Abstract
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.
Highlights
The cyclin-dependent kinase inhibitor 2A (CDKN2a) locus—frequently mutated or deleted in human cancer—encodes two different tumor suppressors, INK4a and ARF [1,2]
Active epidermalsite growth factor receptor (EGFR) interacts with VPS34, which moves to the nucleus, inhibiting ARF expression via binding to the AT-rich sequence of the ARF promoter
chromobox protein homolog 7 (CBX7)-induced suppression of ARF and INK4a expression occurs in a BMI-1-independent manner, suggesting that CBX7 may repress ARF and INK4a transcription by interacting with another polycomb-repressive complex-1 (PRC1) subset, but not with BMI-1
Summary
The cyclin-dependent kinase inhibitor 2A (CDKN2a) locus—frequently mutated or deleted in human cancer—encodes two different tumor suppressors, INK4a (referred to as p16INK4a ) and ARF (referred to as p14ARF in humans and p19ARF in mice) [1,2]. E3 ligase for tetrameric p53, ARF-induced sequestration and inhibition preventsof inducesisthe formation of p53 complexes MDM2 in the nucleus, thereby activating the expression ubiquitination proteasome-dependent degradation of ARF p53, involvement resulting in p53 stabilization [9,10]. In MDM2 sequestration p53 accumulation induces the formation of p53 tetrameric complexes in the nucleus, thereby and the p53 axis has been considered a major part of the tumor-suppressive function of ARF; activating expression ofroles genes related cycle arrest or apoptosisof ARF inhibits E2F transcriptional activity by binding to E2F, thereby inducing cell cycle interactions of ARF various proteins with celltranslocation proliferationtoand fromby arrest [11,12,13,14]. This review focused on the newly extended regulatory network of ARF and its therapeutic implications in cancer
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