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

Abstract

PTEN 4 (phosphatase and tensin homologue deleted on chromosome ten) is the first phosphatase identified as a tumor suppressor (1-3). Loss of function mutations or reduced expression of the PTEN gene are found at high frequencies in a wide variety of human tumors, including glioblastoma, as well as endometrial, prostate, colorectal, lung, and breast cancers. Experimental and clinical evidence demonstrate that PTEN is a critical tumor suppressor (4).PTEN acts primarily as a negative regulator of the phosphoinositide 3-kinase (PI3K) pathway by virtue of its lipid phosphatase activity (5-7). Loss of PTEN leads to an increase in the phosphatidylinositol 3-phosphate level, mimicking the effect of constitutive PI3K activation. Phosphatidylinositol 3-phosphate accumulation results in the activation of various protein kinases, including the PDK1 and PKB/AKT serine/threonine kinases. AKT is the central node in the PTEN-regulated pathway and activated AKT has been shown to promote cell cycle progression, cell growth, cell survival, cell migration, angiogenesis, protein synthesis, and glucose metabolism through phosphorylation of its substrates (8, 9).Aside from acting as a negative regulator of the PI3K pathway, which depends on its lipid phosphatase activity, PTEN also 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. Freeman et al. (11) demonstrated that PTEN physically associates with p53 in the nucleus, which in turn stabilizes p53 and affects p53 protein levels and transcription activity. Recently, 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.To further understand the biological functions of PTEN, we undertook an unbiased approach by comparing gene expression profiles of a Pten Ϫ/Ϫ mouse embryonic fibroblast (MEF) cell line with that of its isogenic counterpart (11, 13) using microarray technology. Among genes that are differentially expressed in these cell lines, we found that pleiotrophin (Ptn) was up-regulated in the Pten Ϫ/Ϫ MEFs as well as mammary tumor tissues of Pten conditional knock-out mice (14). Further experiments indicated that the expression of Ptn was regulated by the PI3K pathway, and Ptn overexpression contributes to tumorigenesis caused by PTEN loss. Microarray Analysis-Mouse cDNA microarrays containing 8,928 elements were printed by the UCLA Microarray Core Facility. Total RNA was isolated using TRIzol reagent (Invitrogen) according to the manufacturer's instructions. MATERIALS AND METHODS Cell Culture and Generation of Immortalized Fibroblasts-Fibro-For probe labeling and microarray hybridization, a protocol published by Xiang et al. (15) was adopted with minor modifications. Briefly, cDNA probes that incorporate aminoallyl-dUTP (aa-dUTP; Sigma) were synthesized...

Conditional Deletion of Pten Causes Bronchiolar Hyperplasia

“…The observed neuroepithelial cell hyperplasia in Pten D/D mice is not caused by a cell autonomous mechanism, but is likely due to paracrine signaling from adjacent cells that are deficient in PTEN, consistent with previous studies in which epithelial cells that are adjacent to NEBs contribute to PNE cell hyperplasia (31). Deletion of PTEN in fibroblast and mammary tumor cells in vivo enhanced secretion of growth factors, including pleotrophin, that may influence cell adhesion, migration, survival, growth, and differentiation via a paracrine mechanism (50).…”

Nitric oxide stimulates migration of human endothelial and prostate cancer cells through up‐regulation of pleiotrophin expression and its receptor protein tyrosine phosphatase β/ζ

“…24,25 HP activates eNOS through activation of Akt, 26,27 which in the studied pathway lies down-stream of p38 (supplementary file 2) and has been also implicated in the regulation of PTN expression. 28 We have recently shown that NO mediates HP-induced angiogenesis in vivo 5 and endothelial cell migration in vitro. 6 The results of the present study suggest that this may be due to eNOS/ NO mediated PTN expression, which is also angiogenic in the same systems.…”

The effect of pleiotrophin signaling on adipogenesis

“…Both PTN and Wnt repress adipocyte differentiation through cytosolic accumulation and nuclear translocation of b-catenin, so it is possible that there is cross-talk between the Wnt and PTN signaling pathways during preadipocyte differentiation. To confirm our hypothesis, we searched for the molecule directly connected to both pathways and found GSK-3b [21,29]. Wnt signals through the frizzled receptor (Fz) and the low density lipoprotein receptor-related protein (LRP) co-receptors [35,36].…”

“…As a growth factor, PTN stimulates mitogenesis of fibroblasts, endothelial cells, and epithelial cells in culture, as well as neurite outgrowth in neonatal neuronal cells [10,15,16]. As a potent proto-oncogene, a ratelimiting angiogenic factor during tumor growth, and a potential tumor promoter, PTN transforms NIH 3T3 cells and is highly expressed in various tumor cell lines and tumor tissues, such as in breast cancer, melanoma, pancreatic cancer, prostate cancer, and colon cancer [17][18][19][20][21]. PTN also induces differentiation of oligodendrocyte progenitors and regulates branching morphogenesis of the ureteric bud during development of the kidney [4,22].…”