Thyrotropin-induced mitogenesis is Ras dependent but appears to bypass the Raf-dependent cytoplasmic kinase cascade
Thyrotropin-induced mitogenesis is Ras dependent but appears to bypass the Raf-dependent cytoplasmic kinase cascade
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促甲状腺素诱导的有丝分裂是 Ras 依赖性的，但似乎绕过了 Raf 依赖性细胞质激酶级联
DOI：
10.1128/mcb.15.3.1162
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发表时间：
1995
影响因子：
5.3
通讯作者：
J. Feramisco
中科院分区：
文献类型：
--
作者：
N. Al;D. Rose;C. Buckmaster;N. Ahn;U. Rapp;J. Meinkoth;J. Feramisco
细胞生长控制需要协调和整合可能同时被激活的多种信号通路。促甲状腺激素（TSH）在甲状腺细胞中启动的促有丝分裂信号似乎需要两种不同的信号通路，环腺苷酸（cAMP）依赖性信号通路和Ras依赖性信号通路。这是一个悖论，因为活化的cAMP依赖性蛋白激酶破坏了由生长因子如表皮生长因子和血小板衍生生长因子诱导的Ras依赖性信号传导。这种抑制可能通过阻止Raf-1蛋白激酶与Ras结合而发生，这一事件被认为是Raf-1活化和随后促分裂原活化蛋白（MAP）/细胞外信号调节激酶（ERK）激酶（MEK）和MAP激酶（MAPK）/ERK活化所必需的。在这里，我们报告说，血清刺激的Raf-1的过度磷酸化抑制TSH治疗Wistar大鼠甲状腺细胞，表明在这个细胞系，在其他细胞类型，细胞内cAMP水平的增加抑制Ras靶向的下游激酶的激活。同样，TSH也抑制了Ras刺激的含有AP-1启动子元件的基因表达。另一方面，用TSH刺激甲状腺细胞导致刺激DNA合成，这是Ras依赖的，但Raf-1和MEK都不依赖。我们还表明，Ras刺激的DNA合成需要使用这种激酶级联在未经处理的静止细胞，但不是在TSH处理的细胞。这些数据表明，在TSH处理的甲状腺细胞，Ras可能能够通过效应器以外的信号，而不是充分研究的细胞质激酶级联。
Cellular growth control requires the coordination and integration of multiple signaling pathways which are likely to be activated concomitantly. Mitogenic signaling initiated by thyrotropin (TSH) in thyroid cells seems to require two distinct signaling pathways, a cyclic AMP (cAMP)-dependent signaling pathway and a Ras-dependent pathway. This is a paradox, since activated cAMP-dependent protein kinase disrupts Ras-dependent signaling induced by growth factors such as epidermal growth factor and platelet-derived growth factor. This inhibition may occur by preventing Raf-1 protein kinase from binding to Ras, an event thought to be necessary for the activation of Raf-1 and the subsequent activation of the mitogen-activated protein (MAP)/extracellular signal-regulated kinase (ERK) kinases (MEKs) and MAP kinase (MAPK)/ERKs. Here we report that serum-stimulated hyperphosphorylation of Raf-1 was inhibited by TSH treatment of Wistar rat thyroid cells, indicating that in this cell line, as in other cell types, increases in intracellular cAMP levels inhibit activation of downstream kinases targeted by Ras. Ras-stimulated expression of genes containing AP-1 promoter elements was similarly inhibited by TSH. On the other hand, stimulation of thyroid cells with TSH resulted in stimulation of DNA synthesis which was Ras dependent but both Raf-1 and MEK independent. We also show that Ras-stimulated DNA synthesis required the use of this kinase cascade in untreated quiescent cells but not in TSH-treated cells. These data suggest that in TSH-treated thyroid cells, Ras might be able to signal through effectors other than the well-studied cytoplasmic kinase cascade.
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DOI：
10.1073/pnas.90.21.10300
发表时间：
1993-11-01
影响因子：
11.1
作者：
GRAVES, LM;BORNFELDT, KE;KREBS, EG
通讯作者：
KREBS, EG
催化抗体：结构和功能。
DOI：
10.1385/cbb:35:1:63
发表时间：
2001
期刊：
Cell biochemistry and biophysics.
影响因子：
--
作者：
WentworthJr,P;Janda,KD
通讯作者：
Janda,KD
影响因子：
56.9
作者：
COOK, SJ;MCCORMICK, F
通讯作者：
MCCORMICK, F
影响因子：
56.9
作者：
WU, J;DENT, P;STURGILL, TW
通讯作者：
STURGILL, TW
Raf-1 和 p21v-ras 协同激活丝裂原激活蛋白激酶。
DOI：
10.1073/pnas.90.12.5772
发表时间：
1993
影响因子：
11.1
作者：
Williams,NG;Paradis,H;Agarwal,S;Charest,DL;Pelech,SL;Roberts,TM
通讯作者：
Roberts,TM