When this grant proposal was originally submitted over five years ago, the STAT proteins had just been identified, cloned and initially characterized through the studies of interferon systems.
Aims of the original proposal were to investigate a transcription factor ISGF3, which involves STAT1 and STAT2 activated by interferon. However, in the past five years we have made significant progress that went far beyond what I proposed in the original proposal. We have shown that the STAT pathway involves not only in the interferon system, but also as a common pathway mediating essential signals for gene regulation in response to other polypeptide ligands, such as EGF. We have further shown that the STAT signaling pathway plays critical roles in negative regulation of the cell growth. This finding provides a molecular basis why cytokines and growth factors, which usually promote cell proliferation, may also negatively regulate cell growth under certain conditions. Recently, we have also shown, for the first time, that the activation of the PTK-STAT signaling pathway can cause induction of apoptosis. These novel and important findings have significantly advanced our understanding of the cellular and molecular regulatory mechanisms mediated by cytokines and other polypeptide ligands, providing a solid explanation, at the molecular level, of a long-time puzzle that cyokines and growth factors may have dual (negative and positive) functions in regulation of cell growth and survival. Here, I propose to continue our studies on the functional roles of the STAT signaling pathway. We will focus on molecular mechanisms of STAT-mediated differentiation and apoptosis of lymphocyte. I propose the following aims: 1) To reveal the molecular basis of apoptosis by default after growth factor withdrawal. We will use Ba/F3 cells derived from pro B-cell as the model system to investigate functions of STAT proteins in the negative control of cell growth and in the induction of apoptosis after IL-3 withdrawal. 2) To use embryonic fibroblasts isolated from STAT-1 or STAT3 null (minus/minus) mice to investigate STAT functions in the induction of cell death by default. The possible cross-interactions of different signaling pathways in control of survival or apoptosis will be studied. We will also investigate whether IFNs can act as a survival signal if the STAT pathway is blocked. 3) To analyze STAT functions in the regulation of intracellular pathways to differentiation or to apoptosis using transgenic mice expressing dominant-negative mutant of STAT proteins. In particular, we will choose B-cells as model systems. The functions of STAT proteins in determining cell death during the B-cell development will be investigated. 4) To search systematically for the target genes that are specifically regulated by STAT proteins during lymphocyte development. In particular, we will try to identify the genes which may be involved in the control of lymphocyte proliferation, differentiation and apoptosis.
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