LKB1 catalytically deficient mutants enhance cyclin D1 expression.

Mutations in the serine-threonine tumor-suppressor kinase LKB1 are responsible for Peutz-Jeghers syndrome, characterized by hamartomatous proliferation and an increased risk of developing cancer. Mutations in lkb1 have also been identified in sporadic cancers, suggesting a wider role for LKB1 in cancer that is not limited to hamartomatous polyposis syndromes. Here, we show that LKB1 catalytically deficient mutants, when introduced into DLD1p21-/-p53-/- colorectal cancer cells, allowed for progression of cells through to S phase of cell cycle and elicited the expression of Rb, cyclin E, and cyclin A2 whereas the introduction of LKB1 lead to G1 cell cycle arrest independent of p21(WAF/CIP1) and/or p53 expression. Furthermore, we show that LKB1 catalytically deficient mutants activate the expression of cyclin D1 through recruitment to response elements within the promoter of the oncogene. In addition to compromising the tumor-suppressor function of LKB1, our findings highlight an emerging role for LKB1 catalytically deficient mutants, a gain of oncogenic properties.

[1]  H. Clevers,et al.  Dysfunctional AMPK activity, signalling through mTOR and survival in response to energetic stress in LKB1-deficient lung cancer , 2007, Oncogene.

[2]  S. Berger,et al.  LKB1 is recruited to the p21/WAF1 promoter by p53 to mediate transcriptional activation. , 2006, Cancer research.

[3]  Kei Sakamoto,et al.  LKB1-dependent signaling pathways. , 2006, Annual review of biochemistry.

[4]  T. Akiyama,et al.  The tumor suppressor LKB1 induces p21 expression in collaboration with LMO4, GATA-6, and Ldb1. , 2006, Biochemical and biophysical research communications.

[5]  J. Mester,et al.  p21WAF1/CIP1 Selectively Controls the Transcriptional Activity of Estrogen Receptor α , 2005, Molecular and Cellular Biology.

[6]  P. Marignani.  LKB1, the multitasking tumour suppressor kinase , 2004, Journal of Clinical Pathology.

[7]  A. Prescott,et al.  Analysis of the LKB1-STRAD-MO25 complex , 2004, Journal of Cell Science.

[8]  Lucia Altucci,et al.  Estrogens and Progesterone Promote Persistent CCND1 Gene Activation during G1 by Inducing Transcriptional Derepression via c-Jun/c-Fos/Estrogen Receptor (Progesterone Receptor) Complex Assembly to a Distal Regulatory Element and Recruitment of Cyclin D1 to Its Own Gene Promoter , 2004, Molecular and Cellular Biology.

[9]  C. Sherr,et al.  Principles of Tumor Suppression , 2004, Cell.

[10]  S. Gruber,et al.  Cyclooxygenase 2 expression and molecular alterations in Peutz-Jeghers hamartomas and carcinomas. , 2003, Clinical cancer research : an official journal of the American Association for Cancer Research.

[11]  T. Mäkelä,et al.  Growth arrest by the LKB1 tumor suppressor: induction of p21(WAF1/CIP1). , 2002, Human molecular genetics.

[12]  F. Kanai,et al.  LKB1 Associates with Brg1 and Is Necessary for Brg1-induced Growth Arrest* , 2001, The Journal of Biological Chemistry.

[13]  V. Rotter,et al.  Oncogenic mutations of the p53 tumor suppressor: the demons of the guardian of the genome. , 2000, Cancer research.

[14]  T. Mäkelä,et al.  Growth suppression by Lkb1 is mediated by a G(1) cell cycle arrest. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[15]  Frank McCormick,et al.  β-Catenin regulates expression of cyclin D1 in colon carcinoma cells , 1999, Nature.

[16]  P. Guldberg,et al.  Somatic mutation of the Peutz-Jeghers syndrome gene, LKB1/STK11, in malignant melanoma , 1999, Oncogene.

[17]  L. Aaltonen,et al.  LKB1 somatic mutations in sporadic tumors. , 1999, The American journal of pathology.

[18]  Y. Doki,et al.  Antisense to cyclin D1 inhibits the growth and tumorigenicity of human colon cancer cells. , 1997, Cancer research.

[19]  K. Kinzler,et al.  p21 is necessary for the p53-mediated G1 arrest in human cancer cells. , 1995, Cancer research.

[20]  James M. Roberts,et al.  Inhibitors of mammalian G1 cyclin-dependent kinases. , 1995, Genes & development.

[21]  P. Fisher,et al.  Cell cycle arrest. , 1995, Science.

[22]  Arnold J. Levine,et al.  The E6 oncoprotein encoded by human papillomavirus types 16 and 18 promotes the degradation of p53 , 1990, Cell.

[23]  Darryl Shibata,et al.  Localization of a susceptibility locus for Peutz-Jeghers syndrome to 19p using comparative genomic hybridization and targeted linkage analysis , 1997, Nature Genetics.