title: STAT1 interacts directly with cyclin D1/Cdk4 and mediates cell cycle arrest.
abstract: In response to IFN-γ, the latent cytoplasmic STAT1 protein is tyrosine phosphorylated and translocates to the nucleus where it transactivates STAT1-responsive genes. We now present data that shows that STAT1 has additional non-transcriptional functions. We first demonstrate that STAT1 can interact directly with the G1 cell cycle regulatory cyclin D1 and CDK4 proteins, suggesting a role for STAT1 in G1 cell cycle regulation. Acute IFN-γ treatment dramatically reduced cyclin D1 protein expression and the interaction of STAT1 with cyclin D1. The IFN-γ-induced reduction in cyclin D1 was dependent on the proteasome pathway. Interestingly, the STAT1 serine 727 phosphorylation site and not the STAT1 tyrosine 701 site is required for cyclin D1-dependent proteosomal degradation. Furthermore, IFN-γ-STAT1 cyclin D1 reduction correlated with decreased amount of p-Rb Ser-795, cyclin E and increased amounts of the cell cycle inhibitors p27(Kip1) and p21(Cip1). Finally, STAT1 deficient cells not only proliferate at a greater rate, but have enhanced phosphorylated pRb-(S795), cyclin E and reduced p27(Kip1) and p21(Cip1). Our results suggest that there is a time-dependent hierarchy of events following IFN-γ-STAT1 which begins with the rapid reduction of cyclin D1 levels that is dependent on STAT1 directly interacting with the cyclin D1/Cdk4 complex. This is then followed by a later sustained up-regulation of p27(Kip1) and p21(Cip1) that may be dependent on STAT1 transcriptional activity. Thus, these results highlight a dual role of STAT1 that may require both its non-transcriptional as well as it known transcriptional function.
authors.affiliation: Medical Molecular Biology Unit, Institute of Child Health, University College London, London, UK.
authors.forename: Gloria
authors.initials: G
authors.lastname: Dimco
authors.forename: Richard A
authors.initials: RA
authors.lastname: Knight
authors.forename: David S
authors.initials: DS
authors.lastname: Latchman
authors.forename: Anastasis
authors.initials: A
authors.lastname: Stephanou
mesh_terms: D045744:Cell Line, Tumor; D019938:Cyclin D1 / Q000378:metabolism*; D019927:Cyclin E / Q000378:metabolism; D051358:Cyclin-Dependent Kinase 4 / Q000378:metabolism*; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000378:metabolism; D016193:G1 Phase; D006801:Humans; D007371:Interferon-gamma / Q000494:pharmacology; D010766:Phosphorylation; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D016160:Retinoblastoma Protein / Q000378:metabolism; D016196:S Phase; D050794:STAT1 Transcription Factor / Q000378:metabolism / Q000502:physiology*; D015854:Up-Regulation
chemical_list: D019927:Cyclin E; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016160:Retinoblastoma Protein; D050794:STAT1 Transcription Factor; D019938:Cyclin D1; D050760:Cyclin-Dependent Kinase Inhibitor p27; D007371:Interferon-gamma; D051358:Cyclin-Dependent Kinase 4; D046988:Proteasome Endopeptidase Complex