The RASSF1A tumor suppressor blocks cell cycle progression and inhibits cyclin D1 accumulation.
The RASSF1A locus at 3p21.3 is epigenetically inactivated at high frequency in a variety of solid tumors. Expression of RASSF1A is sufficient to revert the tumorigenicity of human cancer cell lines. We show here that RASSF1A can induce cell cycle arrest by engaging the Rb family cell cycle checkpoint. RASSF1A inhibits accumulation of native cyclin D1, and the RASSF1A-induced cell cycle arrest can be relieved by ectopic expression of cyclin D1 or of other downstream activators of the G(1)/S-phase transition (cyclin A and E7). Regulation of cyclin D1 is responsive to native RASSF1A activity, because RNA interference-mediated downregulation of endogenous RASSF1A expression in human epithelial cells results in abnormal accumulation of cyclin D1 protein. Inhibition of cyclin D1 by RASSF1A occurs posttranscriptionally and is likely at the level of translational control. Rare alleles of RASSF1A, isolated from tumor cell lines, encode proteins that fail to block cyclin D1 accumulation and cell cycle progression. These results strongly suggest that RASSF1A is an important human tumor suppressor protein acting at the level of G(1)/S-phase cell cycle progression.
Shivakumar
Latha
L
Department of Cell Biology, UT Southwestern Medical Center, Dallas, Texas 75390-9039, USA.
Minna
John
J
Sakamaki
Toshiyuki
T
Pestell
Richard
R
White
Michael A
MA
D000818:Animals; D001665:Binding Sites; D002453:Cell Cycle / Q000235:genetics*; D019938:Cyclin D1 / Q000235:genetics / Q000378:metabolism*; D005347:Fibroblasts; D016193:G1 Phase / Q000235:genetics; D016147:Genes, Tumor Suppressor; D006801:Humans; D051379:Mice; D009154:Mutation; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism*; D009856:Oncogene Proteins, Viral / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation; D011401:Promoter Regions, Genetic; D011494:Protein Kinases / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D016160:Retinoblastoma Protein / Q000378:metabolism; D058570:TOR Serine-Threonine Kinases; D014407:Tumor Cells, Cultured; D025521:Tumor Suppressor Proteins; D018631:ras Proteins / Q000235:genetics / Q000378:metabolism
D009363:Neoplasm Proteins; D009856:Oncogene Proteins, Viral; C411762:RASSF1 protein, human; D012333:RNA, Messenger; D016160:Retinoblastoma Protein; D025521:Tumor Suppressor Proteins; D019938:Cyclin D1; D011494:Protein Kinases; C546842:MTOR protein, human; C546843:mTOR protein, mouse; D058570:TOR Serine-Threonine Kinases; D018631:ras Proteins