Knockdown of protein tyrosine phosphatase SHP-1 inhibits G1/S progression in prostate cancer cells through the regulation of components of the cell-cycle machinery.

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.

• 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)

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

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