DBT-AIST International Laboratory for Advanced Biomedicine (DAILAB), National Institute of Advanced Industrial Science and Technology (AIST), Central 5-41, 1-1-1 Higashi, Tsukuba, Ibaraki, 305 8565 Japan.
DBT-AIST International Laboratory for Advanced Biomedicine (DAILAB), National Institute of Advanced Industrial Science and Technology (AIST), Central 5-41, 1-1-1 Higashi, Tsukuba, Ibaraki, 305 8565 Japan.
Mech Ageing Dev. 2017 Sep;166:64-68. doi: 10.1016/j.mad.2017.07.008. Epub 2017 Jul 25.
CARF (Collaborator of ARF) was first identified as an ARF (Alternative Reading Frame, p14ARF)-interacting protein in a yeast two-hybrid interactive screening. Subsequently, it was shown to stabilize the p53-tumor suppressor protein in an ARF-dependent or -independent manner. It acts as a transcriptional repressor of HDM2 that exerts a negative feedback on p53 by its proteasomal-mediated degradation. CARF-driven control over p53-HDM2-p21 axis was shown to regulate cell proliferative fates. Cells with CARF-overexpression (CARF-OE) and superexpression (CARF-SE) showed growth arrest and pro-proliferative phenotypes, respectively. On the other hand, apoptosis was triggered in CARF-compromised cells. In the present review, we provide a comprehensive current understanding into the molecular mechanisms of CARF functions in regulation of DNA damage response, cell cycle checkpoints, cell survival and death signaling pathways. We discuss how thresh-hold of CARF level determines fate of cells to senescence and malignant transformation.
CARF（ARF 的合作者）最初在酵母双杂交互作筛选中被鉴定为 ARF（Alternative Reading Frame，p14ARF）相互作用蛋白。随后，研究表明它以 ARF 依赖或非依赖的方式稳定 p53 肿瘤抑制蛋白。它作为 HDM2 的转录抑制剂，通过其蛋白酶体介导的降解对 p53 产生负反馈。CARF 对 p53-HDM2-p21 轴的驱动控制被证明可以调节细胞增殖命运。过表达 CARF（CARF-OE）和超表达 CARF（CARF-SE）的细胞分别表现出生长停滞和促增殖表型，而 CARF 功能受损的细胞则触发凋亡。在本综述中，我们提供了对 CARF 功能在调节 DNA 损伤反应、细胞周期检查点、细胞存活和死亡信号通路中的分子机制的全面理解。我们讨论了 CARF 水平的阈值如何决定细胞衰老和恶性转化的命运。
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