Ahonen Tommi J, Härkönen Pirkko L, Rui Hallgeir, Nevalainen Marja T
United States Military Cancer Institute, Uniformed Services University of the Health Sciences, 4301 Jones Bridge Road, Bethesda, MD 20814, USA.
Endocrinology. 2002 Jan;143(1):228-38. doi: 10.1210/endo.143.1.8576.
Using long-term organ cultures of rat prostate tissue explants, we previously demonstrated that PRL both stimulates proliferation and acts as an androgen-independent suppressor of apoptosis in prostate epithelial cells, leading to epithelial hyperplasia. In this work we delineate intracellular signaling molecules activated by PRL in prostate tissue to identify candidate signaling proteins that are responsible for maintaining survival and proliferation of prostate epithelium in androgen-deprived growth environment. We now show that signal transducer and activator of transcription-5a (Stat5a) and Stat5b become tyrosine phosphorylated in response to PRL stimulation in rat prostate using prostate organ culture as an experimental model. Stat5 was translocated to the nuclei of epithelial cells of prostate tissue as demonstrated by immunohistochemistry. Furthermore, EMSA showed PRL-inducible binding of Stat5a homodimers and Stat5a/5b heterodimers to the PRL response element of the beta-casein gene promoter. Signaling molecules Stat3, Stat1, MAPK, or protein kinase B, which can be activated by PRL in other target cells, were not activated by PRL in prostate tissue. Furthermore, we show that Stat5a and Stat5b are continuously phosphorylated in rat prostate in vivo, although they are expressed to varying degree in separate lobes of rat prostate. Collectively, our results suggest that PRL signaling in rat prostate tissue is primarily transduced via Stat5a and Stat5b. The Stat5 pathway represents one candidate signaling mechanism, used by PRL and possibly other growth factors and cytokines, that supports the viability of prostate epithelial cells during long-term androgen deprivation.
利用大鼠前列腺组织外植体的长期器官培养，我们先前证明催乳素（PRL）既能刺激前列腺上皮细胞增殖，又能作为雄激素非依赖性凋亡抑制因子，导致上皮增生。在这项研究中，我们描绘了PRL在前列腺组织中激活的细胞内信号分子，以确定在雄激素剥夺生长环境中负责维持前列腺上皮细胞存活和增殖的候选信号蛋白。我们现在以前列腺器官培养作为实验模型，表明在大鼠前列腺中，信号转导及转录激活因子5a（Stat5a）和Stat5b在PRL刺激下会发生酪氨酸磷酸化。免疫组织化学显示Stat5转移至前列腺组织上皮细胞核。此外，电泳迁移率变动分析（EMSA）表明，PRL可诱导Stat5a同二聚体和Stat5a/5b异二聚体与β-酪蛋白基因启动子的PRL反应元件结合。在其他靶细胞中可被PRL激活的信号分子Stat3、Stat1、丝裂原活化蛋白激酶（MAPK）或蛋白激酶B，在前列腺组织中未被PRL激活。此外，我们发现Stat5a和Stat5b在大鼠前列腺体内持续磷酸化，尽管它们在大鼠前列腺的不同叶中表达程度不同。总体而言，我们的结果表明，大鼠前列腺组织中的PRL信号主要通过Stat5a和Stat5b转导。Stat5途径代表了一种候选信号机制，PRL以及可能的其他生长因子和细胞因子利用该机制在长期雄激素剥夺期间维持前列腺上皮细胞的活力。
