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

JAVIER RODRIGUEZ-UBREVA; ARIEL E. CARIAGA-MARTINEZ; M. ALICIA CORTÉS; M. ROMERO-DE PABLOS; SANTIAGO ROPERO; PILAR LÓPEZ-RUIZ; BEGOÑA COLÁS

ONCOGENE

NATURE PUBLISHING GROUP

Lugar: Londres; Año: 2010 vol. 29 p. 345 - 355

0950-9232

Factor de impacto: 7,414 /Journal Ranking: Q1. SHP-1, a haematopoietic cell-specific tyrosine phosphatase,is also expressed in human prostate. In this study, wereport that SHP-1 depletion in PC-3 cells induced bysmall interfering RNAs causes G1 phase cell-cycle arrestaccompanied by changes in some components of the cellcyclemachinery. SHP-1 knockdown increases p27Kip1(p27) protein stability, its nuclear localization and p27gene transcription. These effects could be mediated byPI3K-AKT pathway as SHP-1 interacts with PI3Kregulating its activity and p110 catalytic subunit phosphorylation.The increase in p27 protein stability couldalso 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 theCDK2 activity. However, the codepletion of SHP-1 andp27 does not produce re-entry into the cycle, implying thatp27 is not required to maintain cell-cycle arrest induced bySHP-1 depletion. The maintenance of the PC-3 cell antiproliferativeresponse after p27 loss could be because ofmislocalization of CDK2 induced by SHP-1 knockdown.This study shows that SHP-1 depletion promotes cellcyclearrest by modulating the activity of cell-cycleregulators and suggests that SHP-1 may be required forthe proper functioning of events governing cell-cycleprogression.