Journal Article

Mimicking p14ARF Phosphorylation Influences Its Ability to Restrain Cell Proliferation

Santoriello, Cristina, Sansone, Federica, Calogero, Raffaele A., Calabrò, Viola, La Mantia, Girolama, Pollice, Alessandra, Ranieri, Michela, Vivo, Maria

2013

Overview

The INK4a/ARF locus on the short arm of chromosome 9 is one of the most frequently altered loci in human cancer. It is generally accepted that ARF is involved in oncogenic checkpoint pathways by sensitizing incipient cancer cells to undergo growth arrest or apoptosis through both p53-dependent and independent pathways. While intensive studies have been focused on ARF activation at the transcriptional level, only recently mechanisms governing ARF turnover have been identified. Here, we show for the first time that p14ARF is a PKC target. Prediction analysis showed many potential phosphorylation sites in PKC consensus sequences within ARF protein, and, among them, the threonine at position 8 was the most conserved. Substitution of this threonine influences both ARF stability and localization. Furthermore, a phosphomimetic ARF mutation reduces the ability to arrest cell growth although the ability to bind MDM2 and stabilize p53 result unaffected. Thus we propose that phosphorylation of ARF in both immortalized and tumor cell lines could be a mechanism to escape ARF surveillance following proliferative and oncogenic stress.

• Publisher: Public Library of Science,Public Library of Science (PLoS)
• Subject: Amino acids / Apoptosis / ARF protein / Biology / Cancer / Cell cycle / Cell Cycle Checkpoints - genetics / Cell growth / Cell Line, Tumor / Cell Proliferation / Cell Transformation, Neoplastic - genetics / Cell Transformation, Neoplastic - metabolism / Chromosome 9 / Cyclin-dependent kinase inhibitors / Gene Expression Regulation, Neoplastic / Genetic Loci / Humans / INK4 protein / Kinases / Localization / Loci / MDM2 protein / Medicine / Mimicry / Mutation / p53 Protein / Pathways / Phosphorylation / Protein kinase C / Protein Kinase C - genetics / Protein Kinase C - metabolism / Protein Stability / Proteins / Proto-Oncogene Proteins c-mdm2 - genetics / Proto-Oncogene Proteins c-mdm2 - metabolism / Sensitizing / Signal Transduction / Threonine / Threonine - genetics / Threonine - metabolism / Transcription activation / Transfection / Tumor cell lines / Tumor proteins / Tumor Suppressor Protein p14ARF - genetics / Tumor Suppressor Protein p14ARF - metabolism / Tumor Suppressor Protein p53 - genetics / Tumor Suppressor Protein p53 - metabolism / Tumors