. (1994) Alternative 5' splice site selection induced by heat shock. Mol. Cell Biol., 14, 567–575.[Abstract/Free Full Text]

100 Marrs, K.A. and Walbot, V. (1997) Expression and RNA splicing of the maize glutathione S-transferase Bronze2 gene is regulated by cadmium and other stresses. Plant Physiol., 113, 93–102.[Abstract]

101 Tabaczewski, P., Shirwan, H., Lewis, K. and Stroynowski, I. (1994) Alternative splicing of class Ib major histocompatibility complex transcripts in vivo leads to the expression of soluble Qa-2 molecules in murine blood. Proc. Natl Acad. Sci. USA, 91, 1883–1887.[Abstract/Free Full Text]

CiteULike    Connotea    Del.icio.us    What's this?

This article has been cited by other articles:

				R. J. Katzenberger, M. S. Marengo, and D. A. Wassarman Control of Alternative Splicing by Signal-dependent Degradation of Splicing-regulatory Proteins J. Biol. Chem., April 17, 2009; 284(16): 10737 - 10746. [Abstract] [Full Text] [PDF]

				J. Yu, Y. Hai, G. Liu, T. Fang, S. K. P. Kung, and J. Xie The Heterogeneous Nuclear Ribonucleoprotein L Is an Essential Component in the Ca2+/Calmodulin-dependent Protein Kinase IV-regulated Alternative Splicing through Cytidine-Adenosine Repeats J. Biol. Chem., January 16, 2009; 284(3): 1505 - 1513. [Abstract] [Full Text] [PDF]

				J. Feng, M. A. Lawson, and P. Melamed A Proteomic Comparison of Immature and Mature Mouse Gonadotrophs Reveals Novel Differentially Expressed Nuclear Proteins that Regulate Gonadotropin Gene Transcription and RNA Splicing Biol Reprod, September 1, 2008; 79(3): 546 - 561. [Abstract] [Full Text] [PDF]

				P. Stoilov, C.-H. Lin, R. Damoiseaux, J. Nikolic, and D. L. Black A high-throughput screening strategy identifies cardiotonic steroids as alternative splicing modulators PNAS, August 12, 2008; 105(32): 11218 - 11223. [Abstract] [Full Text] [PDF]

				M. S. Marengo and D. A. Wassarman A DNA damage signal activates and derepresses exon inclusion in Drosophila TAF1 alternative splicing RNA, August 1, 2008; 14(8): 1681 - 1695. [Abstract] [Full Text] [PDF]

				M. Okada, S.-W. Jang, and K. Ye Akt phosphorylation and nuclear phosphoinositide association mediate mRNA export and cell proliferation activities by ALY PNAS, June 24, 2008; 105(25): 8649 - 8654. [Abstract] [Full Text] [PDF]

				Y. Hai, W. Cao, G. Liu, S.-P. Hong, S. A. Elela, R. Klinck, J. Chu, and J. Xie A G-tract element in apoptotic agents-induced alternative splicing Nucleic Acids Res., June 1, 2008; 36(10): 3320 - 3331. [Abstract] [Full Text] [PDF]

				S. Stamm Regulation of Alternative Splicing by Reversible Protein Phosphorylation J. Biol. Chem., January 18, 2008; 283(3): 1223 - 1227. [Abstract] [Full Text] [PDF]

				T. Novoyatleva, B. Heinrich, Y. Tang, N. Benderska, M. E.R. Butchbach, C. L. Lorson, M. A. Lorson, C. Ben-Dov, P. Fehlbaum, L. Bracco, et al. Protein phosphatase 1 binds to the RNA recognition motif of several splicing factors and regulates alternative pre-mRNA processing Hum. Mol. Genet., January 1, 2008; 17(1): 52 - 70. [Abstract] [Full Text] [PDF]

				A. A. Melton, J. Jackson, J. Wang, and K. W. Lynch Combinatorial Control of Signal-Induced Exon Repression by hnRNP L and PSF Mol. Cell. Biol., October 1, 2007; 27(19): 6972 - 6984. [Abstract] [Full Text] [PDF]

				K. A. Sergeant, C. F. Bourgeois, C. Dalgliesh, J. P. Venables, J. Stevenin, and D. J. Elliott Alternative RNA splicing complexes containing the scaffold attachment factor SAFB2 J. Cell Sci., January 15, 2007; 120(2): 309 - 319. [Abstract] [Full Text] [PDF]

				R. J. Katzenberger, M. S. Marengo, and D. A. Wassarman ATM and ATR Pathways Signal Alternative Splicing of Drosophila TAF1 Pre-mRNA in Response to DNA Damage Mol. Cell. Biol., December 15, 2006; 26(24): 9256 - 9267. [Abstract] [Full Text] [PDF]

				D. J Elliott and S. N Grellscheid Alternative RNA splicing regulation in the testis. Reproduction, December 1, 2006; 132(6): 811 - 819. [Abstract] [Full Text] [PDF]

				S. Guil, J. C. Long, and J. F. Caceres hnRNP A1 Relocalization to the Stress Granules Reflects a Role in the Stress Response Mol. Cell. Biol., August 1, 2006; 26(15): 5744 - 5758. [Abstract] [Full Text] [PDF]

				Z Xiong, A Shaibani, Y-P Li, Y Yan, S Zhang, Y Yang, F Yang, H Wang, and X-F Yang Alternative splicing factor ASF/SF2 is down regulated in inflamed muscle J. Clin. Pathol., August 1, 2006; 59(8): 855 - 861. [Abstract] [Full Text] [PDF]

				G. Thill, V. Castelli, S. Pallud, M. Salanoubat, P. Wincker, P. de la Grange, D. Auboeuf, V. Schachter, and J. Weissenbach ASEtrap: A biological method for speeding up the exploration of spliceomes Genome Res., June 1, 2006; 16(6): 776 - 786. [Abstract] [Full Text] [PDF]

				X. Shao, V. Shepelev, and A. Fedorov Bioinformatic analysis of exon repetition, exon scrambling and trans-splicing in humans Bioinformatics, March 15, 2006; 22(6): 692 - 698. [Abstract] [Full Text] [PDF]

				M. Arniges, J. M. Fernandez-Fernandez, N. Albrecht, M. Schaefer, and M. A. Valverde Human TRPV4 Channel Splice Variants Revealed a Key Role of Ankyrin Domains in Multimerization and Trafficking J. Biol. Chem., January 20, 2006; 281(3): 1580 - 1586. [Abstract] [Full Text] [PDF]

				S.-J. Noh, K. Lee, H. Paik, and C.-G. Hur TISA: Tissue-specific Alternative Splicing in Human and Mouse Genes DNA Res, January 1, 2006; 13(5): 229 - 243. [Abstract] [Full Text] [PDF]

				J. XIE, C. JAN, P. STOILOV, J. PARK, and D. L. BLACK A consensus CaMK IV-responsive RNA sequence mediates regulation of alternative exons in neurons RNA, December 1, 2005; 11(12): 1825 - 1834. [Abstract] [Full Text] [PDF]

				R. Lutter and M. Spiteri Current perspectives in epithelial cell injury and repair: consequences for epithelial functions Eur. Respir. Rev., December 1, 2005; 14(97): 126 - 130. [Abstract] [Full Text] [PDF]

				E. Buratti, A. Brindisi, M. Giombi, S. Tisminetzky, Y. M. Ayala, and F. E. Baralle TDP-43 Binds Heterogeneous Nuclear Ribonucleoprotein A/B through Its C-terminal Tail: AN IMPORTANT REGION FOR THE INHIBITION OF CYSTIC FIBROSIS TRANSMEMBRANE CONDUCTANCE REGULATOR EXON 9 SPLICING J. Biol. Chem., November 11, 2005; 280(45): 37572 - 37584. [Abstract] [Full Text] [PDF]

				M. Hiller, K. Huse, M. Platzer, and R. Backofen Non-EST based prediction of exon skipping and intron retention events using Pfam information Nucleic Acids Res., October 4, 2005; 33(17): 5611 - 5621. [Abstract] [Full Text] [PDF]

				C. M. A. Coelho, B. Kolevski, C. D. Walker, I. Lavagi, T. Shaw, A. Ebert, S. J. Leevers, and S. J. Marygold A Genetic Screen for Dominant Modifiers of a Small-Wing Phenotype in Drosophila melanogaster Identifies Proteins Involved in Splicing and Translation Genetics, October 1, 2005; 171(2): 597 - 614. [Abstract] [Full Text] [PDF]

				J. P. Venables, C. F. Bourgeois, C. Dalgliesh, L. Kister, J. Stevenin, and D. J. Elliott Up-regulation of the ubiquitous alternative splicing factor Tra2{beta} causes inclusion of a germ cell-specific exon Hum. Mol. Genet., August 15, 2005; 14(16): 2289 - 2303. [Abstract] [Full Text] [PDF]

				M. Hollyoake, R. D. Campbell, and B. Aguado NKp30 (NCR3) is a Pseudogene in 12 Inbred and Wild Mouse Strains, but an Expressed Gene in Mus caroli Mol. Biol. Evol., August 1, 2005; 22(8): 1661 - 1672. [Abstract] [Full Text] [PDF]

				F. Pelisch, M. Blaustein, A. R. Kornblihtt, and A. Srebrow Cross-talk between Signaling Pathways Regulates Alternative Splicing: A NOVEL ROLE FOR JNK J. Biol. Chem., July 8, 2005; 280(27): 25461 - 25469. [Abstract] [Full Text] [PDF]

				T. Gustafsson, H. Ameln, H. Fischer, C. J. Sundberg, J. A. Timmons, and E. Jansson VEGF-A splice variants and related receptor expression in human skeletal muscle following submaximal exercise J Appl Physiol, June 1, 2005; 98(6): 2137 - 2146. [Abstract] [Full Text] [PDF]

				N. Shomron, M. Alberstein, M. Reznik, and G. Ast Stress alters the subcellular distribution of hSlu7 and thus modulates alternative splicing J. Cell Sci., March 15, 2005; 118(6): 1151 - 1159. [Abstract] [Full Text] [PDF]

				P. Fehlbaum, C. Guihal, L. Bracco, and O. Cochet A microarray configuration to quantify expression levels and relative abundance of splice variants Nucleic Acids Res., March 10, 2005; 33(5): e47 - e47. [Abstract] [Full Text] [PDF]

				E. Buratti and F. E. Baralle Influence of RNA Secondary Structure on the Pre-mRNA Splicing Process Mol. Cell. Biol., December 15, 2004; 24(24): 10505 - 10514. [Full Text] [PDF]

				J. R. Sanford and J. F. Caceres Pre-mRNA splicing: life at the centre of the central dogma J. Cell Sci., December 15, 2004; 117(26): 6261 - 6263. [Full Text] [PDF]

				Y. Hitomi, N. Tsuchiya, A. Kawasaki, J. Ohashi, T. Suzuki, C. Kyogoku, T. Fukazawa, S. Bejrachandra, U. Siriboonrit, D. Chandanayingyong, et al. CD72 polymorphisms associated with alternative splicing modify susceptibility to human systemic lupus erythematosus through epistatic interaction with FCGR2B Hum. Mol. Genet., December 1, 2004; 13(23): 2907 - 2917. [Abstract] [Full Text] [PDF]

				Y. Li, Y.-p. Qian, X.-j. Yu, Y.-q. Wang, D.-g. Dong, W. Sun, R.-m. Ma, and B. Su Recent Origin of a Hominoid-Specific Splice Form of Neuropsin, a Gene Involved in Learning and Memory Mol. Biol. Evol., November 1, 2004; 21(11): 2111 - 2115. [Abstract] [Full Text] [PDF]

				I. G. Bruno, W. Jin, and G. J. Cote Correction of aberrant FGFR1 alternative RNA splicing through targeting of intronic regulatory elements Hum. Mol. Genet., October 1, 2004; 13(20): 2409 - 2420. [Abstract] [Full Text] [PDF]

				C. E. Willoughby, L. L. Y. Chan, S. Herd, G. Billingsley, N. Noordeh, A. V. Levin, Y. Buys, G. Trope, M. Sarfarazi, and E. Heon Defining the Pathogenicity of Optineurin in Juvenile Open-Angle Glaucoma Invest. Ophthalmol. Vis. Sci., September 1, 2004; 45(9): 3122 - 3130. [Abstract] [Full Text] [PDF]

				Q. Xu, M. P. Belcastro, S. T. Villa, R. D. Dinkins, S. G. Clarke, and A. B. Downie A Second Protein L-Isoaspartyl Methyltransferase Gene in Arabidopsis Produces Two Transcripts Whose Products Are Sequestered in the Nucleus Plant Physiology, September 1, 2004; 136(1): 2652 - 2664. [Abstract] [Full Text] [PDF]

				I. Rafalska, Z. Zhang, N. Benderska, H. Wolff, A. M. Hartmann, R. Brack-Werner, and S. Stamm The intranuclear localization and function of YT521-B is regulated by tyrosine phosphorylation Hum. Mol. Genet., August 1, 2004; 13(15): 1535 - 1549. [Abstract] [Full Text] [PDF]

				J. P. Venables, C. Dalgliesh, M. P. Paronetto, L. Skitt, J. K. Thornton, P. T. Saunders, C. Sette, K. T. Jones, and D. J. Elliott SIAH1 targets the alternative splicing factor T-STAR for degradation by the proteasome Hum. Mol. Genet., July 15, 2004; 13(14): 1525 - 1534. [Abstract] [Full Text] [PDF]

				X. He, P. L. R. Ee, J. S. Coon, and W. T. Beck Alternative Splicing of the Multidrug Resistance Protein 1/ATP Binding Cassette Transporter Subfamily Gene in Ovarian Cancer Creates Functional Splice Variants and Is Associated with Increased Expression of the Splicing Factors PTB and SRp20 Clin. Cancer Res., July 15, 2004; 10(14): 4652 - 4660. [Abstract] [Full Text] [PDF]

				C. D. Nicholls, M. A. Shields, P. W. K. Lee, S. M. Robbins, and T. L. Beattie UV-dependent Alternative Splicing Uncouples p53 Activity and PIG3 Gene Function through Rapid Proteolytic Degradation J. Biol. Chem., June 4, 2004; 279(23): 24171 - 24178. [Abstract] [Full Text] [PDF]

				M. Muraki, B. Ohkawara, T. Hosoya, H. Onogi, J. Koizumi, T. Koizumi, K. Sumi, J.-i. Yomoda, M. V. Murray, H. Kimura, et al. Manipulation of Alternative Splicing by a Newly Developed Inhibitor of Clks J. Biol. Chem., June 4, 2004; 279(23): 24246 - 24254. [Abstract] [Full Text] [PDF]

				P.-P. Zheng, A. M. Sieuwerts, T. M. Luider, M. van der Weiden, P. A.E. Sillevis-Smitt, and J. M. Kros Differential Expression of Splicing Variants of the Human Caldesmon Gene (CALD1) in Glioma Neovascularization versus Normal Brain Microvasculature Am. J. Pathol., June 1, 2004; 164(6): 2217 - 2228. [Abstract] [Full Text] [PDF]

				M. Blaustein, F. Pelisch, O. A. Coso, M. J. Bissell, A. R. Kornblihtt, and A. Srebrow Mammary Epithelial-Mesenchymal Interaction Regulates Fibronectin Alternative Splicing via Phosphatidylinositol 3-Kinase J. Biol. Chem., May 14, 2004; 279(20): 21029 - 21037. [Abstract] [Full Text] [PDF]

				N. A. Patel, H. S. Apostolatos, K. Mebert, C. E. Chalfant, J. E. Watson, T. S. Pillay, J. Sparks, and D. R. Cooper Insulin Regulates Protein Kinase C{beta}II Alternative Splicing in Multiple Target Tissues: Development of a Hormonally Responsive Heterologous Minigene Mol. Endocrinol., April 1, 2004; 18(4): 899 - 911. [Abstract] [Full Text] [PDF]

				P. Stoilov, R. Daoud, O. Nayler, and S. Stamm Human tra2-beta1 autoregulates its protein concentration by influencing alternative splicing of its pre-mRNA Hum. Mol. Genet., March 1, 2004; 13(5): 509 - 524. [Abstract] [Full Text] [PDF]

				M. P. Sowden, D. M. Lehmann, X. Lin, C. O. Smith, and H. C. Smith Identification of Novel Alternative Splice Variants of APOBEC-1 Complementation Factor with Different Capacities to Support Apolipoprotein B mRNA Editing J. Biol. Chem., January 2, 2004; 279(1): 197 - 206. [Abstract] [Full Text] [PDF]

				T. A. Thanaraj, S. Stamm, F. Clark, J.-J. Riethoven, V. Le Texier, and J. Muilu ASD: the Alternative Splicing Database Nucleic Acids Res., January 1, 2004; 32(90001): D64 - 69. [Abstract] [Full Text] [PDF]

				Y.-Q. Zhu, Y. Lu, and X.-D. Tan Monochloramine induces reorganization of nuclear speckles and phosphorylation of SRp30 in human colonic epithelial cells: role of protein kinase C Am J Physiol Cell Physiol, November 1, 2003; 285(5): C1294 - C1303. [Abstract] [Full Text] [PDF]

This Article Abstract FREE Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in ISI Web of Science Similar articles in PubMed Alert me to new issues of the journal Add to My Personal Archive Download to citation manager Search for citing articles in: ISI Web of Science (101) Request Permissions Google Scholar Articles by Stamm, S. Search for Related Content PubMed PubMed Citation Articles by Stamm, S. Social Bookmarking          What's this?

Online ISSN 1460-2083 - Print ISSN 0964-6906

Copyright © 2009 Oxford University Press

Oxford Journals Oxford University Press

• Site Map
• Privacy Policy
• Frequently Asked Questions

Other Oxford University Press sites: Oxford University Press Oxford Journals China Oxford Journals Japan American National Biography Booksellers' Information Service Children's Fiction and Poetry Children's Reference Corporate & Special Sales Dictionaries Dictionary of National Biography Digital Reference English Language Teaching Higher Education Textbooks Humanities International Education Unit Law Medicine Music Online Products Oxford English Dictionary Reference Rights and Permissions Science School Books Social Sciences Very Short Introductions World's Classics