SMOKE INDUCED MUCIN TRANSCRIPTION AND MITOGENESIS

烟草烟雾导致慢性支气管炎和肺癌的机制尚不清楚。 然而，我们最近的研究结果表明，烟雾直接诱导肺上皮细胞中的粘蛋白mRNA和有丝分裂，这是由Src激酶的激活和EGF受体（EGFr）的磷酸化之前提供的线索。 Src激酶抑制剂消除烟雾诱导的EGFr磷酸化，粘蛋白转录诱导和有丝分裂。 EGFr激酶抑制剂消除烟雾诱导的EGFr磷酸化和有丝分裂，但只能部分阻断粘蛋白转录上调。 这使我们假设，烟雾激活一个分支信号通路从Src激酶发出。 该通路的一个分支是EGFR依赖性的，足以解释烟雾诱导的有丝分裂;另一个是EGFR非依赖性的，其作用与另一个分支的作用相加，以介导粘蛋白转录。 本提案中描述的实验将提供有关EGFR依赖性和非依赖性信号通路的信息。 在特定目标I下描述的实验中，我们将鉴定导致（a）粘蛋白诱导和（B）有丝分裂的烟雾信号通路的EGFR相互作用元件。 在特定目标II下描述的实验中，我们将鉴定导致（a）粘蛋白诱导和（B）有丝分裂的烟雾信号通路的Src相互作用元件。 在特定目标III下描述的实验中，我们将鉴定负责激活（a）粘蛋白诱导和（B）有丝分裂的烟雾组分。 这些研究的结果应揭示控制点服从抑制药物。

The mechanisms by which tobacco smoke cause chronic bronchitis and lung cancer are unknown. Clues are provided, however, by our recent findings showing that smoke directly induces mucin mRNA and mitogenesis in lung epithelial cells and that this is preceded by activation of Src kinase and phosphorylation of the EGF receptor (EGFr). Src kinase inhibitors abrogate smoke-induced EGFr phosphorylation, mucin transcription induction and mitogenesis. EGFr kinase inhibitors abrogate smoke-induced EGFr phosphorylation and mitogenesis but only partially block mucin transcriptional upregulation. This leads us to hypothesize that smoke activates a branched signaling pathway emanating from Src kinase. One arm of the pathway is EGFr-dependent and is sufficient to account for smoke-induced mitogenesis; the other is EGFr-independent and its effects summate with those of the other branch to mediate mucin transcription. The experiments described in this proposal will provide information regarding both the EGFr-dependent and -independent signaling pathways. In experiments described under Specific Aim I, we will identify EGFr-interacting elements of the smoke-signaling pathway leading to (a) mucin induction and (b) mitogenesis. In experiments described under Specific Aim II, we will identify Src-interacting elements of the smoke signaling pathway leading to (a) mucin induction and (b) mitogenesis. In experiments described under Specific Aim III, we will identify components of smoke responsible for activating (a) mucin induction and (b) mitogenesis. The results of these studies should reveal control points amenable to inhibition by pharmacological agents.