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Human Molecular Genetics 2007 16(R1):R73-R79; doi:10.1093/hmg/ddm036
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© The Author 2007. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Susceptibility to pituitary neoplasia related to MEN-1, CDKN1B and AIP mutations: an update

Auli Karhu and Lauri A. Aaltonen*

Department of Medical Genetics, University of Helsinki, PO Box 63 (Haartmaninkatu 8), FIN-00014, Helsinki, Finland

* To whom the correspondence should be addressed. Tel: +358 91911; Fax: +358 919125105; Email: lauri.aaltonen{at}helsinki.fi

Received February 15, 2007; Accepted February 16, 2007


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 MULTIPLE ENDOCRINE NEOPLASIA...
 CDKN1B
 PITUITARY ADENOMA PREDISPOSITION
 CONCLUSION
 REFERENCES
 
Pituitary tumors are common intracranial neoplasms. Although histologically benign, pituitary tumors can cause significant morbidity due to their critical location, expanding size and oversecretion of pituitary hormone expression. The majority of pituitary tumors are sporadic, but some arise as a component of hereditary syndromes. Our understanding of these genetic conditions has expanded rapidly due to the identification of new predisposing genes. Four specific genes have been identified that predispose to hereditary pituitary neoplasia; MEN1, PRKAR1A, CDKN1B and AIP, of which CDKN1B and AIP have been identified only recently. These genes underlie multiple endocrine neoplasia type 1, Carney complex, MEN1-like phenotype and pituitary adenoma predisposition, respectively. The present study review the current state of knowledge regarding the genes associated to inherited pituitary neoplasia, with a particular focus on the novel pituitary adenoma predisposing genes, CDKN1B and AIP.


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
MULTIPLE ENDOCRINE NEOPLASIA...
 CDKN1B
 PITUITARY ADENOMA PREDISPOSITION
 CONCLUSION
 REFERENCES
 
Pituitary adenomas are common tumors of the anterior lobe accounting for ~15% of all intracranial tumors. Pituitary adenomas are benign but associated with significant morbidity due to local compressive effects as well as oversecretion of pituitary hormones. The anterior pituitary comprises several different cell types, each responsible for the synthesis and secretion of a specific hormone. The most common hormone-secreting pituitary tumor types oversecrete prolactin (PRL) (40–45%) or growth hormone (GH) (20%). Less common are adrenocorticotropin hormone (ACTH) secreting adenomas (10–12%), causing Cushing's disease. The remaining one-third of pituitary adenomas are endocrinologically silent—known as null cell or non-functional pituitary adenomas (NFPAs) (5–10%)—and expand as a pituitary mass (1,2).

The majority of pituitary adenomas are sporadic, although some arise as a component of familial syndromes. Identification of genes responsible for heritable pituitary neoplasias has enabled early detection of patients with suspected pituitary adenoma syndromes. Without pre-existing risk awareness, the patients are typically diagnosed after years of delay, leading to significant morbidity (3).

So far, four genes have been identified that predispose to familial pituitary tumorigenesis. Previously identified, multiple endocrine neoplasia type I (MEN1) (11q13) and protein kinase A regulatory subunit-1-alpha (PRKAR1A) (17q24) genes have been associated in multiple endocrine neoplasia type 1 (MEN1) and Carney complex (CNC), respectively. More recently identified pituitary adenoma predisposition (PAP) genes cyclin-dependent kinase inhibitor 1B (CDKN1B) (12p13) and aryl hydrocarbon receptor (AHR) interacting protein (AIP) (11q13) (4,5) are associated in MEN1-like phenotype and PAP, respectively. In addition, familial pituitary adenoma is seen in the isolated familial somatotropinomas (IFS) (linkage to 11q13) (6) and familial isolated pituitary adenomas (FIPA) (7), the former probably in part allelic to PAP and caused by mutations in AIP gene, and in the FIPA phenotype, the main underlying genetic components remain to be dissected.

The purpose of this review is to outline the current state of knowledge regarding the genes that are associated to inherited pituitary adenomas, with a particular focus on the novel pituitary adenoma predisposing genes, CDKN1B and AIP. PRKAR1A and related genes, as well as sporadic tumorigenesis are covered in an accompanying article.


   MULTIPLE ENDOCRINE NEOPLASIA TYPE 1 (MEN1)
TOP
 ABSTRACT
 INTRODUCTION
 MULTIPLE ENDOCRINE NEOPLASIA...
CDKN1B
 PITUITARY ADENOMA PREDISPOSITION
 CONCLUSION
 REFERENCES
 
MEN1 (11q13) is one of the first identified tumor suppressor genes. MEN1 syndrome is inherited as an autosomal-dominant trait. The condition is characterized by predisposition to pituitary adenomas, parathyroid hyperplasia, and pancreatic endocrine tumors. In familial MEN1, an affected individual has at least two out of three above mentioned tumors and at least one first-degree relative has at least one of the three (8). Solitary MEN1 patients have features of MEN1 syndrome but no family history indicating possible de novo germline mutation. Somatic MEN1 mutations are very rare in sporadic pituitary tumors (9,10). Pituitary adenomas affect ~25–30% of MEN1 patients (11). MEN1 germline mutations predispose to all major pituitary adenoma subtypes. The most common subtypes seen are those secreting PRL (60%) and GH (20%), respectively. ACTH secreting and non-functional adenomas represent < 15% of MEN1 pituitary tumors (12,13). Since the cloning of MEN1, more than 600 germline mutations have been found. Mutations occur mostly in coding exons, but also in intronic sequences (14,15). Approximately 10% of the clinically suspected MEN1 patients do not exhibit MEN1 mutations (16), implicating that other predisposition genes may play a role in this phenotype.

Function of MEN1 protein (MENIN)
The role of MENIN in tumorigenesis and its physiological functions are not completely understood. MEN1 consists of 10 exons with 1830 bp protein coding region. It encodes 610 amino acids, and the protein is referred as MENIN (17). MENIN is predominantly a nuclear protein which have shown to interact with proteins that are involved in transcriptional regulation and the control of genome stability. MENIN interacts, e.g. with transcription factors JUND (AP-1 family member) (18) and JUN (19) to inhibit of JUN-activated transcription. In addition, MENIN has been proposed to interact with many other proteins, such as the nuclear factor-{kappa}B (NF-{kappa}B), the Smad family, DNA, cell cycle regulators, and variety of other transcription factors and cell structural elements (20–26).


   CDKN1B
TOP
 ABSTRACT
 INTRODUCTION
 MULTIPLE ENDOCRINE NEOPLASIA...
 CDKN1B
PITUITARY ADENOMA PREDISPOSITION
 CONCLUSION
 REFERENCES
 
A germline nonsense mutation in the human cyclin-dependent kinase inhibitor 1B (CDKN1B, known also as p27 and KIP1) (12p13) gene was recently identified in a family with a MEN1-like condition (4). The work was based on studies on a recessively inherited MEN-like syndrome (MENX) in the rat characterized by bilateral pheochromocytomas, parathyroid adenomas, multifocal thyroid C cell hyperplasia, paragangliomas, and hyperplasia of the endocrine pancreas (27). Affected rats were homozygous for a tandem duplication of 8 bp in exon 2 of CDKN1B, resulting a frameshift change and premature stop codon. The subsequent identification of a heterozygous nonsense germline mutation in the human CDKN1B gene supported an association between germline mutations of CDKN1B and a heritable human MEN1-like condition. The mutation was found from a suspected MEN1 patient with GH secreting pituitary adenoma and parathyroid tumor. Although no loss of wild-type allele was detected, the immunohistochemical staining showed no CDKN1B protein in tumor tissue. The pedigree analysis revealed that the mutation segregated with a development of an MEN1-like phenotype (4). Subsequently, an inactivating CDKN1B germline mutation was also detected in a Dutch MEN1-like patient. This patient had a 19 bp heterozygous duplication in exon 1 that results in a premature stop codon. The patient had been diagnosed with three typical MEN1 associated lesions; hyperparathyroidism/parathyroid tumor, pituitary adenoma, and neuroendocrine carcinoid tumor (M. Georgitsi et al., manuscript in preparation). Thus, this study confirms the previous observation that germline mutations in the CDKN1B gene predispose to a MEN1-like syndrome.

Function of CDKN1B protein
CDKN1B gene consists 3 exons and it encodes 198 amino acids. CDKN1B protein is a well-characterized cyclin-dependent kinase inhibitor. Nuclear CDKN1B protein regulates negatively cell cycle progression by inhibiting cyclin and cyclin-dependent kinase complexes. CDKN1B-knockout mice display enhanced growth with multiorgan hyperplasia that include tumors in the pituitary intermediate lobe, and increased cell proliferation. CDKN1B negative rats developed, e.g. pheocromocytomas, thyroid cell and parathyroid neoplasias, and pituitary adenomas. Knockout rats had also increased body weight when compared with wild-type animals (4). It is noticed earlier that immunodetectable CDKN1B protein is underexpressed or even absent in most human pituitary tumors (28). More recent studies indicate that CDKN1B is an important read out of the MENIN signaling pathway and a possible target of oncogenic RET in endocrine cells (29–31). CDKN1B is also a direct transcriptional target of AHR, which is a toxic agent having a known affect to cell proliferation (32). However, the precise role of CDKN1B protein in genesis of pituitary adenoma remains to be elucidated.


   PITUITARY ADENOMA PREDISPOSITION
TOP
 ABSTRACT
 INTRODUCTION
 MULTIPLE ENDOCRINE NEOPLASIA...
 CDKN1B
 PITUITARY ADENOMA PREDISPOSITION
CONCLUSION
 REFERENCES
 
LOH of 11q13 is observed in up to 30% of sporadic pituitary tumors. However, MEN1 mutations explain only < 2% of these. Also efforts establishing a genetic locus for isolated familial somototropinoma (IFS) have provided evidence for linkage to chromosome 11q13 close but distinct from MEN1 locus (e.g. 33,34). Taken together, evidence from these studies predicts the presence of a distinct tumor suppressor gene for these pituitary adenomas (35,36).

In a recent effort to unravel the genetic basis of site-specific PAP, two clusters of familial pituitary adenoma from northern Finland were detected. These families displayed prolactinoma (PRL oversecretion) and somatitropinoma (GH oversecretion) causing acromegaly and gigantism (5). The penetrance appeared to be low. The PAP locus was identified in these families using whole genome single-nucleotide polymorphism genotyping which revealed linkage to chromosome 11q12–13. After expression profile analyses AIP gene was chosen as a prime candidate for mutation analysis. Indeed, germline mutations in the AIP were found to be responsible for PAP phenotype in many of the examined subjects (5). A nonsense mutation Q14X segregated perfectly with the GH secreting adenomas, and was also present in three prolactinoma patients. In addition, a nonsense mutation R304X was found in two Italian siblings with GH-secreting adenomas. In population-based material from northern Finland 6 out of the 45 acromegaly patients displayed Q14X, and one IVS3-1G > A splice site mutations. These mutations accounted 16% of all patients diagnosed with pituitary adenomas secreting GH and 40% of the subset of patients who were diagnosed when they were younger than 35 years of age. Typically, PAP patients had a young age at disease onset but did not display a strong family history of pituitary adenomas. Loss of normal allele was detected in 8/8 pituitary adenomas. Thus, AIP is likely to act as a tumor suppressor gene (5).

The contribution of AIP has also recently been evaluated in other, more heterogenous sample sets. Altogether, 460 pituitary adenoma patients and patients from families with MEN1 features from different European populations and the United States were screened by AIP sequencing. Sample sets included young acromegaly patients, unselected acromegaly patients, unselected pituitary adenoma patients and endocrine neoplasia predisposition patients who were negative for MEN1 mutations. Mutation percentages varied between 0.8–7.4% depending on the sample set and population (Table 1) (37). The highest mutation percentages were found among young acromegaly patients. Altogether, the mean age at diagnosis among the AIP mutation carriers was 23.8 years. Thus this study also revealed that young age of onset signals well an underlying AIP mutation. Instead, positive family history was a weak indicator of PAP. Loss of AIP in immunohistochemical analysis of pituitary adenomas was proposed to be a useful tool for PAP identification.


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  		Table 1. Contribution of AIP germline mutations in different populations from Europe and USA

 
Recently, affected members from 73 FIPA families without MEN1 or CNC were screened for AIP mutations (38). In seven families, truncating, frame shift or in-frame deletion mutations were detected (Table 2, Fig.1), and four families displayed three missense changes. From these missense changes, H16R may be a rare polymorphism based on the AIP screening study from different European and the United State populations (37). In addition, the FIPA family study showed that the tumors were larger and diagnosed at a younger age in AIP mutation positive patients when compared with mutation negative patients (38). Because many FIPA families are not associated with AIP mutations, we propose that the term PAP would be used in the context of cases with verified AIP mutations. This would serve clarity.


Figure 1
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  		Figure 1. Germline AIP mutations detected in PAP. The locations of FKBP-homology region and three TPRs are shown in colored boxes. AHR and HSP90 interaction regions are shown with black lines.

 


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  		Table 2. AIP gene germline mutations detected and predicted effect

 
Altogether 107 sporadic pituitary adenoma patients from France, Italy and Belgium and 41 tumor samples were screened for AIP mutations. Only one tumor sample showed a germline nonsense mutation. Thus AIP mutations do not seem to play an important role in the sporadic pituitary tumors (39).

Involvement of AIP in the genesis of common cancers has been studied in colorectal cancers, breast cancers and prostate tumors. No somatic mutations were found, suggesting that AIP is not strongly involved in tumorigenesis of these tumor types (40). This does not, however, rule out the possibility that AIP can be more often somatically mutated in other tumor types more closely related to pituitary adenoma.

Early evidence indicates that AIP germline mutations are scattered quite evenly throughout the coding region of the AIP, but it is of note that all presumably pathogenic missense mutations reside in a region between codons 241–304 at exons 5 and 6 (Fig. 1) (5,37,38). Mutations include point mutations, splice site mutations, an insertion and small deletions causing either frame shift or in-frame changes (Table 2) which are thought to alter the structure and biological function of the protein.

Function of AIP protein
AIP contains 6 exons and it encodes a protein of 330 amino acids (Fig. 1). It has a FKBP-homology region in the amino terminus, and three protein–protein interaction mediating tetratricopeptide repeats (TPR) in the C-terminal region. AIP interacts in cytoplasm with the AHR. AHR is a transcription factor that regulates many xenobiotic metabolizing enzymes (41,42). Dioxins and dioxin-like chemicals display high affinity binding to AHR, which mediates most of the toxic responses of these agents. Carcinogenic effect of dioxins is likely the result of their tumor promoting activity produced by activation of the AHR. AHR also participates in cellular signaling pathways, e.g. through interaction with known cell-cycle regulators such as retinoblastoma protein (43). AIP modulates also the sub-cellular localization of AHR and prevents the AHR to undergo nucleocytoplasmic shuttling (44). For example, the R304X mutation found in the Italian family removes the C-terminal region of AIP that is required for the binding to AHR (45,46). AIP has also been reported to interact with two 90 kDa heat-shock proteins (HSP90), phosphodiesterase 4A5 (PDE4A5), peroxisome proliferation-activated receptor-{alpha} (PPAR{alpha}), survivin (BIRC5), translocase of the outer membrane of mitochondria 20 (TOMM20), and ß thyroid receptor (THRß1) (41,47–51). PDE4A5 is known to be one of the cAMP-specific phosphodiesterases that modulate cAMP signaling by their ability to hydrolyze cAMP and thereby contribute to the regulation of its levels in the cells (47). Although these protein interactions can be linked to tumorigenesis, the exact mechanisms by which AIP exerts its tumor suppressive action in the pituitary tumorigenesis remain to be determined.


   CONCLUSION
TOP
 ABSTRACT
 INTRODUCTION
 MULTIPLE ENDOCRINE NEOPLASIA...
 CDKN1B
 PITUITARY ADENOMA PREDISPOSITION
 CONCLUSION
REFERENCES
 
Familial pituitary adenomas are associated with at least four genes (MEN1, PRKAR1A, CDKN1B and AIP) that predispose to pituitary hyperplasia and tumorigenesis. The distinction of familial pituitary adenomas from sporadic forms should precede the genetic screening of families suspected to harbor such mutations, to identify individuals at genetic disease risk. The genetic counseling and surveillance of family members identified as mutation carriers allows efficient non-invasive clinical follow-up. Means for this include biochemical screening markers, such as measuring levels of serum PRL (for prolactinoma) and insulin-like growth factor 1(IGF-I) (for somatotropinoma), and possibly pituitary MRI imaging. For instance, MEN1 mutation positive patients can show biochemical evidence of neoplasia on an average of 10 years prior to clinically evident disease (52). Thus, the knowledge of mutation status will facilitate earlier diagnosis and prognostic information crucial to improve the quality of life and obviate the deleterious effects associated with, for instance, GH-secreting pituitary adenomas. In some syndromes, selection of patients for genetic testing can be difficult. This can be the case with the PAP syndrome, since most cases do not show strong family history due the apparently low penetrance. Immunohistochemical (IHC) staining of predisposing gene product can be useful when selecting patients for genetic testing. AIP IHC screening was tested in 50 pituitary adenomas for loss of the AIP gene product (Fig. 2). Negative AIP IHC staining proved to be a strong predictor of PAP (5,37).


Figure 2
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  		Figure 2. Immunohistochemical analysis of AIP in pituitary tumors. (A) Positive immunostaining seen in both the cytoplasm and the nucleus in normal adenohypophysis. (B) AIP positive staining in AIP proficient pituitary adenoma. (C) Negative AIP staining in AIP deficient adenoma having a Q14X mutation; note preserved nuclear immunoreaction against normal tissue component (leucocytes in a blood), indicated by black arrows.

 
Study of human pituitary tissue is challenging due to several limitations including, e.g. the anatomic inaccessibility of the pituitary gland and the lack of functional human cell lines. Further challenges include better understanding the functional role of proteins involved in genesis of pituitary adenomas. It also seems obvious that more genes for susceptibility to pituitary adenomas are to be identified, and much work has already been done to characterize adequate materials for identification of such genes (7). The mechanisms that lead to selection of the abnormal proteins during pituitary tumorigenesis are largely unknown, but the identification of the many pieces in the puzzle is an essential first step towards profound understanding of the underlying processes. This information should in the long-run lead to development of novel therapeutic approaches.


   ACKNOWLEDGEMENTS
 
This work was supported by the Academy of Finland (grants 212901, 213183, the Centre of Excellence in Translational Genome-Scale Biology), the Sigrid Jusélius Foundation, the Finnish Cancer Society and the Association for International Cancer Research (grant 05-001).

Conflict of Interest statement. None declared.


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 MULTIPLE ENDOCRINE NEOPLASIA...
 CDKN1B
 PITUITARY ADENOMA PREDISPOSITION
 CONCLUSION
 REFERENCES
 

  1. Heaney A.P., Melmed S. Molecular targets in pituitary tumours. Nat. Rev. Cancer (2004) 4:285–295.[CrossRef][ISI][Medline]

  2. Arafah B.M., Nasrallah M.P. Pituitary tumors: pathology, clinical manifestation and management. Endocr. Relat. Cancer (2001) 8:287–305.[Abstract]

  3. Farrell W.E., Clayton R.N. Molecular pathogenesis of pituitary tumors. Front. Neuroendocrinol. (2000) 21:174–198.[CrossRef][ISI][Medline]

  4. Pellegata N.S., Quintanilla-Martinez L., Siggelkow H., Samson E., Bink K., Höfler H., Fend F., Graw J., Atkinson M.J. Germ-line mutations in p27Kip1 cause a multiple endocrine neoplasia syndrome in rats and humans. Proc. Natl. Acad. Sci. USA (2006) 103:15558–15566.[Abstract/Free Full Text]

  5. Vierimaa O., Georgitsi M., Lehtonen R., Vahteristo P., Kokko A., Raitila A., Tuppurainen K., Ebeling T.M., Salmela P.I., Paschke R., et al. Pituitary adenoma predisposition caused by germline mutations in the AIP gene. Science (2006) 312:1228–1230.[Abstract/Free Full Text]

  6. Lucio-Camelo D.C., Une K.N., Ferreira R.E.S., Khoo S.K., Nickolov R., Bronstein M.D., Vaisman M., Teh B.T., Frohman L.A., Mendonça B.B., Gadelha M.R. A meiotic recombination in a new isolated familial somatotropinoma kindred. Eur. J. Endocrinol. (2004) 150:643–648.[Abstract]

  7. Daly A.F., Jaffrain-Rea M.L., Ciccarelli A., Valdes-Socin H., Rohmer V., Tamburrano G., Borson-Chazot C., Estour B., Ciccarelli E., Brue T., et al. Clinical characterization of familial isolated pituitary adenomas. J. Clin. Endocrinol. Metab. (2006) 91:3316–3323.[Abstract/Free Full Text]

  8. Marx S.J., Agarwal S.K., Kester M.B., Heppner C., Kim Y.S., Skarulis M.C., James L.A., Goldsmith P.K., Saggar S.K., Park S.Y., et al. Multiple endocrine neoplasia type 1: clinical and genetic features of the hereditary endocrine neoplasias. Recent. Prog. Horm. Res. (1999) 54:397–438.[Medline]

  9. Zhuang Z., Ezzat S.Z., Vortmeyer A.O., Weil R., Oldfield E.H., Park W.S., Paolo S., Huang S., Agarwal S.K., Guru S.C., et al. Mutations of the MEN1 tumor suppressor gene in pituitary tumors. Cancer Res. (1997) 57:5446–5451.[Abstract/Free Full Text]

  10. Poncin J., Stevenaert A., Beckers A. Somatic MEN1 gene mutation does not contribute significantly to sporadic pituitary tumorigenesis. Eur. J. Endocrinol. (1999) 140:573–576.[Abstract]

  11. Burgess J.R., Greenaway T.M., Shepherd J.J. Expression of the MEN-1 gene in a large kindred with multiple endocrine neoplasia type 1. J. Intern. Med. (1998) 243:465–470.[CrossRef][ISI][Medline]

  12. Thakker R.V. Multiple endocrine neoplasia-syndromes of the twentieth century. J. Clin. Endocrinol. Metab. (1998) 83:2617–2620.[Free Full Text]

  13. Jagannathan J., Dumont A.S., Prevedello D.M., Lopes B., Oskouian R.J., Jane J.A. Jr, Laws E.R. Jr. Genetics of pituitary adenomas: current theories and future implications. Neurosurg. Focus (2005) 19:E4.[Medline]

  14. Pannett A.A.J., Thakker R.V. Multiple endocrine neoplasia type 1. Endocr. Relat. Cancer. (1999) 6:449–473.[Abstract]

  15. Turner J.J., Leotlela P.D., Pannett A.A., Forbes S.A., Bassett J.H., Harding B., Christie P.T., Bowen-Jones D., Ellard S., Hattersley A., et al. Frequent occurrence of an intron 4 mutation in multiple endocrine neoplasia type 1. J Clin Endocrinol. Metab. (2002) 87:2688–2693.[Abstract/Free Full Text]

  16. Hai N., Aoki N., Shimatsu A., Mori T., Kosugi S. Clinical features of multiple endocrine neoplasia type 1 (MEN1) phenocopy without germline MEN1 gene mutations: analysis of 29 Japanese sproradic cases with MEN1. Clin. Endocrinol. (Oxf) (2000) 52:509–518.[CrossRef][Medline]

  17. Chandrasekharappa S.C., Guru S.C., Manickam P., Olufemo S.E., Collins F.S., Emmert-Buck M.R., Debelenko L.V., Zhuang Z., Lubensky I.A., Liotta L.A., et al. Positional cloning of the gene for multiple endocrine neoplasia-type I. Science (1997) 276:404–407.[Abstract/Free Full Text]

  18. Agarwal S.K., Guru S.C., Heppner C., Erdos M.R., Collins R.M., Park S.Y., Saggar S., Chandrasekharappa S.C., Collins F.S., Spiegel A.M., et al. Menin interacts with the AP1 transcription factor JunD and represses JunD-activated transcription. Cell (1999) 96:143–152.[CrossRef][ISI][Medline]

  19. Yumita W., Ikeo Y., Yamauchi K., Sakurai A., Hashizume K. Suppression of insulin-induced AP-1 transactivation by menin accompanies inhibition of c-Fos induction. Int. J. Cancer (2003) 103:738–744.[CrossRef][ISI][Medline]

  20. Hepner C., Bilimoria K.Y., Agarwal S.K., Kester M., Whitty L.J., Guru S.C., Chandrasekharappa S.C., Collins F.S., Spiegel A.M., Marx S.J., et al. The tumor suppressor protein menin interacts with NF-kappaB proteins and inhibits NFkappaB-mediated transactivation. Oncogene (2001) 20:4917–4925.[CrossRef][ISI][Medline]

  21. Kaji H., Canaff L., Lebrun J.-J., Goltzman D., Hendy G.N. Inactivation of menin, a Smad3-interacting protein, blocks transforming growth factor type beta signaling. Proc. Natl. Acad. Sci. USA (2001) 98:3837–3842.[Abstract/Free Full Text]

  22. Lemmens I.H., Forsberg L., Pannet A.A., Meyen E., Piehl F., Turner J.J., Van de Ven W.J., Thakker R.V., Larsson C., Kas K. Menin interacts directly with the homeobox-containinig protein Pem. Biochem. Biophys. Res. Commun. (2001) 286:426–431.[CrossRef][ISI][Medline]

  23. Ohkura N., Kishi M., Tsukada T., Yamaguchi K. Menin, a gene product responsible for multiple endocrine neoplasia type 1, interacts with the putative tumor metastasis suppressor nm23. Biochem. Biophys. Res. Commun. (2001) 282:1206–1210.[CrossRef][ISI][Medline]

  24. Yaguchi H., Ohkura N., Tsukada T., Yamaguchi K. Menin, multiple endocrine neoplasia type 1 gene product, exhibits GTP-hydrolyzing activity in the presence of the tumor metastasis suppressor nm23. J. Biol. Chem. (2002) 277:38197–38204.[Abstract/Free Full Text]

  25. Lopez-Egido J., Cunningham J., Berg M., Oberg K., Bongcam-Rudloff E., Gobl A. Menin's interaction with glial fibrillary acidic protein and vimentin suggests a role for the intermediate filament network in regulating menin activity. Exp. Cell Res. (2002) 278:175–183.[CrossRef][ISI][Medline]

  26. La P., Canaff A.C., Hou Z., Wang H., Schnepp R.W., Yan N., Shi Y., Hua X. Direct binding of DNA tumor suppressor menin. J. Biol. Chem. (2004) 279:49045–49054.[Abstract/Free Full Text]

  27. Fritz A., Walch A., Piotrowska K., Rosemann M., Schaffer E., Weber K., Timper A., Wildner G., Graw J., Hofler H., et al. Recessive transmission of a multiple endocrine neoplasia syndrome in the rat. Cancer Res. (2002) 62:3048–3051.[Abstract/Free Full Text]

  28. Lidhar K., Korbonits M., Jordan S., Khalimova Z., Kaltsas G., Lu X., Clayton R.N., Jenkins P.J., Monson J.P., Besser G.M., et al. Low expression of the cell cycle inhibitor p27Kip1 in normal corticotroph cells, corticotroph tumors, and malignant pituitary tumors. J. Clin. Endocrinol. Metab. (1999) 84:3823–3830.[Abstract/Free Full Text]

  29. Milne T.A., Hughes C.M., Lloyd R., Yang Z., Rozenblatt-Rosen O., Dou Y., Schnepp R.W., Krankel C., Livolsi V.A., Gibbs D., et al. Menin and MLL cooperatively regulate expression of cyclin-dependent kinase inhibitors. Proc. Natl. Acad. Sci. USA. (2005) 102:749–754.[Abstract/Free Full Text]

  30. Karnik S.K., Hughes C.M., Gu X., Rozenblatt-Rosen O., McLean G.W., Xiong Y., Meyerson M., Kim S.K. Menin regulates pancreatic islet growth by promoting histone methylation and expression of genes encoding p27Kip1 and p18INK4c. Proc. Natl. Acad. Sci. USA (2005) 102:14659–14664.[Abstract/Free Full Text]

  31. Drosten M., Hilken G., Bockmann M., Rodicker F., Mise N., Cranston A.N., Dahmen U., Ponder B.A., Putzer B.M. Role of MEN2A-derived RET in maintenance and proliferation of medullary thyroid carcinoma. J. Natl. Cancer Inst. (2004) 96:1231–1239.[Abstract/Free Full Text]

  32. Kolluri S.K., Weiss C., Koff A., Göttlicher M. p27Kip1 induction and inhibition of proliferation by the intracellular Ah receptor in developing thymus and hepatoma cells. Genes Dev. (1999) 13:1742–1753.[Abstract/Free Full Text]

  33. De Menis E., Prezant T.R. Isolated familial somatotropinomas: clinical features and analysis of the MEN1 gene. Pituitary (2002) 5:11–15.[CrossRef][Medline]

  34. Verloes A., Stevenaert A., Teh B.T., Petrossians P., Beckers A. Familial acromegaly: case report and review of the literature. Pituitary (2000) 1:273–277.[CrossRef]

  35. Frohman L.A., Eguchi K. Familial acromegaly. Growth Horm. IGF Res. (2004) 14:90–96.[CrossRef]

  36. Soares B.S., Eguchi K., Frohman L.A. Tumor deletion mapping on chromosome 11q13 in 8 families with isolated familial somatotropinoma and in 15 sporadic somatotropinomas. J. Clin. Endocrinol. Metabol. (2005) 90:6580–6587.[Abstract/Free Full Text]

  37. Georgitsi M., Raitila A., Karhu A., Tuppurainen K., Mäkinen M.J., Vierimaa O., Paschke R., Saeger W., van der Luijt R.B., Sane T., et al. Molecular diagnosis of pituitary adenoma predisposition, caused by aryl hydrocarbon receptor interacting protein gene mutations. Proc. Natl. Acad. Sci. USA (2007) 104:4101–4105.[Abstract/Free Full Text]

  38. Daly A.F., Vanbellinghen J-F., Khoo S.K., Jaffrain-Rea M-L., Naves L.A., Guitelma M.A., Murat A., Emy P., Gimenez-Roqueplo A-P., Tamburrano G., et al. Aryl hydrocarbon interacting protein gene mutations in familial isolated pituitary adenomas: analysis in 73 families. In: J. Clin. Endocrin. Metab. (2007) doi:10.1210/jc.2006–2513.

  39. Barlier A., Vanbellinghen J-F., Daly A.F., Silvy M., Jaffrain-Rea M-L., Trouillas J., Tamagno G., Cazabat L., Bours V., Enjalbert A., et al. Mutations in aryl hydrocarbon receptor interacting protein gene are not highly prevalent among subjects with sporadic pituitary adenomas. In: J. Clin. Endocrin. Metab. (2007) doi:10.1210/jc.2006–2702.

  40. Georgitsi M., Karhu A., Winqvist R., Visakorpi T., Waltering K., Vahteristo P., Launonen V., Aaltonen L.A. Mutation analysis of aryl hydrocarbon receptor interacting protein (AIP) in colorectal, breast, and prostate cancers. Br. J. Cancer (2006) 96:352–356.[CrossRef][ISI]

  41. Carver L.A., Bradfield C.A. Ligand-dependent interaction of the aryl hydrocarbon receptor with a novel immunophilin homolog in vivo. J. Biol. Chem. (1997) 272:11452–11456.[Abstract/Free Full Text]

  42. Meyer B.K., Perdew G.H. Characterization of the AhR-hsp90-XAP2 core complex and the role of the immunophilin-related protein XAP2 in AhR stabilization. Biochemistry (1999) 38:8907–8917.[CrossRef][Medline]

  43. Marlowe J.L., Puga A. Aryl hydrocarbon receptor, cell cycle regulation, toxicity, and tumorigenesis. J. Cell Biochem. (2005) 96:1174–1184.[CrossRef][ISI][Medline]

  44. Pollenz R.S., Dougherty E.J. Redefining the role of the endogenous XAP2 and C-terminal hsp70-interacting protein on the endogenous Ah receptors expressed in mouse and rat cell lines. J. Biol. Chem. (2005) 280:33346–33356.[Abstract/Free Full Text]

  45. Bell D.R., Poland A. Binding of aryl hydrocarbon receptor (AhR) to AhR-interacting protein. The role of hsp90. J. Biol. Chem. (2000) 275:36407–36414.[Abstract/Free Full Text]

  46. Petrulis J.R., Perdew G.H. The role of chaperone proteins in the aryl hydrocarbon receptor core complex. Chem. Biol. Interact. (2002) 141:25–40.[CrossRef][ISI][Medline]

  47. Bolger G.B., Peden A.H., Steele M.R., MacKenzie C., McEwan D.G., Wallace D.A., Huston E., Baillie G.S., Houslay M.D. Attenuation of the activity of the cAMP-specific phosphodiesterase PDE4A5 by interaction with the immunophilin XAP2. J. Biol. Chem. (2003) 278:3351–3363.

  48. Sumanasekera W.K., Tien E.S., Turpey R., Vanden Heuvel J.P., Perdew G.H. Evidence that peroxisome proliferator-activated receptor alpha is complexed with the 90-kDa heat shock protein and the hepatitis virus B X-associated protein 2. J. Biol. Chem. (2003) 278:4467–4473.[Abstract/Free Full Text]

  49. Kang B.H., Altieri D.C. Regulation of survivin stability by the aryl hydrocarbon receptor-interacting protein. J. Biol. Chem. (2006) 281:24721–24727.[Abstract/Free Full Text]

  50. Yano M., Terada K., Mori M. AIP is a mitochondrial import mediator that binds to both import receptor Tom20 and preproteins. J. Cell Biol. (2003) 163:45–56.[Abstract/Free Full Text]

  51. Clerget Froidevaux M-S.C., Berg P., Seugnet I., Decherf S., Becker N., Sachs L.M., Bilesimo P., Nygård M., Pongratz I., Demeneix B.A. The co-chaperone XAP2 is required for activation of hypothalamic thyrotropin-releasing hormone transcription in vivo. EMBO Rep. (2006) 7:1035–1039.[CrossRef][ISI][Medline]

  52. Larimore T.C., Piersall M.K., DeBenedetti M.K., Dilley W.G., Mutch M.G., Whelan A.J., Zehnbauer B. Clinical genetic testing and early surgical intervention in patients with multiple endocrine neoplasia type 1 (MEN1). Ann. Surg. (2004) 239:645–647.[ISI]


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