DIFFERENTIAL ACTIVATION OF HER BY MEKK1 IN TUMOR CELLS

他莫昔芬治疗卵巢癌具有很大的潜力 女性生殖组织。不幸的是，许多肿瘤是 抵抗治疗并独立生长荷尔蒙。整体而言 拟议研究的目的是阐明其分子机制。 雌激素在肿瘤细胞中的作用，希望能有更好的 了解雌激素和抗雌激素的作用可以 转化为临床上开发的更有效的抗病毒药物 雌激素治疗模式。 雌激素和抗雌激素的作用是通过 雌激素受体(ER)。多项研究表明，内质网可以 被非类固醇生长信号激活，如肽生长因子。 生长因子受体和内质网之间的串扰可能会刺激 雌激素受体阳性肿瘤的激素非依赖性生长 这些肿瘤对他莫昔芬的耐药性。我们的初步结果显示， 人ER由MEKK1在肿瘤细胞中激活，这可能参与了 调停这段相声。拟议研究的具体目标是 为了阐明激活的分子机制，进一步 表征激活的特异性，并检查 激活与激素非依赖性之间的功能关系 肿瘤生长和他莫昔芬耐药。 为了实现这些目标，从MEKK1到ER的信令步骤将 被涉及分析受体的生化方法解剖 在存在或存在的情况下磷酸化和测定受体活性 没有已知的活性或显性阴性形式的激酶 由MEKK1激活。内质网激活的细胞特异性 他莫昔芬敏感和激素非依赖性卵巢、乳腺和子宫 将对肿瘤细胞进行分析和比较。最后，一个稳定和可诱导的 MEKK1的显性负性表达将在 检测肿瘤细胞内源性MEKK1活性是否受到抑制 阻断肿瘤细胞不依赖激素的生长，并改变它们的 对他莫昔芬敏感。

Tamoxifen therapy has great potential for the treatment of tumors of the female reproductive tissues. Unfortunately, many of the tumors are resistant to the therapy and grow hormone-independently. The overall objective of the proposed studies is to elucidate the molecular mechanism of estrogen action in the tumor cells with the hope that a better understanding about action of estrogens and anti-estrogens can be translated clinically into the development of a more effective anti- estrogen therapeutic model. The effects of estrogen and anti-estrogens are mediated through the estrogen receptor (ER). Multiple studies have shown that the ER can be activated by non-steroid growth signals such as peptide growth factors. The cross talk between growth factors receptors and the ER may stimulate the hormone-independent growth of ER-positive tumors and contribute to the resistance of these tumors to tamoxifen. Our preliminary indicate that the human ER is activated in tumor cells by MEKK1, which may be involved in mediating this cross talk. The specific aims of the proposed studies are to elucidate the molecular mechanism underlying the activation, to further characterize the specificity of the activation, and to examine the functional relationship between the activation and hormone-independent tumor growth and tamoxifen resistance. To achieve these objectives, the signaling steps from MEKK1 to the ER will be dissected by biochemical approaches involving in analyzing receptor phosphorylation and assaying the receptor activity in the presence or absence of either activity or dominant negative forms of kinases known to be activated by MEKK1. The cell specificity of the ER activation in tamoxifen-sensitive and hormone independent ovarian, breast and uterine tumor cells will be analyzed and compared. Finally, a stable and inducible expression of a dominant negative form of MEKK1 will be established in the tumor cells to test whether the inhibition of endogenous MEKK1 activity blocks the Hormone-independent growth of the tumor cells and changes their sensitivity to tamoxifen.