title: Inhibition of cell-cycle effectors of proliferation in bladder tumor epithelial cells by the p75NTR tumor suppressor.
abstract: The neurotrophin (NTR) receptor (p75(NTR)) is a cell-surface glycoprotein that binds to the neurotrophin family of growth factors, of which the prototypic member is nerve growth factor (NGF). This receptor was previously shown to retard cell-cycle progression by inducing accumulation of cells in G(1) with a concomitant reduction of cells in the S phase of the cell cycle. Furthermore, p75(NTR) was shown to be an effective tumor suppressor of bladder cancer cell growth in vivo. In order to investigate the mechanism of p75(NTR)-dependent suppression of cell-cycle progression, we utilized transgenic clones of bladder tumor cells that express p75(NTR) in increasing concentrations to demonstrate an effect of p75(NTR) on the levels of cell-cycle regulatory proteins that modulate proliferation of tumor cells. A rank-order (dose-dependent) increase in p75(NTR) protein expression was associated with a decrease in cell proliferation. This p75(NTR)-dependent suppression of proliferation was rescued with NGF. In the absence of ligand, a dose-dependent increase in p75(NTR) protein expression was associated with reduced expression of cyclin D1, cyclin E, and cyclin-dependent kinase 2 (cdk2) as well as decreased cdk2 activity. There was also a decrease in the expression of hyper-phosphorylated retinoblastoma protein, the transcription factor E2F1, and proliferating cell nuclear antigen, and there was an increase in expression of hypophosphorylated Rb and the cdk inhibitor p16(Ink4a) with increasing p75(NTR) expression. Treatment of tumor cells with NGF ameliorated these p75(NTR)-dependent changes in the levels of cell-cycle regulatory proteins and rescued the tumor cells from p75(NTR)-dependent inhibition of proliferation. Hence, it can be concluded that p75(NTR) inhibits proliferation by altering the expression of cell-cycle regulatory proteins and that NGF ameliorates this effect.
authors.affiliation: Department of Cell Biology, Georgetown University Medical Center, Washington, DC 20057-1436, USA.
authors.forename: Fatima
authors.initials: F
authors.lastname: Khwaja
authors.forename: Daniel
authors.initials: D
authors.lastname: Djakiew
mesh_terms: D042846:CDC2-CDC28 Kinases; D002453:Cell Cycle / Q000187:drug effects / Q000502:physiology*; D018797:Cell Cycle Proteins; D002455:Cell Division / Q000187:drug effects / Q000502:physiology; D019938:Cyclin D1 / Q000187:drug effects / Q000378:metabolism; D019927:Cyclin E / Q000187:drug effects / Q000378:metabolism; D051357:Cyclin-Dependent Kinase 2; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000187:drug effects / Q000378:metabolism; D018844:Cyclin-Dependent Kinases / Q000187:drug effects / Q000378:metabolism; D004268:DNA-Binding Proteins; D050684:E2F Transcription Factors; D050687:E2F1 Transcription Factor; D004847:Epithelial Cells / Q000473:pathology; D016147:Genes, Tumor Suppressor; D020932:Nerve Growth Factor / Q000494:pharmacology; D018809:Proliferating Cell Nuclear Antigen / Q000187:drug effects / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000187:drug effects / Q000378:metabolism; D020800:Receptor, Nerve Growth Factor; D017475:Receptors, Nerve Growth Factor / Q000187:drug effects / Q000235:genetics* / Q000378:metabolism; D016160:Retinoblastoma Protein / Q000187:drug effects / Q000378:metabolism; D014157:Transcription Factors / Q000187:drug effects / Q000378:metabolism; D014407:Tumor Cells, Cultured; D001749:Urinary Bladder Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*
chemical_list: D018797:Cell Cycle Proteins; D019927:Cyclin E; D019941:Cyclin-Dependent Kinase Inhibitor p16; D004268:DNA-Binding Proteins; D050684:E2F Transcription Factors; D050687:E2F1 Transcription Factor; D018809:Proliferating Cell Nuclear Antigen; D020800:Receptor, Nerve Growth Factor; D017475:Receptors, Nerve Growth Factor; D016160:Retinoblastoma Protein; D014157:Transcription Factors; D019938:Cyclin D1; D020932:Nerve Growth Factor; D017346:Protein Serine-Threonine Kinases; D042846:CDC2-CDC28 Kinases; D051357:Cyclin-Dependent Kinase 2; D018844:Cyclin-Dependent Kinases