SnoN functions as a tumour suppressor by inducing premature senescence.
SnoN represses TGF-beta signalling to promote cell proliferation and has been defined as a proto-oncogene partly due to its elevated expression in many human cancer cells. Although the anti-tumourigenic activity of SnoN has been suggested, the molecular basis for this has not been defined. We showed here that high levels of SnoN exert anti-oncogenic activity by inducing senescence. SnoN interacts with the promyelocytic leukaemia (PML) protein and is recruited to the PML nuclear bodies where it stabilizes p53, leading to premature senescence. Furthermore, overexpression of SnoN inhibits oncogenic transformation induced by Ras and Myc in vitro and significantly blocks papilloma development in vivo in a carcinogen-induced skin tumourigenesis model. The few papillomas that were developed displayed high levels of senescence and spontaneously regressed. Our study has revealed a novel Smad-independent pathway of SnoN function that mediates its anti-oncogenic activity.
Pan
Deng
D
Department of Molecular and Cell Biology, University of California, Berkeley, CA, USA.
Zhu
Qingwei
Q
Luo
Kunxin
K
D000818:Animals; D002273:Carcinogens; D002471:Cell Transformation, Neoplastic / Q000235:genetics; D002478:Cells, Cultured; D016922:Cellular Senescence / Q000235:genetics*; D055879:Gene Knock-In Techniques; D016147:Genes, Tumor Suppressor / Q000502:physiology*; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008954:Models, Biological; D050505:Mutant Proteins / Q000235:genetics / Q000502:physiology; D010212:Papilloma / Q000139:chemically induced / Q000235:genetics; D000090063:Proto-Oncogene Mas; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000502:physiology*; D012878:Skin Neoplasms / Q000139:chemically induced / Q000235:genetics; D013997:Time Factors
D002273:Carcinogens; C000715470:MAS1 protein, human; D050505:Mutant Proteins; D000090063:Proto-Oncogene Mas; D011518:Proto-Oncogene Proteins; C486157:Skil protein, mouse