title: Gamma-interferon induces an irreversible growth arrest in mid-G1 in mammary epithelial cells which correlates with a block in hyperphosphorylation of retinoblastoma.
abstract: In this study, we analyze effects of IFN-gamma on the proliferation of normal human mammary epithelial cells (MECs) and several mammary carcinoma cell lines. We demonstrate that IFN-gamma blocks the proliferation of MECs in a time- and concentration-dependent manner. This growth arrest is irreversible and occurs at a specific stage in the G1 phase of the cell cycle. IFN-gamma caused a rapid (within 12-24 h) down-regulation of cyclin A, c-myc, and cdc2 proteins, as well as a disappearance of hyperphosphorylated forms of the retinoblastoma family proteins, Rb and p130. The synthesis of several other growth control proteins, p53, p21/Waf1, and proliferating cell nuclear antigen, was down-regulated between 24 and 48 h. In MECs synchronized by epidermal growth factor deprivation and released for cell cycle traverse by re-addition of epidermal growth factor to the medium, IFN-gamma was able to block DNA synthesis only if added in the first 6 to 7 h after epidermal growth factor. The block in Rb phosphorylation and cyclin A expression was coordinately regulated during the same narrow window of G1. Several mammary carcinoma cell lines demonstrated resistance to the growth-inhibitory effects of IFN-gamma and did not exhibit down-regulation of cdc2 and cyclin A expression or a change in hyperphosphorylation of Rb when treated with IFN-gamma. Initial studies suggest, in some carcinoma cell lines, that resistance to IFN-gamma may be caused by defects in the IFN-gamma signal transduction pathway (measured by expression of the IFN-gamma-responsive gene GBP), while resistance in others may be due to defects in cell cycle regulatory proteins that are the targets of IFN-gamma action.
authors.affiliation: National Institute of Environmental Health Sciences, NIH, Research Triangle Park, North Carolina 27709, USA.
authors.forename: B L
authors.initials: BL
authors.lastname: Harvat
authors.forename: A M
authors.initials: AM
authors.lastname: Jetten
mesh_terms: D001940:Breast / Q000166:cytology* / Q000378:metabolism; D001943:Breast Neoplasms / Q000378:metabolism / Q000473:pathology; D002277:Carcinoma / Q000378:metabolism / Q000473:pathology; D018797:Cell Cycle Proteins / Q000096:biosynthesis; D002455:Cell Division; D002460:Cell Line; D004247:DNA / Q000096:biosynthesis; D015536:Down-Regulation; D004815:Epidermal Growth Factor / Q000494:pharmacology; D004847:Epithelial Cells; D004848:Epithelium / Q000378:metabolism; D016193:G1 Phase; D006801:Humans; D007371:Interferon-gamma / Q000494:pharmacology*; D010750:Phosphoproteins / Q000378:metabolism; D010766:Phosphorylation; D018809:Proliferating Cell Nuclear Antigen / Q000096:biosynthesis; D011506:Proteins; D016271:Proto-Oncogene Proteins c-myc / Q000096:biosynthesis; D016160:Retinoblastoma Protein / Q000378:metabolism*; D050717:Retinoblastoma-Like Protein p130; D015398:Signal Transduction; D014407:Tumor Cells, Cultured
chemical_list: D018797:Cell Cycle Proteins; D010750:Phosphoproteins; D018809:Proliferating Cell Nuclear Antigen; D011506:Proteins; D016271:Proto-Oncogene Proteins c-myc; C493837:RBL2 protein, human; D016160:Retinoblastoma Protein; D050717:Retinoblastoma-Like Protein p130; D004815:Epidermal Growth Factor; D007371:Interferon-gamma; D004247:DNA