期刊
CELL CYCLE
卷 9, 期 23, 页码 4638-4649出版社
TAYLOR & FRANCIS INC
DOI: 10.4161/cc.9.23.13955
关键词
STAT1; cyclin D1; p27(Kip1) and IFN gamma; p21(Cip1)
类别
资金
- British Heart Foundation [FS/04/021]
In response to IFN gamma, 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 G 1 cell cycle regulatory cyclin D1 and CDK4 proteins, suggesting a role for STAT1 in G(1) cell cycle regulation. Acute IFN gamma treatment dramatically reduced cyclin D1 protein expression and the interaction of STAT1 with cyclin D1. The IFN gamma-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 gamma-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 gamma-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 upregulation 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.
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