The long-term objective of this proposal is to understand how transforming growth factor beta (TGF-beta), a multi-functional growth hormone which regulates many different aspects of cellular function, inhibits cell proliferation. The recent isolation and characterization of the TGF-beta signaling receptor complex has led to a better understanding of how the TGF-beta signal is transmitted across the membrane. However, the signaling pathway downstream of the receptors through which TGF-beta controls cell cycle progression is still poorly understood. We and others have recently demonstrated that TGF-beta may exert its growth inhibitory effect through the activation and/or upregulation of several cyclin- dependent kinase inhibitors (cdkI's), including p21, p15, and p27. The connection between the TGF-beta signal and the regulation of cdkI's activity, which have been demonstrated to play crucial roles in cell cycle control, opens a great opportunity for studying TGF-beta signaling mechanism. Preliminary results indicate that TGF-beta activates the transcription of the p21 gene through a unique TGF-beta responsive element (TbetaRE) and transcription factor Sp1 and its family members which interact specifically with this element. Based on these findings, we propose two specific aims to elucidate the precise molecular mechanism by which TGF-beta regulates the expression of p21 through the function of Sp1.
Aim 1 is to determine the mechanism by which Sp1 is activated by the TGF-beta signal. Phosphorylation of Sp1 in response to TGF-beta and the interactions between Sp1 and other proteins which may be directly regulated by the TGF-beta signal will be the focus of research.
Aim 2 is to identify and isolate either kinases or other associated proteins that serve as effectors of the TGF-beta growth inhibitory signal. The accomplishment of these two aims will represent a significant step in the elucidation of the entire TGF-beta signaling pathway downstream of the receptor complex. Since TGF-beta is involved in the control of many cellular functions, a better understanding of its signaling pathway will contribute greatly to our knowledge of how growth hormones function generally. Cellular transformation and tumorigenesis in vivo are sequential multistep processes and loss of cellular responsiveness to negative growth signals may represent a crucial step of those processes. Therefore, results from the proposed research will not only reveal the mechanism of TGF-beta signaling, but also provide insight into molecular events that lead to carcinogenesis in humans.
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