期刊
ONCOGENE
卷 29, 期 3, 页码 345-355出版社
SPRINGERNATURE
DOI: 10.1038/onc.2009.329
关键词
prostate cancer; cell cycle; p27; CDK2; SHP-1
资金
- Consejeria de Sanidad de Castilla-La Mancha [04077-00]
- Fundacion de Investigacion Mutua Madrilena grant
- Instituto de Salud Carlos III grant [PI060109]
- FPI fellowship, Comunidad de Madrid
- Fundacion Carolina
- FPI fellowship Consejeria de Educacion de Castilla-La Mancha
SHP-1, a haematopoietic cell-specific tyrosine phosphatase, is also expressed in human prostate. In this study, we report that SHP-1 depletion in PC-3 cells induced by small interfering RNAs causes G1 phase cell-cycle arrest accompanied by changes in some components of the cell-cycle machinery. SHP-1 knockdown increases p27(Kip1) (p27) protein stability, its nuclear localization and p27 gene transcription. These effects could be mediated by PI3K-AKT pathway as SHP-1 interacts with PI3K regulating its activity and p110 catalytic subunit phosphorylation. The increase in p27 protein stability could also because of reduced cyclin-dependent kinase (CDK2) activity. SHP-1 knockdown decreases the CDK6 levels, inducing retinoblastoma protein hypophosphorylation, downregulation of cyclin E and thereby a decrease in the CDK2 activity. However, the codepletion of SHP-1 and p27 does not produce re-entry into the cycle, implying that p27 is not required to maintain cell-cycle arrest induced by SHP-1 depletion. The maintenance of the PC-3 cell anti-proliferative response after p27 loss could be because of mislocalization of CDK2 induced by SHP-1 knockdown. This study shows that SHP-1 depletion promotes cell-cycle arrest by modulating the activity of cell-cycle regulators and suggests that SHP-1 may be required for the proper functioning of events governing cell-cycle progression. Oncogene (2010) 29, 345-355; doi:10.1038/onc.2009.329; published online 19 October 2009
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