Hasan Kamrul, Cheung Caroline, Kaul Zeenia, Shah Navjot, Sakaushi Shinji, Sugimoto Kenji, Oka Shigenori, Kaul Sunil C, Wadhwa Renu
National Institute of Advanced Industrial Science & Technology (AIST), 1-1-1 Higashi, Tsukuba, Ibaraki 305-8562, Japan.
J Biol Chem. 2009 Jan 16;284(3):1664-72. doi: 10.1074/jbc.M805778200. Epub 2008 Nov 10.
The tumor suppressor protein, p53, is central to the pathways that monitor the stress, DNA damage repair, cell cycle, aging, and cancer. Highly complex p53 networks involving its upstream sensors and regulators, downstream effectors and regulatory feedback loops have been identified. CARF (Collaborator of ARF) was shown to enhance ARF-dependent and -independent wild-type p53 function. Here we report that (i) CARF overexpression causes premature senescence of human fibroblasts, (ii) it is vital for replicative and stress-induced senescence, and (iii) the lack of CARF function causes aneuploidy and apoptosis. We provide evidence that CARF plays a dual role in regulating p53-mediated senescence and apoptosis, the two major tumor suppressor mechanisms.
肿瘤抑制蛋白p53是监测应激、DNA损伤修复、细胞周期、衰老和癌症等通路的核心。现已确定了高度复杂的p53网络，其中涉及它的上游传感器和调节因子、下游效应器以及调节反馈环。CARF（ARF协同因子）被证明可增强ARF依赖性和非依赖性野生型p53功能。在此我们报告：（i）CARF过表达导致人成纤维细胞过早衰老；（ii）它对复制性衰老和应激诱导的衰老至关重要；（iii）CARF功能缺失会导致非整倍体和细胞凋亡。我们提供的证据表明，CARF在调节p53介导的衰老和凋亡这两种主要的肿瘤抑制机制中发挥双重作用。
