STAT1 interacts directly with cyclin D1/Cdk4 and mediates cell cycle arrest

• Published in: Cell cycle (Georgetown, Tex.) Vol. 9; no. 23; pp. 4638 - 4649
• Main Authors: Dimco, Gloria, Knight, Richard A., Latchman, David S., Stephanou, Anastasis
• Format: Journal Article
• Language: English
• Published: United States Taylor & Francis 01.12.2010
• Subjects: Binding; Biology; Bioscience; Calcium; Cancer; Cell; Cell Line, Tumor; Cycle; Cyclin D1 - metabolism; Cyclin E - metabolism; Cyclin-Dependent Kinase 4 - metabolism; Cyclin-Dependent Kinase Inhibitor p21 - metabolism; Cyclin-Dependent Kinase Inhibitor p27 - metabolism; G1 Phase; Humans; Interferon-gamma - pharmacology; Landes; Organogenesis; Phosphorylation; Proteasome Endopeptidase Complex - metabolism; Proteins; Retinoblastoma Protein - metabolism; S Phase; STAT1 Transcription Factor - metabolism; STAT1 Transcription Factor - physiology; Up-Regulation
• ISSN: 1538-4101; 1551-4005
• DOI: 10.4161/cc.9.23.13955

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 Cip 1 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.