Non-Canonical Functions of the ARF Tumor Suppressor in Development and Tumorigenesis

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.

Automated summary

P14ARF is a well-characterized tumor suppressor involved in regulating cell cycle arrest and apoptosis in response to oncogenic stimuli. It is frequently lost through methylation in a variety of human malignancies and has been linked to melanomas and glioblastomas through mutations and deletions. In addition to its role in tumorigenesis, P14ARF is also involved in developmental processes such as spermatogenesis, mammary gland development, ocular development, and angiogenesis.