Suppression of RAD21 induces senescence of MDA-MB-231 human breast cancer cells through RB1 pathway activation via c-Myc downregulation.
Suppression of RAD21 induces senescence of MDA-MB-231 human breast cancer cells through RB1 pathway activation via c-Myc downregulation.
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抑制 RAD21 通过 c-Myc 下调激活 RB1 通路诱导 MDA-MB-231 人乳腺癌细胞衰老
DOI：
10.1002/jcb.25426
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发表时间：
2016
影响因子：
4
通讯作者：
Zhang Yu
中科院分区：
文献类型：
--
作者：
Zhu Shan;Zhao Li;Li Yueyang;Hou Pingfu;Yao Ruosi;Tan Jiang;Liu Dongxu;Han Liping;Huang Baiqu;Lu Jun;Zhang Yu
细胞衰老通过限制不受控制的细胞增殖来阻止癌症进展。为了鉴定控制衰老的新遗传事件，我们进行了小干扰RNA筛选人类癌细胞，并鉴定了一些可能参与MDA-MB-231人类乳腺癌细胞衰老的靶点。重要的是，我们发现敲低RAD 21导致几种衰老标记物的出现，包括增强的衰老相关β-半乳糖苷酶活性和异染色质病灶形成，以及升高的p21蛋白水平和RB 1通路激活。进一步的生物化学分析显示，RAD 21敲低导致c-Myc及其靶点下调，包括RB 1的负调节因子CDK 4和阻断RB 1磷酸化（pRB 1），以及RB 1介导的E2 F转录抑制。此外，c-Myc下调部分由早幼粒细胞白血病（PML）核小体内的蛋白酶体依赖性降解介导，发现在RAD 21敲低诱导的衰老期间，这些核小体高度丰富。外源性c-Myc重建拯救细胞免于RAD 21沉默诱导的衰老。总而言之，本研究产生的数据暗示了RAD 21在MDA-MB-231细胞中的细胞衰老中的新功能，其主要依赖于通过c-Myc下调的RB 1途径激活。J.细胞。117：1359-1369，2016.© 2015威利期刊公司.
Cellular senescence impedes cancer progression by limiting uncontrolled cell proliferation. To identify new genetic events controlling senescence, we performed a small interfering RNA screening human cancer cells and identified a number of targets potentially involved in senescence of MDA‐MB‐231 human breast cancer cells. Importantly, we showed that knockdown of RAD21 resulted in the appearance of several senescent markers, including enhanced senescence‐associated β‐galactosidase activity and heterochromatin focus formation, as well as elevated p21 protein levels and RB1 pathway activation. Further biochemical analyses revealed that RAD21 knockdown led to the downregulation of c‐Myc and its targets, including CDK4, a negative regulator of RB1, and blockedRB1 phosphorylation (pRB1), and the RB1‐mediated transcriptional repression of E2F. Moreover, c‐Myc downregulation was partially mediated by proteasome‐dependent degradation within promyelocytic leukemia (PML) nuclear bodies, which were found to be highly abundant during RAD21 knockdown‐induced senescence. Exogenous c‐Myc reconstitution rescued cells from RAD21 silencing‐induced senescence. Altogether, data arising from this study implicate a novel function of RAD21 in cellular senescence in MDA‐MB‐231 cells that is mainly dependent onRB1 pathway activation via c‐Myc downregulation. J. Cell. Biochem. 117: 1359–1369, 2016. © 2015 Wiley Periodicals, Inc.