The role of p27Kip1 in gamma interferon-mediated growth arrest of mammary epithelial cells and related defects in mammary carcinoma cells
Abstract
Interferon gamma (IFNgamma) induces growth arrest in normal human mammary epithelial cells by establishing a block during mid-G1 corresponding to the time when the retinoblastoma protein (Rb) would normally be inactivated by hyperphosphorylation. IFNgamma inhibits the kinase activities of cdk2, cdk4 and cdk6 within 24 h of treatment. Protein levels of the cdks and G1 cyclins do not change within this time period, although cdk4 levels are significantly reduced by 48 h. IFNgamma treatment induces p27Kip1 protein levels, presumably by a post-transcriptional mechanism as no change was observed in the mRNA levels. In addition, IFNgamma-induced inhibition of cdk2 and cyclin E-associated kinase activities is accompanied by a 4.5-fold or greater increase of p27Kip1 in cdk2 complexes. p27 may also have a role in the inhibition of cdk4/6 kinase activities, as p27 protein associated with these complexes was increase by 55-70% after IFNgamma. In mammary carcinoma cell lines which are resistant to growth inhibition by IFNgamma, p27 levels are not induced by IFNgamma nor is cdk2 kinase activity inhibited, despite high baseline levels of p27 in cdk2 complexes. However, exogenous expression of p27 in these cells induces growth arrest. In addit...Continue Reading
Citations
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