Ballaré Cecilia, Vallejo Griselda, Vicent Guillermo P, Saragüeta Patricia, Beato Miguel
Centre de Regulació Genòmica (CRG), Universitat Pompeu Fabra (UPF), PRBB, Dr. Aiguader 88, E-08003 Barcelona, Spain.
J Steroid Biochem Mol Biol. 2006 Dec;102(1-5):2-10. doi: 10.1016/j.jsbmb.2006.09.030. Epub 2006 Oct 27.
In addition to transcriptional effects, steroid hormones rapidly activate cytoplasmic signaling cascades. The ultimate targets of these cascades are not well-defined and likely include transcription factors and coactivators. To better understand the role of the rapid "non-transcriptional" effects of progestins, we investigated the mechanisms leading to activation of these pathways and their relevance in the biological response, using two model systems: breast cancer and endometrial stromal cells. Our results demonstrated that progestins rapidly activate the Src/Erk1/2 and PI3K/Akt pathways in both cellular types via crosstalk between PR and ERalpha or ERbeta. This activation is essential for triggering proliferative response. However, even when the activation of kinase cascades is similar in both cellular types, the biological outcome of progestin treatment is different. A different ability of PR to mediate transcriptional effects might account for this discrepancy. Also differences in amount and subcellular location of PR, presence of ERalpha or ERbeta and alternative receptors could be also important for determining the cellular response. We also explored the connection between rapid activation of kinase cascades and transcriptional induction by progestins. Our results uncover a novel function of the rapid Erk activation by progestins, namely its direct involvement in transcriptional induction of MMTV promoter and other progesterone-target genes.
除了转录作用外，类固醇激素还能迅速激活细胞质信号级联反应。这些级联反应的最终靶点尚未明确界定，可能包括转录因子和共激活因子。为了更好地理解孕激素快速“非转录”作用的作用机制，我们使用乳腺癌和子宫内膜基质细胞这两种模型系统，研究了导致这些信号通路激活的机制及其在生物学反应中的相关性。我们的结果表明，孕激素通过孕激素受体（PR）与雌激素受体α（ERα）或雌激素受体β（ERβ）之间的相互作用，在这两种细胞类型中迅速激活Src/Erk1/2和PI3K/Akt信号通路。这种激活对于触发增殖反应至关重要。然而，即使两种细胞类型中激酶级联反应的激活情况相似，孕激素处理的生物学结果也有所不同。PR介导转录作用的能力差异可能是造成这种差异的原因。PR的数量和亚细胞定位、ERα或ERβ的存在以及其他替代受体的差异，对于确定细胞反应也可能很重要。我们还探讨了孕激素对激酶级联反应的快速激活与转录诱导之间的联系。我们的结果揭示了孕激素快速激活Erk的一种新功能，即它直接参与MMTV启动子和其他孕激素靶基因的转录诱导。
