TATA-binding protein, a novel target of EGFR signaling

描述（由申请人提供）：表皮生长因子受体（EGFR）介导的信号转导失调是许多人类癌症发病机制的关键。随着靶向这些受体的新治疗药物的开发，我们必须确定其下游靶点，以更好地了解这些药物的功能，从而设计出更具选择性的治疗药物。TATA结合蛋白TBP是所有细胞基因使用的中心转录因子。我们以前的工作表明，致癌Ras增加TBP的表达，产生选择性，但对细胞转录多效性的影响。此外，增加TBP浓度可促进细胞转化。尽管所有EGFR都激活Ras，我们的初步结果表明EGFR 1、HER-2和EGFR 1变体EGFRvIII差异性地调节TBP表达。我们的建议将测试的假设：（1）TBP的表达是由EGFR家族成员的差异调节，（2）EGFR介导的TBP表达的诱导有助于EGFR的转化功能。我们提出的研究将（1）确定由单个EGFR激活的信号事件，负责其调节TBP表达的能力;（2）确定这些EGFR介导的信号事件直接调节TBP启动子的转录组分;（3）测试细胞TBP浓度是否对EGFR或其下游信号事件诱导的表型变化至关重要。这些研究将极大地影响我们对细胞如何转化的理解。这些研究结果将TBP定义为这些受体和信号分子的新靶点，并建立通用转录起始因子与转化之间的第一个联系。这一信息将成为未来在小鼠中进行基因测试的基础，这些测试将解决TBP在肿瘤发生中的作用。

DESCRIPTION (provided by applicant): 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.