Abstract
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.
Highlights
Regarding its established role in cancer biology, ARF was identified as a second line of defense against cancer following DNA damage response, with a higher threshold of oncogenic signals being potentially required for its activation [12]
Given that RASSF1A is actively involved in YAP–p73-mediated apoptosis, ARF suppression by Ataxia Telangiectasia Mutated (ATM) may be a mechanism employed by cells to prevent ARF-mediated YAP inactivation, a meaningful scenario at least in the case of p53-deficient tumors
We sought to summarize key findings regarding non-canonical roles of ARF signaling in cancer and developmental biology
Summary
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations. The CDKN2A locus which is found on human chromosome 9p21 encodes two overlapping transcripts that produce two different proteins, p16INK4a and p14ARF (ARF) [1], both of which are established tumor suppressors. Studies on the role of ARF in response to DNA damage had originally dismissed its contribution [10,11], mainly on account of the fact that p53 could still become activated. Biomolecules 2021, 11, 86 in the absence of ARF, which was elevated in response to oncogenic stimuli These initial studies considered the DNA damage and oncogenic response as separate processes with different mediators and outcomes. Regarding its established role in cancer biology, ARF was identified as a second line of defense against cancer following DNA damage response, with a higher threshold of oncogenic signals being potentially required for its activation [12]. We aim to underline the interplay between ARF and key signaling pathways regulating major aspects of both cancer and stem cell biology
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