A Molecular Basis for Neuroendocrine Carcinogenesis

描述（申请人提供）：近二十年来，癌基因和抑癌基因的克隆使人们对癌症的分子基础有了深刻的认识，并为临床干预提供了分子靶点。然而，神经内分泌肺肿瘤如小细胞肺癌（SCLC）的分子基础尚不清楚。我们假设生长因子独立-1 （GFI1）转录抑制因子癌蛋白和碱性螺旋-环-螺旋（bHLH）转录因子人achaete和鳞片同源物-1 （ASH1）是SCLC的调节剂，因为它们控制肺上皮的神经内分泌分化。果蝇同源基因GFI - 1和ASH - 1在果蝇神经发生中的活性与肺神经内分泌细胞和SCLC的发育有着惊人的相似之处。通过条件敲除和转基因小鼠模型，我们将确定GFI1和ASH1在SCLC肿瘤发生、急性肺气道损伤修复和肺神经内分泌细胞发育中的需求。最后，GFI1靶基因调控的分子解剖将把转录效应与肺表型联系起来。提出的实验应该批判性地确定新发现的果蝇发育级联的关键参与者如何与体内SCLC的诱导相关。

DESCRIPTION (provided by applicant): The cloning of oncogenes and tumor suppressor genes over the last twenty years has allowed profound insight into the molecular basis of cancer, and subsequently provided molecular targets for clinical intervention. However, the molecular basis of neuroendocrine lung tumors such as small cell lung carcinoma (SCLC) is still not understood. We hypothesize that the Growth factor independence-1 (GFI1) transcriptional repressor oncoprotein and the basic helix-loop-helix (bHLH) transcription factor human achaete and scute homolog- 1 (ASH1) are modifiers of SCLC because they control neuroendocrine differentiation of lung epithelium. Striking parallels can be drawn between the activity of Drosophila orthologs of GFI 1 and ASH 1 in fly neurogenesis, and the development of pulmonary neuroendocrine cells and SCLC. Using conditional knockout and transgenic mouse models, we will determine the requirement for GFI1 and ASH1 in SCLC oncogenesis, acute lung airway injury repair and pulmonary neuroendocrine cell development. Finally, a molecular dissection of GFI1 target gene regulation will link transcription effects to lung phenotypes. The proposed experiments should critically determine how key participants in a newly discovered Drosophila developmental cascade are relevant to the induction of SCLC in vivo.