The investigators long term objectives are to elucidate the role of Smads (Sma/MAD), two of which have been demonstrated as tumor suppressor genes, in the mediation of transforming growth factor beta (TGF-b) growth inhibitory signal and evaluate the potential involvement of Smads in the process of tumorigenesis in an animal model system. As a multi-functional growth hormone, TGF-b regulates many different aspects of cellular functions, such as proliferation, differentiation, extracellular matrix deposition. However, the signal transduction pathways through which the various biological effects of TGF-b are mediated remain largely unknown. Recently, it has been demonstrated, by the investigator s laboratory and others, that Smads, discovered originally in the TGF-b-like DPP pathway in Drosophila, function as intermediators to transmit the TGF-b signal from the cytoplasm to the nucleus. Once in the nucleus, Smads participate in transcriptional activation of specific genes through a still poorly defined mechanism. In this context, they propose four specific aims to achieve the stated research goals. Their preliminary results demonstrated that Smad3/4 complex is induced by TGF-b to bind to promoter sequences. However, the mechanism by which Smad3/4 activates transcription through AP1 sites is still unclear. Based on those findings, Aim 1 will determine how the endogenous PAI-1 gene is activated by the Smads and Aim 2 will focus on the functional relationship between the Smads and AP1 complexes in the process of TGF-b mediated transcription activation.
Aim 3 will identify and isolate novel downstream target genes for Smad2 and Smad3 as mediators of TGF-b growth inhibitory signal.
Aim 4 will generate the expression profiles of Smad2 and Smad3 and create Smad3 null mice for analysis of the physiological roles of Smad3 during mouse development and its potential involvement in carcinogenesis. The accomplishment of these four aims will represent a significant step in the elucidation of a specific TGF-b signaling pathway downstream of the receptor complex. Since TGF-b is involved in the control of many cellular functions, a better understanding of its signaling pathways will not only provide insight into molecular events that lead to carcinogenesis in humans, but also help the development of new strategies for the treatment of human cancers.
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