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Biomolecules 2019, 9(3), 87;

Dual Role of the Alternative Reading Frame ARF Protein in Cancer

Department of Pharmacology, Moores Cancer Center, University of California, San Diego, La Jolla, CA 92093, USA
Division of Hematology and Medical Oncology, Laura and Isaac Perlmutter Cancer Center, NYU Langone Medical Center, New York, NY 10016, USA
Department of Biology, University of Naples Federico II, 80126 Naples, Italy
Author to whom correspondence should be addressed.
Contributed equally to this manuscript.
Received: 11 December 2018 / Revised: 20 February 2019 / Accepted: 22 February 2019 / Published: 4 March 2019
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The CDKN2a/ARF locus expresses two partially overlapping transcripts that encode two distinct proteins, namely p14ARF (p19Arf in mouse) and p16INK4a, which present no sequence identity. Initial data obtained in mice showed that both proteins are potent tumor suppressors. In line with a tumor-suppressive role, ARF-deficient mice develop lymphomas, sarcomas, and adenocarcinomas, with a median survival rate of one year of age. In humans, the importance of ARF inactivation in cancer is less clear whereas a more obvious role has been documented for p16INK4a. Indeed, many alterations in human tumors result in the elimination of the entire locus, while the majority of point mutations affect p16INK4a. Nevertheless, specific mutations of p14ARF have been described in different types of human cancers such as colorectal and gastric carcinomas, melanoma and glioblastoma. The activity of the tumor suppressor ARF has been shown to rely on both p53-dependent and independent functions. However, novel data collected in the last years has challenged the traditional and established role of this protein as a tumor suppressor. In particular, tumors retaining ARF expression evolve to metastatic and invasive phenotypes and in humans are associated with a poor prognosis. In this review, the recent evidence and the molecular mechanisms of a novel role played by ARF will be presented and discussed, both in pathological and physiological contexts. View Full-Text
Keywords: tumor suppression; autophagy; anoikis; CDKN2a/ARF locus; chemoresistance; FAK sumoylation; actin cytoskeleton tumor suppression; autophagy; anoikis; CDKN2a/ARF locus; chemoresistance; FAK sumoylation; actin cytoskeleton

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Fontana, R.; Ranieri, M.; La Mantia, G.; Vivo, M. Dual Role of the Alternative Reading Frame ARF Protein in Cancer. Biomolecules 2019, 9, 87.

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