CALMODULIN IN ANDROGEN REGULATION OF PROSTATE CANCER

描述（改编自应用程序） 所有哺乳动物细胞，包括前列腺上皮细胞， 研究需要多肽生长因子用于增殖。前列腺细胞 增殖还受雄激素调节。然而，我们非常了解 雄激素是如何调节细胞增殖的。 细胞从G1期进入S期的进程依赖于由 钙离子和钙调素（CaM）。在G1/S边界抑制CaM，防止 细胞进入S期。CaM的这一关键作用似乎是 由68 kDa的特异性CaM结合蛋白（CaMBP 68）介导。CaMBP 68 表现出生长因子依赖性的从细胞质易位到 细胞核进入S期，在那里它与DNA紧密结合 聚合酶-α/引物酶，DNA复制所需的复制酶复合物的一种成分 复制的雄激素敏感性（LNCaP）前列腺癌细胞也在生长 抑制抗钙调素药物，表明钙调素的关键作用，也在前列腺 癌细胞增殖此外，雄激素非依赖性（DU 145和PC 3） 前列腺癌细胞在其细胞核中具有显著更高水平的CaMBP 68 （与LNCaP细胞相比），并且对LNCaP细胞的敏感性低6-8倍。 钙调素拮抗剂的生长抑制作用优于雄激素敏感细胞。 综上所述，这些观察结果使我们假设钙调素和钙离子通道蛋白 在前列腺癌细胞的雄激素调节中起重要作用 增殖 为了验证这一假设，我们将首先确定细胞周期中的点， 当同步雄激素敏感性 前列腺癌细胞从G1期进入S期，然后鉴定是否 在细胞周期的这一点上，雄激素刺激的事件是由CaM介导的， 或CaMBP 68。基于早期对雌激素受体的观察，我们将 确定钙调素是否是雄激素受体（AR）结合所必需的， 雄激素反应元件（ARE）和雄激素反应元件的表达 基因.由于我们观察到雄激素非依赖性细胞， 雄激素敏感细胞中CaMBP 68的水平显著增加， 细胞核，并且由于CaMBP 68是复制酶复合物的必需组分， 我们将检查复制酶的组装是否有任何差异， 这两个细胞系统之间的联系。阐明了 雄激素调节细胞周期及钙调素在雄激素调节中的作用 这些研究中的行动可能为以下方面提供新的见解和机会： 控制前列腺癌细胞增殖和治疗该疾病。

DESCRIPTION (adapted from the application) All mammalian cells, including prostate epithelial cells, that have been studied require polypeptide growth factors for proliferation. Prostate cell proliferation is additionally regulated by androgen. However, we know very little about how androgen regulates cell proliferation. Progression of cells from G1 into S phase is dependent on events regulated by calcium ion and calmodulin (CaM). Inhibition of CaM at G1/S boundary, prevents cells from entering into S phase. This critical role of CaM appears to be mediated by a specific CaM binding protein of 68 kDa (CaMBP68). CaMBP68 exhibits growth factor dependent translocation from the cytoplasm into the nucleus of cells entering into S phase, where it binds tightly to DNA polymerase-alpha/primase, a component of the replitase complex required for DNA replication. Androgen sensitive (LNCaP) prostate cancer cells also are growth inhibited by antiCaM drugs, suggesting a critical role of CaM also in prostate cancer cell proliferation. Moreover, androgen independent (DU145 and PC3) prostate cancer cells have a markedly higher level of CaMBP68 in their nuclei (compared to that in LNCaP cells) and are 6-8 times less sensitive to the growth inhibitory effect of CaM antagonists than are androgen sensitive cells. Taken together, these observations lead us to postulate that CaM and CaMBPs play an essential role in androgen regulation of prostate cancer cell proliferation. To test this hypothesis we will first determine the point in the cell cycle when androgen is required for progression of synchronized androgen sensitive prostate cancer cells from G1 into S phase and then identify whether androgen-stimulated events at that point in cell cycle are being mediated CaM or CaMBP68. Based on earlier observations with the estrogen receptor, we will determine whether CaM is essential for the binding of androgen receptor (AR) to androgen responsive element (ARE) and for the expression of androgen responsive genes. Since we observed that androgen independent cells, as compared to androgen sensitive cells, contain markedly increased levels of CaMBP68 in their nuclei, and since CaMBP68 is an essential component of the replitase complex, we will examine whether there are any differences in the assembly of replitase complexes between these two cell systems. Elucidating the mechanism by which androgen regulates the cell cycle and identifying the role of CaM in androgen action in these studies may provide new insights and opportunities for controlling prostate cancer cell proliferation and treatment of the disease.