National Institute of Advanced Industrial Science & Technology, Ibaraki, Japan.
Ann N Y Acad Sci. 2010 Jun;1197:129-33. doi: 10.1111/j.1749-6632.2009.05392.x.
Collaborator of ARF (CARF) was first cloned as an ARF partner in yeast two-hybrid screens. It enhances ARF-dependent and -independent p53 functions, which are central to the control of cell growth and tumor suppression in human cells. CARF interacts with ARF, p53, and MDM2 proteins, and in turn gets regulated by MDM2-mediated degradation, suggesting a self-regulatory loop. CARF is upregulated during replicative, oncogenic, and stress-induced senescence. Overexpression of CARF induced premature senescence in normal human fibroblasts that was mediated by upregulation of p53-p21(CIP1/WAF1) and p16(INK4a)- pRB pathways. Knockdown of CARF resulted in mitotic arrest leading to excessive chromosomal condensation, aneuploidy, and apoptosis, suggesting that CARF is essential for cell survival. Most recently, we have found that CARF causes bidirectional regulation of p53 and pRB pathways, either arresting or promoting growth, and thus, it could be a potential threshold link between aging and cancer.
ARF 的合作者（CARF）最初在酵母双杂交筛选中被克隆为 ARF 伴侣。它增强了 ARF 依赖和非依赖的 p53 功能，这对于控制人类细胞的细胞生长和肿瘤抑制至关重要。CARF 与 ARF、p53 和 MDM2 蛋白相互作用，并反过来受到 MDM2 介导的降解的调节，表明存在一个自我调节环。CARF 在复制、致癌和应激诱导的衰老过程中上调。CARF 的过表达在正常人类成纤维细胞中诱导过早衰老，这是通过 p53-p21(CIP1/WAF1)和 p16(INK4a)-pRB 途径的上调介导的。CARF 的敲低导致有丝分裂 arrest，导致染色体过度浓缩、非整倍体和细胞凋亡，表明 CARF 对于细胞存活是必需的。最近，我们发现 CARF 对 p53 和 pRB 途径进行双向调节，要么 arrest 生长，要么促进生长，因此，它可能是衰老和癌症之间的潜在阈值联系。
