Regulatory Network of ARF in Cancer Development

Abstract

ARF is a tumor suppressor protein that has a pivotal role in the prevention of cancer development through regulating cell proliferation, senescence, and apoptosis. As a factor that induces senescence, the role of ARF as a tumor suppressor is closely linked to the p53-MDM2 axis, which is a key process that restrains tumor formation. Thus, many cancer cells either lack a functional ARF or p53, which enables them to evade cell oncogenic stress-mediated cycle arrest, senescence, or apoptosis. In particular, the ARF gene is a frequent target of genetic and epigenetic alterations including promoter hyper-methylation or gene deletion. However, as many cancer cells still express ARF, pathways that negatively modulate transcriptional or post-translational regulation of ARF could be potentially important means for cancer cells to induce cellular proliferation. These recent findings of regulators affecting ARF protein stability along with its low levels in numerous human cancers indicate the significance of an ARF post-translational mechanism in cancers. Novel findings of regulators stimulating or suppressing ARF function would provide new therapeutic targets to manage cancer- and senescence-related diseases. In this review, we present the current knowledge on the regulation and alterations of ARF expression in human cancers, and indicate the importance of regulators of ARF as a prognostic marker and in potential therapeutic strategies.

Keywords: ARF; E3 ligases; post-translational modification; transcriptional regulation; tumorigenesis.

Fig. 1. The INK4a/ARF/INK4b locus and tumor suppressive functions of ARF

The INK4a/ARF/INK4b locus encodes potent tumor suppressors including p15ink4b, p16ink4a and p14ARF. ARF stimulates cellular senescence and apoptosis through p53-dependent or -independent pathway, thus suppressing the tumor formation.

Fig. 2. Post-translational regulation of ARF

E3 ubiquitin ligases, SIVA1, MKRN1 and ULF induces ubiquitination dependent pro-teasomal degradation of ARF, which is reversed by deubiquitinase, USP10-mediated deubiquitination. CHIP and HSP90 cooperatively stimulates ubiquitin-independent lysosomal degradation of ARF.