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Disruption of serine/threonine protein phosphatase 5 (PP5:PPP5c) in mice reveals a novel role for PP5 in the regulation of ultraviolet light-induced phosphorylation of serine/threonine protein kinase Chk1 (CHEK1).
- Source :
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The Journal of biological chemistry [J Biol Chem] 2011 Nov 25; Vol. 286 (47), pp. 40413-22. Date of Electronic Publication: 2011 Sep 15. - Publication Year :
- 2011
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Abstract
- PP5 is a ubiquitously expressed Ser/Thr protein phosphatase. High levels of PP5 have been observed in human cancers, and constitutive PP5 overexpression aids tumor progression in mouse models of tumor development. However, PP5 is highly conserved among species, and the roles of PP5 in normal tissues are not clear. Here, to help evaluate the biological actions of PP5, a Cre/loxP-conditional mouse line was generated. In marked contrast to the early embryonic lethality associated with the genetic disruption of other PPP family phosphatases (e.g. PP2A and PP4), intercrosses with mouse lines that ubiquitously express Cre recombinase starting early in development (e.g. MeuCre40 and ACTB-Cre) produced viable and fertile PP5-deficient mice. Phenotypic differences caused by the total disruption of PP5 were minor, suggesting that small molecule inhibitors of PP5 will not have widespread systemic toxicity. Examination of roles for PP5 in fibroblasts generated from PP5-deficient embryos (PP5(-/-) mouse embryonic fibroblasts) confirmed some known roles and identified new actions for PP5. PP5(-/-) mouse embryonic fibroblasts demonstrated increased sensitivity to UV light, hydroxyurea, and camptothecin, which are known activators of ATR (ataxia-telangiectasia and Rad3-related) kinase. Further study revealed a previously unrecognized role for PP5 downstream of ATR activation in a UV light-induced response. The genetic disruption of PP5 is associated with enhanced and prolonged phosphorylation of a single serine (Ser-345) on Chk1, increased phosphorylation of the p53 tumor suppressor protein (p53) at serine 18, and increased p53 protein levels. A comparable role for PP5 in the regulation of Chk1 phosphorylation was also observed in human cells.
- Subjects :
- Actins genetics
Alleles
Animals
Blastocyst metabolism
Breeding
Cell Line
Checkpoint Kinase 1
Female
Fibroblasts drug effects
Fibroblasts metabolism
Fibroblasts radiation effects
HeLa Cells
Humans
Hydroxyurea pharmacology
Integrases genetics
Male
Mice
Nuclear Proteins metabolism
Phenotype
Phosphoprotein Phosphatases metabolism
Phosphorylation drug effects
Phosphorylation genetics
Phosphorylation radiation effects
Promoter Regions, Genetic genetics
Protein Kinases chemistry
Receptors, Neuropeptide Y metabolism
Serine metabolism
Tumor Suppressor Protein p53 metabolism
cdc25 Phosphatases metabolism
Nuclear Proteins deficiency
Nuclear Proteins genetics
Phosphoprotein Phosphatases deficiency
Phosphoprotein Phosphatases genetics
Protein Kinases metabolism
Ultraviolet Rays
Subjects
Details
- Language :
- English
- ISSN :
- 1083-351X
- Volume :
- 286
- Issue :
- 47
- Database :
- MEDLINE
- Journal :
- The Journal of biological chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 21921034
- Full Text :
- https://doi.org/10.1074/jbc.M111.244053