Collaborator of ARF (CARF) Regulates Proliferative Fate of Human Cells by Dose-dependent Regulation of DNA Damage Signaling
Collaborator of ARF (CARF) Regulates Proliferative Fate of Human Cells by Dose-dependent Regulation of DNA Damage Signaling
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DOI：
10.1074/jbc.m114.547208
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发表时间：
2014-06-27
影响因子：
4.8
通讯作者：
Wadhwa, Renu
中科院分区：
文献类型：
--
作者：
Cheung, Caroline T.;Singh, Rumani;Wadhwa, Renu
ARF的合作者（CARF）已被证明直接结合并调节p53，p53是一种通过细胞衰老和凋亡控制肿瘤抑制的中心蛋白。然而，CARF的细胞功能及其对衰老、凋亡或增殖的作用机制仍不清楚。我们以前的研究表明，（i）CARF在复制和应激诱导的衰老过程中上调，其外源性过表达导致细胞衰老样生长停滞，（ii）CARF的抑制诱导非整倍体，DNA损伤和有丝分裂灾难，通过ATR/CHK 1途径导致细胞凋亡。在本研究中，我们通过研究CARF在体外和体内过表达引发的分子通路，剖析了CARF的细胞作用。我们发现CARF的剂量是决定癌细胞增殖潜力的关键因素。最令人惊讶的是，虽然中等水平的CARF过表达诱导衰老，但非常高水平的CARF导致细胞增殖增加。我们证明CARF的水平是至关重要的DNA损伤和细胞的检查点反应，通过ATM/CHK 1/CHK 2，p53和ERK途径，这反过来又决定了癌细胞的增殖命运向生长停滞或促增殖和恶性表型。据我们所知，这是第一份证明基础蛋白CARF在两个相反方向控制细胞增殖的能力的报告，因此可能在肿瘤生物学和癌症治疗中发挥关键作用。
Collaborator of ARF (CARF) has been shown to directly bind to and regulate p53, a central protein that controls tumor suppression via cellular senescence and apoptosis. However, the cellular functions of CARF and the mechanisms governing its effect on senescence, apoptosis, or proliferation are still unknown. Our previous studies have shown that (i) CARF is up-regulated during replicative and stress-induced senescence, and its exogenous overexpression caused senescence-like growth arrest of cells, and (ii) suppression of CARF induces aneuploidy, DNA damage, and mitotic catastrophe, resulting in apoptosis via the ATR/CHK1 pathway. In the present study, we dissected the cellular role of CARF by investigating the molecular pathways triggered by its overexpression in vitro and in vivo. We found that the dosage of CARF is a critical factor in determining the proliferation potential of cancer cells. Most surprisingly, although a moderate level of CARF overexpression induced senescence, a very high level of CARF resulted in increased cell proliferation. We demonstrate that the level of CARF is crucial for DNA damage and checkpoint response of cells through ATM/CHK1/CHK2, p53, and ERK pathways that in turn determine the proliferative fate of cancer cells toward growth arrest or proproliferative and malignant phenotypes. To the best of our knowledge, this is the first report that demonstrates the capability of a fundamental protein, CARF, in controlling cell proliferation in two opposite directions and hence may play a key role in tumor biology and cancer therapeutics.