BRCA1-IRIS过表达在野生型p53细胞中诱导乳腺癌发生。
Induction of breast cancer in wild type p53 cells by BRCA1-IRIS overexpression.
作者信息
Elshamy Wael M
机构信息
Cancer Research Center of Hawaii, University of Hawaii, Honolulu, Hawaii 96813, USA.
出版信息
Hawaii Med J. 2010 Aug;69(8):200-1.
Cells ability to evade cell death and to proliferate post geno-/cell-toxic stresses, likely leads to formation of cancer. Activation of p38MAPK and p53 following these stresses help protect cells against cancer development by initiating apoptosis. The duration of p38MAPK and p53 activation is regulated by the WIP1 phosphatase. BRCA1-IRIS triggers WIP1 expression in p53-dependent and -independent manner. BRCA1-IRIS triggers the expression and cytoplasmic localization of the mRNA stabilization and translation inducer, HuR that binds p53 and PPM1D mRNA. Hence, BRCA1-IRIS overexpression inactivates p38MAPK and/or p53 by upregulating WIP1 expression. BRCA1-IRIS abrogation of the homeostatic balance maintained by p38MAPK-p53-WIP1 pathway suppressed cell death induced by a lethal dose of UVC, high dosages of etoposide or H2O2, and allowed cells to survive and proliferate post geno-/cell-toxic stresses. This mechanism represents a new link between geno-/cell-toxic stress and aggressive breast cancer formation in p53 wild-type cells.
细胞逃避细胞死亡并在基因/细胞毒性应激后增殖的能力，可能会导致癌症的形成。这些应激后p38丝裂原活化蛋白激酶（p38MAPK）和p53的激活通过启动细胞凋亡来帮助保护细胞免受癌症发展的影响。p38MAPK和p53激活的持续时间由WIP1磷酸酶调节。BRCA1-IRIS以p53依赖性和非依赖性方式触发WIP1表达。BRCA1-IRIS触发与p53和PPM1D mRNA结合的mRNA稳定化和翻译诱导剂HuR的表达及细胞质定位。因此，BRCA1-IRIS的过表达通过上调WIP1表达使p38MAPK和/或p53失活。BRCA1-IRIS破坏了由p38MAPK-p53-WIP1途径维持的稳态平衡，抑制了致死剂量的紫外线C（UVC）、高剂量的依托泊苷或过氧化氢诱导的细胞死亡，并使细胞在基因/细胞毒性应激后存活和增殖。这种机制代表了基因/细胞毒性应激与p53野生型细胞中侵袭性乳腺癌形成之间的新联系。
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