Molecular mechanism of cell senescence

细胞衰老的分子机制

• 批准号: 11557121
• 负责人: WAKE Norio
• 金额: $ 8.64万
• 依托单位: KYUSHU UNIVERSITY
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (B)
• 财政年份: 1999
• 资助国家: 日本
• 起止时间: 1999 至 2001
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-11557121/
• 关键词: Senescence gene; 1q42 and 7q11; [12Val] K-Ras; ER α; p14ARF; MDM2; p53; Cell senescence; HDAC; Molecular target therapy; ERドミナント・ネガティブ; p21; 細胞老化; Chromosome 1; Chromosome 7; gene cloning; Endometrial Cancer; Choriocarcinoma; Senescence

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.

本研究探讨了加速细胞衰老的机制及其在肿瘤分子靶向治疗中的应用。[12Val]K-RAS(K12V细胞)激活后，ERα激活了其转录活性，促进了NIH3T3细胞的转化。显性负性ER表达导致K12V细胞衰老。MDM2的下调与p21CDK抑制剂通过p53的稳定上调相对应，参与了该细胞的衰老诱导。NIH3T3细胞ER MDM2c DNA表达上调α的表达。显性阴性ER和c-jun的共同表达恢复了K12V细胞MDM2的表达。这些数据表明K-RAS/ERα/mdm2/p53信号转导通路参与了细胞衰老的调控。诱导细胞衰老的候选基因分别来自1q42和7q11区域。目前，我们正在通过转染子宫内膜癌和绒毛膜癌细胞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，通过非依赖于P53的p21上调，在几个pRb蛋白完整的癌细胞中诱导G0/G1期停滞和随后的细胞衰老。反过来，NAB抑制了G0/G1和G2/M期pRB失活的宫颈癌，并诱导了细胞衰老。因此，NAB诱导细胞衰老不依赖于pRB。NAB上调了p21下游的ECM及其受体。

项目成果

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