CROSSTALK BETWEEN CAMP AND RAS IN TSH GROWTH SIGNALING

环磷酸腺苷是第一个被发现的荷尔蒙作用的第二信使，它能引起特定细胞类型的增殖效应。许多细胞的增殖受到cAMP的抑制，这种作用部分是通过干扰RAS介导的信号来实现的。在内分泌和其他细胞中，cAMP是一种有丝分裂原，在适当的细胞背景下，是一种癌基因。在人类垂体和甲状腺肿瘤中已发现导致cAMP介导信号的结构性激活的突变。尽管如此，关于cAMP是如何刺激增殖的知之甚少。我们在甲状腺上皮细胞中的研究表明，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。RAP1是一种与RAS密切相关的小GTP结合蛋白，最近发现了cAMP调节的鸟嘌呤核苷酸交换因子，证实了cAMP的作用远比目前所认识的更具差异性。CAMP和RAS之间的串扰，以及RAS和Rap之间的串扰，是cAMP介导的有丝分裂的一个重要特征。CAMP在RAS的上游和下游影响RAS介导的信号转导。我们是为数不多的开发和表征细胞模型以研究cAMP调节生长控制的实验室之一。我们研究的长期目标是确定参与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控制中。我们的近期目标是明确PKA和RAS在调节PI3K活性中的作用；确定cAMP上调因子激活RAS和RAP的机制，并阐明RAS和PKA如何协同调节RAP1活性。识别cAMP和RAS之间的串扰位点可能为未来的治疗干预提供新的药物靶点。鉴于在尸检中观察到的甲状腺肿瘤的频率很高(约100%)，识别cAMP靶向的生长调节回路是未来研究的一个重要而令人兴奋的领域。

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.