PTEN Deletion Leads to Up-regulation of a Secreted Growth Factor Pleiotrophin

Hong Wu,De-Chang Wu,Gang Li,Yingchun Hu,Minli Liu,Xin Liu,Jing Gao,Dan Freeman,Yanying Huo

doi:10.1074/jbc.m512509200

Abstract

Tumor suppressor gene PTEN is highly mutated in a wide variety of human tumors. To identify unknown targets or signal transduction pathways that are regulated by PTEN, microarray analysis was performed to compare the gene expression profiles of Pten null mouse embryonic fibroblasts (MEFs) cell lines and their isogenic counterparts. Expression of a heparin binding growth factor, pleiotrophin (Ptn), was found to be up-regulated in Pten-/- MEFs as well as Pten null mammary tumors. Further experiments revealed that Ptn expression is regulated by the PTEN-PI3K-AKT pathway. Knocking down the expression of Ptn by small interfering RNA resulted in the reduction of Akt and GSK-3beta phosphorylation and suppression of the growth and the tumorigenicity of Pten null MEFs. Our results suggest that PTN participates in tumorigenesis caused by PTEN loss and PTN may be a potential target for anticancer therapy, especially for those tumors with PTEN deficiencies.

Highlights

PTEN acts primarily as a negative regulator of the phosphoinositide 3-kinase (PI3K) pathway by virtue of its lipid phosphatase activity [5,6,7]
Among genes that are differentially expressed in these cell lines, we found that pleiotrophin (Ptn) was up-regulated in the PtenϪ/Ϫ mouse embryonic fibroblasts (MEFs) as well as mammary tumor tissues of Pten conditional knock-out mice [14]
Genes Differentially Expressed in Pten WT and Null MEF Cell Lines— To identify unknown targets or signal transduction pathways that are regulated by PTEN, we compared gene expression profiles of Pten WT and null mouse embryonic fibroblast cell lines [7, 13]

Summary

Introduction

PTEN acts primarily as a negative regulator of the phosphoinositide 3-kinase (PI3K) pathway by virtue of its lipid phosphatase activity [5,6,7]. Loss of PTEN leads to an increase in the phosphatidylinositol 3-phosphate level, mimicking the effect of constitutive PI3K activation. Aside from acting as a negative regulator of the PI3K pathway, which depends on its lipid phosphatase activity, PTEN functions independently of its lipid phosphatase activity. Raftopoulou et al [10] showed that PTEN inhibits cell migration through its C2 domain and dephosphorylates itself depending on its protein phosphatase activity. Okumura [12] reports that the PTEN C-terminal domain physically interacts with the oncogenic MSP58 protein and suppresses cell transformation induced by MSP58 expression, independent of its catalytically activity. Further experiments indicated that the expression of Ptn was regulated by the PI3K pathway, and Ptn overexpression contributes to tumorigenesis caused by PTEN loss

Methods

Results

Conclusion