Tumorigenesis can be induced by various stresses that cause aberrant DNA mutations and unhindered cell proliferation. Under such conditions, normal cells autonomously induce defense mechanisms, thereby stimulating tumor suppressor activation. ARF, encoded by the CDKN2a locus, is one of the most frequently mutated or deleted tumor suppressors in human cancer. The safeguard roles of ARF in tumorigenesis are mainly mediated via the MDM2-p53 axis, which plays a prominent role in tumor suppression. Under normal conditions, low p53 expression is stringently regulated by its target gene, MDM2 E3 ligase, which induces p53 degradation in a ubiquitin-proteasome-dependent manner. Oncogenic signals induced by MYC, RAS, and E2Fs trap MDM2 in the inhibited state by inducing ARF expression as a safeguard measure, thereby activating the tumor-suppressive function of p53. In addition to the MDM2-p53 axis, ARF can also interact with diverse proteins and regulate various cellular functions, such as cellular senescence, apoptosis, and anoikis, in a p53-independent manner. As the evidence indicating ARF as a key tumor suppressor has been accumulated, there is growing evidence that ARF is sophisticatedly fine-tuned by the diverse factors through transcriptional and post-translational regulatory mechanisms. In this review, we mainly focused on how cancer cells employ transcriptional and post-translational regulatory mechanisms to manipulate ARF activities to circumvent the tumor-suppressive function of ARF. We further discussed the clinical implications of ARF in human cancer.

中文翻译：

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ARF的翻译后调节：癌症的观点。

可以通过引起异常DNA突变和不受阻碍的细胞增殖的各种压力诱导成瘤。在这种情况下，正常细胞可以自主诱导防御机制，从而刺激肿瘤抑制因子的激活。ARF，由CDKN2a编码基因座是人类癌症中最常见的突变或缺失的抑癌基因之一。ARF在肿瘤发生中的保护作用主要是通过MDM2-p53轴介导的，在肿瘤抑制中起着重要作用。在正常情况下，低p53表达受其靶基因MDM2 E3连接酶严格调节，该酶以泛素-蛋白酶体依赖性方式诱导p53降解。MYC，RAS和E2F诱导的致癌信号通过诱导ARF表达作为一种保护措施，将MDM2捕获在抑制状态，从而激活p53的肿瘤抑制功能。除MDM2-p53轴外，ARF还可以与p53无关的方式与多种蛋白质相互作用，并调节各种细胞功能，例如细胞衰老，凋亡和无神经。随着越来越多的证据表明ARF是关键的肿瘤抑制因子，越来越多的证据表明ARF已通过转录和翻译后调控机制被多种因素精细地微调。在这篇综述中，我们主要关注癌细胞如何利用转录和翻译后调控机制来操纵ARF活性来规避ARF的肿瘤抑制功能。我们进一步讨论了ARF在人类癌症中的临床意义。我们主要关注癌细胞如何利用转录和翻译后调控机制来操纵ARF活性来规避ARF的肿瘤抑制功能。我们进一步讨论了ARF在人类癌症中的临床意义。我们主要关注癌细胞如何利用转录和翻译后调控机制来操纵ARF活性来规避ARF的肿瘤抑制功能。我们进一步讨论了ARF在人类癌症中的临床意义。