): The candidate is an Oncology Research Fellow working under the guidance of Dr. James Darnell at The Rockefeller University. Her project, which focuses on the regulatory mechanisms of interferons on growth control, utilizes the scientific and clinical resources of Rockefeller University and Sloan-Kettering Institute. Interferons (IFNs) have successfully been used in the treatment of a variety of liquid and solid tumors. Both cell cycle arrest at G0/G1 and differentiation of many cell lines follow after interferon therapy. Studies of interferon-stimulated signalling events have identified a cascade in which binding of interferon to its receptor is followed by phosphorylation by Jak kinases of both the receptor and transcription factors called Stats which then are presumed to mediate downstream events. The purpose of this proposal is to determine the mechanisms by which IFN activation of Stat1 mediates cell cycle arrest. Preliminary data demonstrate that a transcriptionally competent Stat1 is required for IFN-alpha and gamma induced G1 arrest. First, cells lacking Stat1 are resistant to growth suppressing activity of IFN-gamma and alpha. Stat1 reconstituted in this cell line will display G1 arrest after treatment with either IFN-alpha or gamma. Secondly, Stat1 becomes transcriptionally activated in cells which are growth suppressed by EGF but not in those which are growth stimulated. Taken together, these data suggest an integral role for Stat1 in mediating growth arrest. The candidate hopes to characterize IFN-alpha and gamma's effect on the G1 components of the cell cycle. Specifically, the investigators will focus their attention on G1 cdk/cyclin complexes, their kinase activity and the potential role of cdk inhibitors on IFN-mediated G1 arrest. She also plans to identify Stat1 inducible genes involved in cell cycle control and growth arrest. This will be approached using a modification of the differential display technique by comparing gene products from INF-treated Stat1 containing cells versus Stat1 deficient cells.
| Bromberg, J F; Horvath, C M; Besser, D et al. (1998) Stat3 activation is required for cellular transformation by v-src. Mol Cell Biol 18:2553-8 |
