Molecular mechanism of cell senescence

本研究探讨了细胞加速衰老的机制及其在肿瘤分子靶向治疗中的应用。ER α通过激活[12Val] K-Ras （K12V细胞）激活其转录活性，促进NIH3T3细胞的转化。ER的显性阴性表达导致K12V细胞衰老。MDM2的下调与p21 CDK抑制剂的上调相对应，通过稳定p53参与了细胞衰老的诱导。NIH3T3细胞ER α cDNA表达上调MDM2表达。显性阴性ER和c-Jun的共表达恢复了K12V细胞中MDM2的表达。这些数据提示K-Ras/ER α/MDM2/p53信号通路参与细胞衰老的调控。诱导细胞衰老的候选基因分别来自1q42和7q11区域。目前，我们正通过转染子宫内膜癌和绒毛膜癌细胞系来研究这些基因的生物学活性。丁酸钠（NaB）是一种有效的HDAC抑制剂，通过p53独立的p21上调，在几种pRb蛋白完整的癌细胞中引发G0/G1阻滞和随后的细胞衰老。反过来，NaB抑制G0/G1和G2/M不活跃的pRb，并诱导细胞衰老。因此，NaB诱导细胞衰老是不依赖于pRb的。NaB上调p21下游的ECM及其受体。

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.