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Implication of p53-dependent cellular senescence related gene, TARSH in tumor suppression

2009; Elsevier BV; Volume: 380; Issue: 4 Linguagem: Inglês

10.1016/j.bbrc.2009.01.171

1090-2104

Takeshi Wakoh, Natsuko Uekawa, Kunihiko Terauchi, Masataka Sugimoto, Akihito Ishigami, Junichi Shimada, Mitsuo Maruyama,

Cancer-related Molecular Pathways

A novel target of NESH-SH3 (TARSH) was identified as a cellular senescence related gene in mouse embryonic fibroblasts (MEFs) replicative senescence, the expression of which has been suppressed in primary clinical lung cancer specimens. However, the molecular mechanism underlying the regulation of TARSH involved in pulmonary tumorigenesis remains unclear. Here we demonstrate that the reduction of TARSH gene expression by short hairpin RNA (shRNA) system robustly inhibited the MEFs proliferation with increase in senescence-associated β-galactosidase (SA-β-gal) activity. Using p53−/− MEFs, we further suggest that this growth arrest by loss of TARSH is evoked by p53-dependent p21Cip1 accumulation. Moreover, we also reveal that TARSH reduction induces multicentrosome in MEFs, which is linked in chromosome instability and tumor development. These results suggest that TARSH plays an important role in proliferation of replicative senescence and may serve as a trigger of tumor development.