CROSSTALK BETWEEN CAMP AND RAS IN TSH GROWTH SIGNALING

环磷酸腺苷是第一个发现的激素作用的第二信使，对增殖具有细胞类型特异性的影响。许多细胞中的增殖被cAMP抑制，其作用部分通过干扰Ras介导的信号传导来介导。 在内分泌和其他细胞中，cAMP是一种有丝分裂原，在适当的细胞环境中，是一种致癌基因。 已在人垂体和甲状腺肿瘤中鉴定了导致cAMP介导的信号传导的组成性激活的突变。尽管如此，关于cAMP如何刺激增殖相对知之甚少。 我们在甲状腺上皮细胞中的工作揭示了cAMP刺激的增殖通过不同的途径进行，其中只有一些需要PKA活性。 最近发现的cAMP调节的鸟嘌呤核苷酸交换因子Rap 1，一个小的GTP结合蛋白密切相关的Ras，建立cAMP的影响是远远超过目前认识到的分歧。 cAMP和Ras之间以及Ras和Rap之间的潜在串扰是cAMP介导的有丝分裂发生的重要特征。 cAMP在Ras上游和下游的点影响Ras介导的信号传导。 我们是少数几个已经开发和表征细胞模型的实验室之一，用于研究cAMP调节的生长控制。我们研究的长期目标是鉴定参与cAMP刺激的细胞周期进程的分子，并阐明cAMP和Ras介导的信号如何整合在上皮细胞增殖的控制中。 我们的近期目标是确定PKA和Ras在PI 3 K活性调节中的贡献;确定cAMP升高剂激活Ras和Rap的机制，并阐明Ras和PKA如何协同调节Rap 1活性。cAMP和Ras之间的串扰位点的鉴定可能为未来的治疗干预揭示新的药物靶点。鉴于在尸检中观察到的甲状腺肿瘤的高频率（约100%），识别cAMP靶向的生长调节回路是未来研究的重要和令人兴奋的领域。

Cyclic AMP, the first discovered second messenger of hormone action, elicits cell type-specific effects on proliferation. Proliferation in many cells is inhibited by cAMP, effects mediated in part through interference with Ras-mediated signaling. In endocrine and other cells, cAMP is a mitogen, and in the appropriate cellular context, an oncogene. Mutations leading to constitutive activation of cAMP-mediated signaling have been identified in human pituitary and thyroid tumors. Despite this, relatively little is known regarding how cAMP stimulates proliferation. Our work in thyroid epithelial cells has revealed that cAMP-stimulated proliferation proceeds through divergent pathways, only some of which require PKA activity. The recent discover of cAMP-regulated guanine nucleotide exchange factors for Rap1, a small GTP-binding protein closely related to Ras, establishes that the effects of cAMP are far more divergent than currently appreciated. Crosstalk between cAMP and Ras, and potentially between Ras and Rap, is an important feature of cAMP- mediated mitogenesis. cAMP influences Ras-mediated signaling at points both upstream and downstream from Ras. We are one of very few laboratories that have developed and characterized cellular models in which to investigate cAMP-regulated growth control. The long term goals of our studies are to identify the molecules which participate in cAMP-stimulated cell cycle progression, and to elucidate how cAMP- and Ras-mediated signals are integrated in the control of epithelial cell proliferation. Our immediate goals are to define the contributions of PKA and Ras in the regulation of PI3K activity; to identify the mechanisms through which cAMP elevating agents activate both Ras and Rap, and to elucidate how Ras and PKA cooperatively regulate Rap1 activity. The identification of sites of crosstalk between cAMP and Ras may reveal novel drug targets for future therapeutic intervention. Given the high frequency (ca 100 percent) of thyroid tumors observed at autopsy, identification of growth regulatory circuits targeted by cAMP is an important and exciting area for future investigation.