Ras signaling through PI3K confers hormone-independent proliferation that is compatible with differentiation
Ras signaling through PI3K confers hormone-independent proliferation that is compatible with differentiation
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DOI：
10.1038/sj.onc.1203393
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发表时间：
2000-02-17
期刊：
影响因子：
8
通讯作者：
Meinkoth, JL
中科院分区：
文献类型：
--
作者：
Cass, LA;Meinkoth, JL
激素是刺激其分化的靶细胞增殖的特化有丝分裂原。促甲状腺激素（TSH）是甲状腺细胞的生理调节因子，刺激cAMP介导的增殖和甲状腺特异性基因表达。TSH的促有丝分裂作用需要Ras，因此Ras活化应与甲状腺分化的维持相容。然而，活化的Ras的表达破坏了甲状腺细胞的分化表型。这种明显矛盾的一种解释是Res效应通路的选择性利用。我们检验了Ras信号通过PI 3 K介导TSH在保持其分化特征的细胞中的促有丝分裂作用的假设。Ras效应突变体（RasV 12 S35）的表达，优先通过Raf-1的信号，虽然足以赋予TSH-独立的增殖，废除甲状腺球蛋白和钠/碘同向转运体的表达，相反，表达的Ras突变体（RasV 12 C40），选择性结合PI 3 K赋予TSH-独立的增殖没有显着影响甲状腺特异性基因表达。与TSH对表达RasV 12 S35的细胞增殖的抑制作用不同，TSH通过进一步增加p70 s6 k的活性来增强RasV 12 C40刺激的增殖，p70 s6 k是TSH和RasV 12 C40的促有丝分裂作用的重要介质。这些结果表明，引导Ras依赖性信号到PI 3 K赋予TSH刺激分化细胞增殖的能力。
Hormones are specialized mitogens that stimulate proliferation in their differentiated target cells. Thyrotropin (TSH), the physiologic regulator of thyroid cells, stimulates cAMP-mediated proliferation and thyroidspecific gene expression. The mitogenic effects of TSH require Ras, therefore Ras activation should be compatible with the maintenance of thyroid differentiation. However, expression of activated Ras extinguishes the differentiated phenotype of thyroid cells, One explanation for this apparent paradox is the selective utilization of Res effector pathways. We tested the hypothesis that Ras signaling through PI3K mediates the mitogenic effects of TSH in cells which retain their differentiated character. Expression of a Ras effector mutant (RasV12S35) that signals preferentially through Raf-1, although sufficient to confer TSH-independent proliferation, abolished hormone-regulated expression of thyroglobulin and the sodium/iodide symporter, In contrast, expression of a Ras mutant (RasV12C40) that binds selectively to PI3K conferred TSH-independent proliferation without marked effects on thyroid-specific gene expression. Unlike the inhibitory effects of TSH on the proliferation of RasV12S35-expressing cells, TSH enhanced RasV12C40-stimulated proliferation by further increasing the activity of p70s6k, an important mediator of the mitogenic effects of TSH and RasV12C40. These results demonstrate that channeling Ras-dependent signals to PI3K confers TSH with the ability to stimulate proliferation in differentiated cells.