Transcriptional hyperactivity of human progesterone receptors is coupled to their ligand-dependent down-regulation by mitogen-activated protein kinase-dependent phosphorylation of serine 294.
Transcriptional hyperactivity of human progesterone receptors is coupled to their ligand-dependent down-regulation by mitogen-activated protein kinase-dependent phosphorylation of serine 294.
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人孕酮受体的转录亢进与丝氨酸 294 的丝裂原激活蛋白激酶依赖性磷酸化与其配体依赖性下调相关。
DOI：
10.1128/mcb.21.18.6122-6131.2001
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发表时间：
2001
影响因子：
5.3
通讯作者：
Lange,CA
中科院分区：
文献类型：
--
作者：
Shen,T;Horwitz,KB;Lange,CA
乳腺癌经常表现为酪氨酸激酶生长因子受体的表达升高；这些途径部分通过靶向类固醇激素受体（包括孕激素受体）来影响乳腺癌细胞的生长。为了模拟生长因子启动的信号通路下游分子的激活，我们在表达PR B亚型的T47D人乳腺癌细胞中过度表达丝裂原激活蛋白激酶（MAPK，也称为细胞外信号调节激酶）激酶1 （MEKK1）。MEKK1是p42和p44 MAPKs的强激活剂。MEKK1的表达使孕激素介导的转录水平比正常pr驱动的转录水平高8- 10倍。这取决于黄体酮反应元件和功能性PR的存在。单独使用MEKK1时PR蛋白水平不变，但MEKK1加黄体酮R5020时PR蛋白水平广泛下调。MEKK1表达导致PR在Ser294上的磷酸化，Ser294是MAPK共识位点，已知介导配体依赖性PR降解。MEK抑制剂阻断Ser294的磷酸化并减弱对MEKK1 + R5020的反应的PR转录过度活性；通过抑制26S蛋白酶体来稳定PR也产生了类似的结果。稳定表达突变体S294A PR（其中丝氨酸294被丙氨酸取代）的T47D细胞无法进行配体依赖性下调，并且对mekk1 - + r5020诱导的转录协同作用具有抗性，但仅对黄体酮有反应。同样，在表达野生型PR的细胞中，表皮生长因子和R5020能协同提高c-myc蛋白水平，而S294A PR则不能。因此，高度稳定的突变型PR对黄体酮有反应，但不能与mapk驱动的通路进行串扰。这些研究证明了类固醇受体下调和转录过度活跃之间的矛盾耦合。他们还提出，在响应肽生长因子信号的MAPKs磷酸化PR和类固醇激素控制乳腺癌细胞生长之间存在联系。
Breast cancers often exhibit elevated expression of tyrosine kinase growth factor receptors; these pathways influence breast cancer cell growth in part by targeting steroid hormone receptors, including progesterone receptors (PR). To mimic activation of molecules downstream of growth factor-initiated signaling pathways, we overexpressed mitogen-activated protein kinase (MAPK; also known as extracellular signal-regulated kinase) kinase kinase 1 (MEKK1) in T47D human breast cancer cells expressing the B isoform of PR. MEKK1 is a strong activator of p42 and p44 MAPKs. MEKK1 expression increased progestin-mediated transcription 8- to 10-fold above normal PR-driven transcription levels. This was dependent on the presence of a progesterone response element and functional PR. PR protein levels were unchanged by MEKK1 alone but were extensively down-regulated by MEKK1 plus the progestin R5020. MEKK1 expression resulted in phosphorylation of PR on Ser294, a MAPK consensus site known to mediate ligand-dependent PR degradation. MEK inhibitors blocked phosphorylation of Ser294 and attenuated PR transcriptional hyperactivity in response to MEKK1 plus R5020; stabilization of PR by inhibition of the 26S proteasome produced similar results. T47D cells stably expressing mutant S294A PR, in which serine 294 is replaced by alanine, fail to undergo ligand-dependent down-regulation and are resistant to MEKK1-plus-R5020-induced transcriptional synergy but respond to progestins alone. Similarly, c-mycprotein levels are synergistically increased by epidermal growth factor and R5020 in cells expressing wild-type PR, but not S294A PR. Thus, highly stable mutant PR are functional in response to progestins but are incapable of cross talk with MAPK-driven pathways. These studies demonstrate a paradoxical coupling between steroid receptor down-regulation and transcriptional hyperactivity. They also suggest a link between phosphorylation of PR by MAPKs in response to peptide growth factor signaling and steroid hormone control of breast cancer cell growth.