Cyclic AMP activates Ras.-猫眼课题宝

环 AMP 激活 Ras。

DOI：

10.1038/sj.onc.1203680

发表时间：

2000

期刊：

Oncogene.

影响因子：

--

通讯作者：

中科院分区：

--

文献类型：

--

作者：

Tsygankova,OM;Kupperman,E;Wen,W;Meinkoth,JL

除了蛋白激酶A （PKA）外，cAMP还调节cAMP门控通道和rap1特异性鸟嘌呤核苷酸交换因子的活性。我们验证了cAMP的靶点可能也包括Ras原癌基因的调节因子的假设。在大鼠甲状腺细胞中，促甲状腺素（TSH）通过camp介导的需要Ras活性的途径刺激增殖。干扰Ras会损害TSH以及cAMP升高剂和类似物刺激的DNA合成，表明对Ras的需求位于cAMP的下游。尽管cAMP能刺激细胞增殖，但微注射纯化的PKA催化亚基却不能，这表明除了PKA外，cAMP刺激的细胞周期进程还需要其他因素。当加入到表达人Ha-Ras的甲状腺细胞中时，TSH迅速而显著地增加了gtp结合Ras的比例。Ras活性在添加TSH后1分钟内升高，在5-15分钟达到最大值，在激素治疗后30-60分钟降至基础水平。环AMP升高剂对Ras也有类似的作用，表明TSH通过camp介导的途径激活Ras。虽然cAMP介导，但TSH和cAMP对Ras的激活与PKA活性无关。此外，酪氨酸激酶抑制剂不会损害camp刺激的Ras活化。这些结果表明，除了PKA外，cAMP还激活甲状腺细胞中的靶标，这些靶标可能包括Ras的调节因子。cAMP升高剂除了激活PKA外，还能激活Ras，这可能解释了PKA催化亚基无法刺激甲状腺细胞的DNA合成。

In addition to protein kinase A (PKA), cAMP regulates the activity of cAMP-gated channels and Rap1-specific guanine nucleotide exchange factors. We tested the hypothesis that the targets of cAMP might also include regulators of the Ras protooncogene. In rat thyroid cells, thyrotropin (TSH) stimulates proliferation through a cAMP-mediated pathway that requires Ras activity. Interference with Ras impairs DNA synthesis stimulated by TSH as well as cAMP elevating agents and analogs, demonstrating that the requirement for Ras lies downstream of cAMP. Although cAMP stimulates proliferation, microinjection of the purified PKA catalytic subunit failed to do so, suggesting that factors in addition to PKA are required for cAMP-stimulated cell cycle progression. When added to thyroid cells expressing human Ha-Ras, TSH rapidly and markedly increased the proportion of GTP-bound Ras. Ras activity was increased within 1 min of TSH addition, maximal at 5–15 min, and declined to basal levels 30–60 min after hormone treatment. Cyclic AMP elevating agents elicited similar effects on Ras, indicating that TSH activates Ras through a cAMP-mediated pathway. Although cAMP-mediated, Ras activation by TSH and cAMP was independent of PKA activity. Moreover, cAMP-stimulated Ras activation was not impaired by tyrosine kinase inhibitors. These results indicate that cAMP activates targets in addition to PKA in thyroid cells, and that these targets may include regulators of Ras. The ability of cAMP elevating agents to activate Ras in addition to PKA may explain the inability of the PKA catalytic subunit to stimulate DNA synthesis in thyroid cells.