Molecular mechanism of cell senescence

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The present study investigated accelerated cell senescence mechanism and its application to molecular target therapy for cancers.1. ER α activated its transcriptional activity in response to the activated [12Val] K-Ras (K12V cells) and contributed to the NIH3T3 cell transformation. Dominant-negative ER expression resulted in the induction of senescence of K12V cells. Downregulation of MDM2 corresponded to the upregulation of p21 CDK inhibitor through p53 stabilization was involved in this cell senescence induction. ER α cDNA expression in NIH3T3 cells upregulated MDM2 expression. Co-expression of dominant-negative ER and c-Jun restored the MDM2 expression in K12V cells. The data implicate K-Ras/ER α/MDM2/p53 signalling in the regulation of cell senescence.2. Cell senescence inducting candidate genes have been from 1q42 and 7q11 regions, respectively. Now, we are investigating biological activities of these genes by transfecting endometrial cancer and choriocarcinoma cell lines.3. Sodium Butyrate (NaB) that is a potent HDAC inhibitor elicited the G0/G1 arrest and subsequent cell senescence in several cancer cells with intact pRb protein through p53 independent p21 upregulation. In turn, NaB arrested cervical cancer with inactive pRb both G0/G1 and G2/M and induced cell senescence. Thus, cell senescence induction by NaB is pRb independent. NaB upregulated ECM and its receptors downstream of p21.