Sherr C J, Bertwistle D, DEN Besten W, Kuo M-L, Sugimoto M, Tago K, Williams R T, Zindy F, Roussel M F
Howard Hughes Medical Institute, St. Jude Children's Research Hospital, Memphis, Tennessee 38105, USA.
Cold Spring Harb Symp Quant Biol. 2005;70:129-37. doi: 10.1101/sqb.2005.70.004.
The Ink4a-Arf locus encodes two closely wedded tumor suppressor proteins (p16(Ink4a) and p19(Arf)) that inhibit cell proliferation by activating Rb and p53, respectively. With few exceptions, the Arf gene is repressed during mouse embryonic development, thereby helping to limit p53 expression during organogenesis. However, in adult mice, sustained hyperproliferative signals conveyed by somatically activated oncogenes can induce Arf gene expression and trigger a p53 response that eliminates incipient cancer cells. Disruption of this tumor surveillance pathway predisposes to cancer, and inactivation of INK4a- ARF by deletion, silencing, or mutation has been frequently observed in many forms of human cancer. Although it is accepted that much of Arf's tumor-suppressive activity is mediated by p53, more recent genetic evidence has pointed to additional p53- independent functions of Arf, including its ability to inhibit gene expression by a number of other transcription factors. Surprisingly, the enforced expression of Arf in mammalian cells promotes the sumoylation of several Arf-interacting proteins, implying that Arf has an associated catalytic activity. We speculate that transcriptional down-regulation in response to Arf-induced sumoylation may account for Arf's p53-independent functions.
Ink4a-Arf基因座编码两种紧密相连的肿瘤抑制蛋白（p16(Ink4a)和p19(Arf)），它们分别通过激活Rb和p53来抑制细胞增殖。除了少数例外情况，Arf基因在小鼠胚胎发育过程中受到抑制，从而有助于在器官发生过程中限制p53的表达。然而，在成年小鼠中，由体细胞激活的癌基因传递的持续过度增殖信号可诱导Arf基因表达并触发p53反应，从而消除初期癌细胞。这种肿瘤监测途径的破坏易引发癌症，并且在许多形式的人类癌症中经常观察到INK4a-ARF因缺失、沉默或突变而失活。尽管人们普遍认为Arf的许多肿瘤抑制活性是由p53介导的，但最近的遗传学证据表明Arf还具有其他独立于p53的功能，包括其通过许多其他转录因子抑制基因表达的能力。令人惊讶的是，在哺乳动物细胞中强制表达Arf会促进几种与Arf相互作用的蛋白的SUMO化，这意味着Arf具有相关的催化活性。我们推测，对Arf诱导的SUMO化作出反应的转录下调可能解释了Arf独立于p53的功能。
