title: Notch-1 signaling is lost in prostate adenocarcinoma and promotes PTEN gene expression.
abstract: Prostate tumorigenesis is associated with loss of PTEN gene expression. We and others have recently reported that PTEN is regulated by Notch-1 signaling. Herein, we tested the hypothesis that alterations of the Notch-1 signaling pathway are present in human prostate adenocarcinoma and that Notch-1 signaling regulates PTEN gene expression in prostate cells. Prostate adenocarcinoma cases were examined by immunohistochemistry for ligand cleaved (activated) Notch-1 protein. Tumor foci exhibited little cleaved Notch-1 protein, but expression was observed in benign tissue. Both tumor and benign tissue expressed total (uncleaved) Notch-1. Reduced Hey-1 expression was seen in tumor foci but not in benign tissue, confirming loss of Notch-1 signaling in prostate adenocarcinoma. Retroviral expression of constitutively active Notch-1 in human prostate tumor cell lines resulted in increased PTEN gene expression. Incubation of prostate cell lines with the Notch-1 ligand, Delta, resulted in increased PTEN expression indicating that endogenous Notch-1 regulates PTEN gene expression. Chromatin immunoprecipitation demonstrated that CBF-1 was bound to the PTEN promoter. These data collectively indicate that defects in Notch-1 signaling may play a role in human prostate tumor formation in part via a mechanism that involves regulation of the PTEN tumor suppressor gene.
authors.affiliation: Division of Hematology/Oncology, Department of Internal Medicine, Brody School of Medicine, East Carolina University, Greenville, North Carolina 27834, USA.
authors.forename: Jarrett T
authors.initials: JT
authors.lastname: Whelan
authors.forename: Anne
authors.initials: A
authors.lastname: Kellogg
authors.forename: Brian M
authors.initials: BM
authors.lastname: Shewchuk
authors.forename: Karlene
authors.initials: K
authors.lastname: Hewan-Lowe
authors.forename: Fred E
authors.initials: FE
authors.lastname: Bertrand
mesh_terms: D045744:Cell Line, Tumor; D002465:Cell Movement; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D051819:Immunoglobulin J Recombination Signal Sequence-Binding Protein / Q000378:metabolism; D008297:Male; D051059:PTEN Phosphohydrolase / Q000235:genetics* / Q000378:metabolism; D011401:Promoter Regions, Genetic / Q000235:genetics; D011471:Prostatic Neoplasms / Q000201:enzymology* / Q000235:genetics* / Q000473:pathology; D011485:Protein Binding; D051880:Receptors, Notch / Q000378:metabolism*; D015398:Signal Transduction; D015533:Transcriptional Activation / Q000235:genetics
chemical_list: D051819:Immunoglobulin J Recombination Signal Sequence-Binding Protein; C497570:RBPJ protein, human; D051880:Receptors, Notch; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human