A Molecular Basis for Neuroendocrine Carcinogenesis

描述(申请人提供)：在过去的二十年里，癌基因和肿瘤抑制基因的克隆使人们能够深刻地了解癌症的分子基础，并随后为临床干预提供了分子靶点。然而，小细胞肺癌(SCLC)等神经内分泌性肺肿瘤的分子基础仍不清楚。我们推测，生长因子独立性-1(GFI1)转录抑制因子癌蛋白和碱性螺旋-环-螺旋(BHLH)转录因子hachaete和scute Homolog-1(ASH1)是小细胞肺癌的修饰物，因为它们控制着肺上皮的神经内分泌分化。果蝇GFI-1和ASH-1同源基因在果蝇神经发生中的活性与肺神经内分泌细胞和小细胞肺癌的发育有显著的相似性。利用条件性基因敲除和转基因小鼠模型，我们将确定GFI1和ASH1在小细胞肺癌发生、急性肺损伤修复和肺神经内分泌细胞发育中的需求。最后，对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。拟议的实验应该关键地确定新发现的果蝇发育级联中的关键参与者如何与体内小细胞肺癌的诱导有关。

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.