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p14ARF induces G2 cell cycle arrest in p53- and p21-deficient cells by down-regulating p34cdc2 kinase activity

Item Type:Article
Title:p14ARF induces G2 cell cycle arrest in p53- and p21-deficient cells by down-regulating p34cdc2 kinase activity
Creators Name:Normand, G. and Hemmati, P.G. and Verdoodt, B. and von Haefen, C. and Wendt, J. and Guener, D. and May, E. and Doerken, B. and Daniel, P.T.
Abstract:The human INK4a gene locus encodes two structurally unrelated tumor suppressor proteins, p16(INK4a) and p14(ARF). Although primarily proposed to require a functional p53.Mdm-2 signaling axis, recently p14(ARF) has been implicated in p53-independent cell cycle regulation. Here we show that p14(ARF) preferentially induces a G(2) arrest in tumor cells lacking functional p53 and/or p21. Expression of p14(ARF) impaired mitotic entry and enforced a primarily cytoplasmic localization of p34(cdc2) that was associated with a decrease in p34(cdc2) kinase activity and reduced p34(cdc2) protein expression. A direct physical interaction between p14(ARF) and p34(cdc2) was, nevertheless, ruled out by lack of co-immunoprecipitation. The p14(ARF)-induced depletion of p34(cdc2) was associated with impaired cdc25C phosphatase expression and a prominent shift to inhibitory Tyr-15-phosphorylation in G(2)-arrested cells lacking either p53, p21, or both. Finally, reconstitution of p34(cdc2) using a constitutively active, phosphorylation-deficient p34(cdc2AF) mutant alleviated this p14(ARF)-induced G(2) arrest, thereby allowing cell cycle progression. Taken together, these data indicate that p14(ARF) arrests cells lacking functional p53/p21 in the G(2) phase of the cell cycle by targeting p34(cdc2) kinase. This may represent an important fail-safe mechanism by which p14(ARF) protects p53/p21-deficient cells from unrestrained proliferation.
Keywords:CDC2 Protein Kinase, Cell Cycle, Cell Cycle Proteins, Cell Proliferation, Cyclin-Dependent Kinase Inhibitor p21, Down-Regulation, G2 Phase, Neoplastic Gene Expression Regulation, Phosphorylation, Tumor Cell Line, Tumor Suppressor Protein p14ARF, Tumor Suppressor Protein p53, cdc25 Phosphatases
Source:Journal of Biological Chemistry
ISSN:0021-9258
Publisher:American Society for Biochemistry and Molecular Biology (U.S.A.)
Volume:280
Page Range:7118-7130
Date:1 January 2005
Official Publication:https://doi.org/10.1074/jbc.M412330200
PubMed:View item in PubMed

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