Abstract |
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.
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Authors | F J Rodríguez-Ubreva, A E Cariaga-Martinez, M A Cortés, M Romero-De Pablos, S Ropero, P López-Ruiz, B Colás |
Journal | Oncogene
(Oncogene)
Vol. 29
Issue 3
Pg. 345-55
(Jan 21 2010)
ISSN: 1476-5594 [Electronic] England |
PMID | 19838216
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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Chemical References |
- Cell Cycle Proteins
- Cyclin E
- Retinoblastoma Protein
- Cyclin-Dependent Kinase Inhibitor p27
- Luciferases
- CDK2 protein, human
- CDK6 protein, human
- Cyclin-Dependent Kinase 2
- Cyclin-Dependent Kinase 6
- PTPN6 protein, human
- Protein Tyrosine Phosphatase, Non-Receptor Type 6
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Topics |
- Blotting, Western
- Cell Cycle
(genetics, physiology)
- Cell Cycle Proteins
(genetics, metabolism)
- Cell Line, Tumor
- Cell Nucleus
(metabolism)
- Cell Proliferation
- Cyclin E
(genetics, metabolism)
- Cyclin-Dependent Kinase 2
(genetics, metabolism)
- Cyclin-Dependent Kinase 6
(genetics, metabolism)
- Cyclin-Dependent Kinase Inhibitor p27
(genetics, metabolism)
- G1 Phase
- Gene Expression Regulation, Neoplastic
- Humans
- Luciferases
(genetics, metabolism)
- Male
- Phosphorylation
- Promoter Regions, Genetic
(genetics)
- Prostatic Neoplasms
(genetics, metabolism, pathology)
- Protein Tyrosine Phosphatase, Non-Receptor Type 6
(genetics, metabolism)
- RNA Interference
- Retinoblastoma Protein
(genetics, metabolism)
- Reverse Transcriptase Polymerase Chain Reaction
- S Phase
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