J. Biol. Chem.

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.

Source:http://purl.uniprot.org/citations/15582998

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http://purl.uniprot.org/cit...rdfs:commentThe 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.lld:uniprot
http://purl.uniprot.org/cit...skos:exactMatchhttp://purl.uniprot.org/pub...lld:uniprot
http://purl.uniprot.org/cit...uniprot:nameJ. Biol. Chem.lld:uniprot
http://purl.uniprot.org/cit...uniprot:authorMay E.lld:uniprot
http://purl.uniprot.org/cit...uniprot:authorNormand G.lld:uniprot
http://purl.uniprot.org/cit...uniprot:authorDaniel P.T.lld:uniprot
http://purl.uniprot.org/cit...uniprot:authorDorken B.lld:uniprot
http://purl.uniprot.org/cit...uniprot:authorVerdoodt B.lld:uniprot
http://purl.uniprot.org/cit...uniprot:authorHemmati P.G.lld:uniprot
http://purl.uniprot.org/cit...uniprot:authorvon Haefen C.lld:uniprot
http://purl.uniprot.org/cit...uniprot:authorWendt J.lld:uniprot
http://purl.uniprot.org/cit...uniprot:authorGuner D.lld:uniprot
http://purl.uniprot.org/cit...uniprot:date2005lld:uniprot
http://purl.uniprot.org/cit...uniprot:pages7118-7130lld:uniprot
http://purl.uniprot.org/cit...uniprot:titlep14ARF induces G2 cell cycle arrest in p53- and p21-deficient cells by down-regulating p34cdc2 kinase activity.lld:uniprot
http://purl.uniprot.org/cit...uniprot:volume280lld:uniprot
http://purl.uniprot.org/cit...dc-term:identifierdoi:10.1074/jbc.M412330200lld:uniprot
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