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对激活的[12 Val] K-Ras（K12 V细胞）有转录激活作用，并参与NIH 3 T3细胞的转化。显性负性ER表达诱导K12 V细胞衰老。MDM 2的下调对应于p21 CDK抑制剂通过p53稳定的上调参与了该细胞衰老诱导。在NIH 3 T3细胞中ER α cDNA表达上调MDM 2表达。显性阴性ER和c-Jun的共表达恢复了K12 V细胞中MDM 2的表达。这些数据暗示K-Ras/ER α/MDM 2/p53信号传导在细胞衰老的调节中.细胞衰老诱导候选基因分别来自1 q42和7 q11区域。目前，我们正在通过对子宫内膜癌和绒毛膜癌细胞系的检测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非依赖性p21上调，在几种具有完整pRb蛋白的癌细胞中引起G 0/G1停滞和随后的细胞衰老。反过来，NaB使pRb失活的宫颈癌细胞停滞在G 0/G1和G2/M期，并诱导细胞衰老。因此，NaB诱导的细胞衰老不依赖于pRb。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.