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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

Oncogene volume 29, pages 345–355 (2010)Cite this article

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 p27Kip1 (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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Acknowledgements

We are very grateful to Dr T Sakai (Department of Molecular-Targeting Cancer Prevention, Kyoto Prefectural University of Medicine, Kyoto, Japan) for providing human p27 promoter containing luciferase reporter construct (p27PF) and control empty vector and also to Dr FD Böhmer (Institute of Molecular Cell Biology, Medical Faculty, Friedrich Schiller University, Jena, Germany) for providing GST–SHP-1 wild type. This work was supported by Consejería de Sanidad de Castilla-La Mancha grant (04077-00); Fundación de Investigación Mutua Madrileña grant; Instituto de Salud Carlos III grant (PI060109); FPI fellowship, Comunidad de Madrid (FJ Rodriguez-Ubreva); Fundación Carolina and FPI fellowship Consejería de Educación de Castilla-La Mancha (AE Cariaga-Martinez).

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  1. Departamento de Bioquímica y Biología Molecular, Universidad de Alcalá, Alcalá de Henares, Madrid, Spain

    F J Rodríguez-Ubreva, A E Cariaga-Martinez, M A Cortés, S Ropero, P López-Ruiz & B Colás

  2. Departamento de Fisiología, Universidad de Alcalá, Alcalá de Henares, Madrid, Spain

    M Romero-De Pablos

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Correspondence to B Colás.

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Rodríguez-Ubreva, F., Cariaga-Martinez, A., Cortés, M. et al. 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. Oncogene 29, 345–355 (2010). https://doi.org/10.1038/onc.2009.329

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