P14ARF (ARF; Alternative Reading Frame) is an extensively characterized tumor suppressor which, in response to oncogenic stimuli, mediates cell cycle arrest and apoptosis via p53-dependent and independent routes. ARF has been shown to be frequently lost through CpG island promoter methylation in a wide spectrum of human malignancies, such as colorectal, prostate, breast, and gastric cancers, while point mutations and deletions in the p14ARF locus have been linked with various forms of melanomas and glioblastomas. Although ARF has been mostly studied in the context of tumorigenesis, it has been also implicated in purely developmental processes, such as spermatogenesis, and mammary gland and ocular development, while it has been additionally involved in the regulation of angiogenesis. Moreover, ARF has been found to hold important roles in stem cell self-renewal and differentiation. As is often the case with tumor suppressors, ARF functions as a pleiotropic protein regulating a number of different mechanisms at the crossroad of development and tumorigenesis. Here, we provide an overview of the non-canonical functions of ARF in cancer and developmental biology, by dissecting the crosstalk of ARF signaling with key oncogenic and developmental pathways.

中文翻译：

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ARF肿瘤抑制因子在发育和肿瘤发生中的非典型功能

P14ARF（ARF;替代阅读框）是一个广泛表征的肿瘤抑制因子，它响应致癌性刺激，通过p53依赖性和独立途径介导细胞周期停滞和凋亡。在大范围的人类恶性肿瘤中，例如大肠癌，前列腺癌，乳腺癌和胃癌，ARF经常通过CpG岛启动子甲基化而丢失，而p14ARF基因座中的点突变和缺失与各种形式的黑色素瘤有关和胶质母细胞瘤。尽管ARF大多是在肿瘤发生的背景下进行研究的，但它也已经涉及到精子发生，乳腺和眼部发育等纯粹的发育过程，同时它还参与了血管生成的调控。此外，已发现ARF在干细胞自我更新和分化中起重要作用。就像抑癌药一样，ARF发挥多效性蛋白的作用，在发育和肿瘤发生的十字路口调节许多不同的机制。在这里，我们通过剖析ARF信号与关键致癌和发育途径的串扰，概述了ARF在癌症和发育生物学中的非经典功能。