title: Hyposmotic stress induces cell growth arrest via proteasome activation and cyclin/cyclin-dependent kinase degradation.
abstract: Ordered cell cycle progression requires the expression and activation of several cyclins and cyclin-dependent kinases (Cdks). Hyperosmotic stress causes growth arrest possibly via proteasome-mediated degradation of cyclin D1. We studied the effect of hyposmotic conditions on three colonic (Caco2, HRT18, HT29) and two pancreatic (AsPC-1 and PaCa-2) cell lines. Hyposmosis caused reversible cell growth arrest of the five cell lines in a cell cycle-independent fashion, although some cell lines accumulated at the G(1)/S interface. Growth arrest was followed by apoptosis or by formation of multinucleated giant cells, which is consistent with cell cycle catastrophe. Hyposmosis dramatically decreased Cdc2, Cdk2, Cdk4, cyclin B1, and cyclin D3 expression in a time-dependent fashion, in association with an overall decrease in cellular protein synthesis. However, some protein levels remained unaltered, including cyclin E and keratin 8. Selective proteasome inhibition prevented Cdk and cyclin degradation and reversed hyposmotic stress-induced growth arrest, whereas calpain and lysosome enzyme inhibitors had no measurable effect on cell cycle protein degradation. Therefore, hyposmotic stress inhibits cell growth and, depending on the cell type, causes cell cycle catastrophe with or without apoptosis. The growth arrest is due to decreased protein synthesis and proteasome activation, with subsequent degradation of several cyclins and Cdks.
authors.affiliation: Department of Medicine, Palo Alto Veterans Affairs Medical Center, Palo Alto, California 94034, USA.
authors.forename: Guo-Zhong
authors.initials: GZ
authors.lastname: Tao
authors.forename: Lusijah S
authors.initials: LS
authors.lastname: Rott
authors.forename: Anson W
authors.initials: AW
authors.lastname: Lowe
authors.forename: M Bishr
authors.initials: MB
authors.lastname: Omary
mesh_terms: D017209:Apoptosis; D016203:CDC2 Protein Kinase / Q000378:metabolism; D042846:CDC2-CDC28 Kinases; D002154:Calpain / Q000378:metabolism; D002470:Cell Survival; D003110:Colonic Neoplasms / Q000473:pathology; D019926:Cyclin B / Q000378:metabolism; D056744:Cyclin B1; D019938:Cyclin D1 / Q000378:metabolism*; D056743:Cyclin D3; D051357:Cyclin-Dependent Kinase 2; D051358:Cyclin-Dependent Kinase 4; D018844:Cyclin-Dependent Kinases / Q000378:metabolism; D016213:Cyclins / Q000378:metabolism; D003546:Cysteine Endopeptidases / Q000378:metabolism; D053938:DNA Fragmentation; D005434:Flow Cytometry; D016193:G1 Phase; D015726:Giant Cells / Q000378:metabolism; D006801:Humans; D007633:Keratins / Q000378:metabolism; D008247:Lysosomes / Q000378:metabolism; D008854:Microscopy, Electron; D008954:Models, Biological; D009097:Multienzyme Complexes / Q000378:metabolism; D009995:Osmosis; D009997:Osmotic Pressure; D010190:Pancreatic Neoplasms / Q000473:pathology; D046988:Proteasome Endopeptidase Complex; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D011518:Proto-Oncogene Proteins; D016196:S Phase; D013997:Time Factors; D014407:Tumor Cells, Cultured
chemical_list: C534699:CCNB1 protein, human; C534696:CCND3 protein, human; D019926:Cyclin B; D056744:Cyclin B1; D056743:Cyclin D3; D016213:Cyclins; D009097:Multienzyme Complexes; D011518:Proto-Oncogene Proteins; D019938:Cyclin D1; D007633:Keratins; D017346:Protein Serine-Threonine Kinases; D016203:CDC2 Protein Kinase; D042846:CDC2-CDC28 Kinases; C495894:CDK2 protein, human; C495900:CDK4 protein, human; D051357:Cyclin-Dependent Kinase 2; D051358:Cyclin-Dependent Kinase 4; D018844:Cyclin-Dependent Kinases; D002154:Calpain; D003546:Cysteine Endopeptidases; D046988:Proteasome Endopeptidase Complex