title: Mechanisms of cell cycle arrest by methylseleninic acid.
abstract: Methylseleninic acid (MSA) is a monomethylated form of selenium effective in inhibiting cell growth in vitro and experimental mammary carcinogenesis in vivo. MSA offers particular advantage in cell culture experiments because it is stable in solution and provides a monomethylated form of selenium that can be reduced by cellular reducing systems and released nonenzymatically within a cell. In the present study, MSA was used to elucidate the mechanisms of cell growth inhibition by selenium. These studies were performed using a mouse mammary hyperplastic epithelial cell line, TM6. MSA induced a rapid arrest of synchronized cells in the G(1) phase of the cell cycle. This effect was accompanied by a reduction in total cellular levels of cyclin D1. Whereas MSA had no effect on total levels of the cyclin-dependent kinase (CDK)4, the amount of CDK4 immunoprecipitated with cyclin D1 in MSA-treated cells was decreased as was the kinase activity of the immunoprecipitated complex. MSA did not significantly affect cyclin E or associated regulatory molecules. Treatment with MSA suppressed the hyperphosphorylated form of retinoblastoma (Rb) with a commensurate increase in the hypophosphorylated form. Levels of E2F-1 bound to Rb also were elevated. Levels of insulin-like growth factor-I receptor and phosphorylated Akt were reduced by MSA. It is concluded that MSA induces a G(1) arrest in the cell cycle. This effect may be induced by MSA via its modulation of insulin-like growth factor-I-mediated signal transduction leading to inhibition of Akt activation and limitation of cyclin D1-CDK4-mediated phosphorylation of Rb.
authors.affiliation: Center for Nutrition in the Prevention of Disease, AMC Cancer Research Center, Lakewood, Colorado 80214, USA.
authors.forename: Zongjian
authors.initials: Z
authors.lastname: Zhu
authors.forename: Weiqin
authors.initials: W
authors.lastname: Jiang
authors.forename: Howard E
authors.initials: HE
authors.lastname: Ganther
authors.forename: Henry J
authors.initials: HJ
authors.lastname: Thompson
mesh_terms: D000818:Animals; D002453:Cell Cycle / Q000187:drug effects* / Q000235:genetics / Q000502:physiology; D018797:Cell Cycle Proteins / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D002455:Cell Division / Q000187:drug effects; D002460:Cell Line; D019938:Cyclin D1 / Q000378:metabolism; D019927:Cyclin E / Q000378:metabolism; D051358:Cyclin-Dependent Kinase 4; D018844:Cyclin-Dependent Kinases / Q000378:metabolism; D004268:DNA-Binding Proteins; D050684:E2F Transcription Factors; D050687:E2F1 Transcription Factor; D004847:Epithelial Cells / Q000166:cytology / Q000187:drug effects; D005260:Female; D008321:Mammary Glands, Animal / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D020411:Oligonucleotide Array Sequence Analysis; D016566:Organoselenium Compounds / Q000494:pharmacology*; D010766:Phosphorylation; D011485:Protein Binding; D011518:Proto-Oncogene Proteins; D016160:Retinoblastoma Protein / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism
chemical_list: D018797:Cell Cycle Proteins; D019927:Cyclin E; D004268:DNA-Binding Proteins; D050684:E2F Transcription Factors; D050687:E2F1 Transcription Factor; C493754:E2f1 protein, mouse; D016566:Organoselenium Compounds; D011518:Proto-Oncogene Proteins; D016160:Retinoblastoma Protein; D014157:Transcription Factors; D019938:Cyclin D1; C008493:methylselenic acid; C495902:Cdk4 protein, mouse; D051358:Cyclin-Dependent Kinase 4; D018844:Cyclin-Dependent Kinases