Deregulation of epidermal growth factor receptor (EGFR)-mediated signaling is key to the pathogenesis of many human cancers. As new therapeutic agents are being developed that target these receptors, it is crucial that we define their downstream targets to better understand the function of these drugs, allowing the design of more selective therapeutic agents. The TATA-binding protein, TBP, is a central transcription factor used by all cellular genes. Our previous work revealed that oncogenic Ras increases TBP expression, producing selective but pleiotrophic effects on cellular transcription. Furthermore, increased concentrations of TBP can promote cellular transformation. Although all EGFRs activate Ras, our preliminary results suggest that EGFR1, HER-2 and the EGFR1 variant, EGFRvlll differentially regulate TBP expression. Our proposal will test the hypotheses that: (1) Expression of TBP is differentially regulated by members of the EGFR family, and that (2) EGFR-mediated induction of TBP expression contributes to the transforming function of EGFR. Our proposed studies will (1) Identify the signaling events activated by individual EGFRs that are responsible for their abilities to regulate TBP expression; (2) Identify the transcription components targeted by these EGFR-mediated signaling events that directly regulate the TBP promoter; (3) Test whether cellular TBP concentrations are critical for the phenotypic changes induced by EGFRs or their downstream signaling events. These studies will significantly impact our understanding of how cells become transformed. The results of these studies will define TBP as a new target of these receptors and signaling molecules, and establish the first link between a general transcription initiation factor and transformation. This information will form the basis for future genetic tests in mice that will address the role of TBP in oncogenesis.
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