CROSSTALK BETWEEN CAMP AND RAS IN TSH GROWTH SIGNALING

描述（改编自申请人摘要）：细胞表面 相互作用影响许多相互通信的信号通路， 最终影响细胞增殖和分化功能。一 信号通路串扰的最佳研究实例包括 cAMP和Ras介导的途径。目前的教条是cAMP抑制了 在大多数细胞类型的增殖中，通过将Ras从其下游解偶联， 效应子如Raf1和细胞质和细胞核的其他成员 激酶级联细胞在文献中的代表性很低， 例如甲状腺细胞，cAMP在其中刺激，而不是抑制， 细胞增殖巧合的是，促甲状腺激素需要Ras作为其促有丝分裂的 尽管激素增加细胞cAMP水平。 在甲状腺细胞中，Ras通过未知的途径发出信号， 涉及Raf1和MAP激酶级联。因此，校长 研究者计划阐明TSH的分子组成 促有丝分裂途径，包括鉴定新的Ras效应子 以及Ras和cAMP之间的相互作用 信号通路这些目标将通过显微注射来实现 转化为单个甲状腺细胞的纯化信号分子， 各种抑制剂。这些研究将导致更好的 了解TSH刺激甲状腺细胞的机制 增长

DESCRIPTION (Adapted from the applicant's abstract): Cell surface interactions influence many intercommunicating signalling pathways that ultimately affect cell proliferation and differentiated functions. One of the best studied examples of signalling pathway crosstalk involves cAMP and Ras-mediated pathways. The present dogma is that cAMP inhibits proliferation in most cell types by uncoupling Ras from its downstream effectors such as Raf1 and other members of a cytoplasmic and nuclear kinase cascade. Very much underrepresented in the literature are cells, such as thyroid cells, in which cAMP stimulates, rather than inhibits, cell proliferation. Paradoxically, TSH requires Ras for its mitogenic effect despite the fact that the hormone increases cellular cAMP levels. In thyroid cells, Ras signals through unknown pathways that do not involve Raf1 and the MAP kinase cascade. Therefore, the principal investigator plans to elucidate the molecular components of TSH mitogenic pathways, including the identification of new Ras effectors active in thyroid cells as well as the interaction between Ras and cAMP signalling pathways. These goals will be accomplished by microinjection into individual thyroid cells of purified signalling molecules and a variety of their inhibitors. These studies will lead to a better understanding of the mechanism by which TSH stimulates thyroid cell growth.