Human Molecular Genetics, 2002, Vol. 11, No. 13 1497-1504
© 2002 Oxford University Press
Growth arrest by the LKB1 tumor suppressor: induction of p21WAF1/CIP1
Haartman Institute and Helsinki University Central Hospital, Biomedicum Helsinki, PO Box 63, 00014 University of Helsinki, Finland
Received January 31, 2002; Accepted April 17, 2002
Germline mutations of the LKB1 tumor suppressor gene lead to Peutz–Jeghers syndrome (PJS), with a predisposition to cancer. LKB1 encodes for a nuclear and cytoplasmic serine/threonine kinase, which is inactivated by mutations observed in PJS patients. Restoring LKB1 activity into cancer cell lines defective for its expression results in a G1 cell cycle arrest. Here we have investigated molecular mechanisms leading to this arrest. Reintroduced active LKB1 was cytoplasmic and nuclear, whereas most kinase-defective PJS mutants of LKB1 localized predominantly to the nucleus. Moreover, when LKB1 was forced to remain cytoplasmic through disruption of the nuclear localization signal, it retained full growth suppression activity in a kinase-dependent manner. LKB1-mediated G1 arrest was found to be bypassed by co-expression of the G1 cyclins cyclin D1 and cyclin E. In addition, the protein levels of the CDK inhibitor p21WAF1/CIP1 and p21 promoter activity were specifically upregulated in LKB1-transfected cells. Both the growth arrest and the induction of the p21 promoter were found to be p53-dependent. These results suggest that growth suppression by LKB1 is mediated through signaling of cytoplasmic LKB1 to induce p21 through a p53-dependent mechanism.
* To whom correspondence should be addressed. Tel: +358 9 19125555; Fax: +358 9 19125554; Email: tomi.makela{at}helsinki.fi
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  Z. Xie, Y. Dong, J. Zhang, R. Scholz, D. Neumann, and M.-H. Zou Identification of the Serine 307 of LKB1 as a Novel Phosphorylation Site Essential for Its Nucleocytoplasmic Transport and Endothelial Cell Angiogenesis Mol. Cell. Biol., July 1, 2009; 29(13): 3582 - 3596. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Nath-Sain and P. A. Marignani LKB1 Catalytic Activity Contributes to Estrogen Receptor {alpha} Signaling Mol. Biol. Cell, June 1, 2009; 20(11): 2785 - 2795. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. Fan, C. Ma, and H. Zhang The molecular mechanisms that underlie the tumor suppressor function of LKB1 Acta Biochim Biophys Sin, February 1, 2009; 41(2): 97 - 107. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 F. C. Denison, N. J. Hiscock, D. Carling, and A. Woods Characterization of an Alternative Splice Variant of LKB1 J. Biol. Chem., January 2, 2009; 284(1): 67 - 76. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. C. Choi, P. Song, Z. Xie, Y. Wu, J. Xu, M. Zhang, Y. Dong, S. Wang, K. Lau, and M.-H. Zou Reactive Nitrogen Species Is Required for the Activation of the AMP-activated Protein Kinase by Statin in Vivo J. Biol. Chem., July 18, 2008; 283(29): 20186 - 20197. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Dorfman and I. G. Macara STRAD{alpha} Regulates LKB1 Localization by Blocking Access to Importin-{alpha}, and by Association with Crm1 and Exportin-7 Mol. Biol. Cell, April 1, 2008; 19(4): 1614 - 1626. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Z. Xie, Y. Dong, R. Scholz, D. Neumann, and M.-H. Zou Phosphorylation of LKB1 at Serine 428 by Protein Kinase C-{zeta} Is Required for Metformin-Enhanced Activation of the AMP-Activated Protein Kinase in Endothelial Cells Circulation, February 19, 2008; 117(7): 952 - 962. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Gurumurthy, A. F. Hezel, J. H. Berger, M. W. Bosenberg, and N. Bardeesy LKB1 Deficiency Sensitizes Mice to Carcinogen-Induced Tumorigenesis Cancer Res., January 1, 2008; 68(1): 55 - 63. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. W. Kim, H. K. Chung, K. C. Park, J. H. Hwang, Y. S. Jo, J. Chung, D. V. Kalvakolanu, N. Resta, and M. Shong Tumor Suppressor LKB1 Inhibits Activation of Signal Transducer and Activator of Transcription 3 (STAT3) by Thyroid Oncogenic Tyrosine Kinase Rearranged in Transformation (RET)/Papillary Thyroid Carcinoma (PTC) Mol. Endocrinol., December 1, 2007; 21(12): 3039 - 3049. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. D. Scott, S. Nath-Sain, M. D. Agnew, and P. A. Marignani LKB1 Catalytically Deficient Mutants Enhance Cyclin D1 Expression Cancer Res., June 15, 2007; 67(12): 5622 - 5627. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P.-Y. Zeng and S. L. Berger LKB1 Is Recruited to the p21/WAF1 Promoter by p53 to Mediate Transcriptional Activation. Cancer Res., November 15, 2006; 66(22): 10701 - 10708. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H. Motoshima, B. J. Goldstein, M. Igata, and E. Araki AMPK and cell proliferation - AMPK as a therapeutic target for atherosclerosis and cancer J. Physiol., July 1, 2006; 574(1): 63 - 71. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. Wei, C. I. Amos, L. C. Stephens, I. Campos, J. M. Deng, R. R. Behringer, A. Rashid, and M. L. Frazier Mutation of Lkb1 and p53 Genes Exert a Cooperative Effect on Tumorigenesis Cancer Res., December 15, 2005; 65(24): 11297 - 11303. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H. Mehenni, N. Lin-Marq, K. Buchet-Poyau, A. Reymond, M. A. Collart, D. Picard, and S. E. Antonarakis LKB1 interacts with and phosphorylates PTEN: a functional link between two proteins involved in cancer predisposing syndromes Hum. Mol. Genet., August 1, 2005; 14(15): 2209 - 2219. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. Forcet, S. Etienne-Manneville, H. Gaude, L. Fournier, S. Debilly, M. Salmi, A. Baas, S. Olschwang, H. Clevers, and M. Billaud Functional analysis of Peutz-Jeghers mutations reveals that the LKB1 C-terminal region exerts a crucial role in regulating both the AMPK pathway and the cell polarity Hum. Mol. Genet., May 15, 2005; 14(10): 1283 - 1292. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 V Schumacher, T Vogel, B Leube, C Driemel, T Goecke, G Moslein, and B Royer-Pokora STK11 genotyping and cancer risk in Peutz-Jeghers syndrome J. Med. Genet., May 1, 2005; 42(5): 428 - 435. [Full Text] [PDF]
|
|
|
|
 |
|
 P A Marignani LKB1, the multitasking tumour suppressor kinase J. Clin. Pathol., January 1, 2005; 58(1): 15 - 19. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. Boudeau, J. W. Scott, N. Resta, M. Deak, A. Kieloch, D. Komander, D. G. Hardie, A. R. Prescott, D. M. F. van Aalten, and D. R. Alessi Analysis of the LKB1-STRAD-MO25 complex J. Cell Sci., December 15, 2004; 117(26): 6365 - 6375. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. G. Hardie The AMP-activated protein kinase pathway - new players upstream and downstream J. Cell Sci., November 1, 2004; 117(23): 5479 - 5487. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. Wei, C. I. Amos, A. Rashid, M. Sabripour, L. Nations, T. J. McGarrity, and M. L. Frazier Correlation of Staining for LKB1 and COX-2 in Hamartomatous Polyps and Carcinomas from Patients with Peutz-Jeghers Syndrome J. Histochem. Cytochem., December 1, 2003; 51(12): 1665 - 1672. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. B. Blumer, M. L. Bernard, Y. K. Peterson, J.-i. Nezu, P. Chung, D. J. Dunican, J. A. Knoblich, and S. M. Lanier Interaction of Activator of G-protein Signaling 3 (AGS3) with LKB1, a Serine/Threonine Kinase Involved in Cell Polarity and Cell Cycle Progression: PHOSPHORYLATION OF THE G-PROTEIN REGULATORY (GPR) MOTIF AS A REGULATORY MECHANISM FOR THE INTERACTION OF GPR MOTIFS WITH Gi{alpha} J. Biol. Chem., June 20, 2003; 278(26): 23217 - 23220. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. I. Jimenez, P. Fernandez, O. Dominguez, A. Dopazo, and M. Sanchez-Cespedes Growth and Molecular Profile of Lung Cancer Cells Expressing Ectopic LKB1: Down-Regulation of the Phosphatidylinositol 3'-Phosphate Kinase/PTEN Pathway Cancer Res., March 15, 2003; 63(6): 1382 - 1388. [Abstract] [Full Text] [PDF]
|
|