Nuclear cofactors in hormone signaling

描述（由申请人提供）：激素信号传导，如雌性生殖组织中雌激素刺激的细胞增殖和分化，涉及基因表达的动态过程。在小鼠子宫中，以及在人类子宫内膜癌和乳腺癌细胞中，雌激素刺激导致基因表达级联，从而导致显著的细胞增殖。此外，雌激素受体-α（ER α）介导的基因转录激活还需要促进转录调控所需的核辅因子的动态组装。在参与这一动态调控过程的蛋白质因子中，核辅因子可能起着关键作用。事实上，我们以前的研究表明，ACTR，p160/SRC辅因子之一，可以作为ER α和激活剂E2 Fs的共激活剂，因此将雌激素信号传导和细胞周期控制的转录程序更紧密地联系起来。在我们的研究过程中，我们发现一种新的核辅因子ATAAB是高度诱导雌激素在ER α阳性癌细胞以及在小鼠子宫和乳腺上皮细胞。与其在雌激素信号传导中的关键作用一致，我们发现ATAAB可以充当ER α共激活剂。这些和其他发现导致了这样的假设，即雌激素刺激细胞增殖涉及激活一种新的核因子ATAAB，其通过将ER导向特定的靶基因并随后重塑ER-辅激活因子复合物来发挥作用。我们将在以下具体目标中检验这一假设：在目标1中，我们将确定ATAAB在指导和整合E2诱导的细胞增殖转录程序中的作用。在目标2中，我们将确定ATAAB介导ER-ACTR控制基因转录的功能机制。在目的3中，我们将检查ATAAB的生理和病理功能。我们将应用生物化学，分子遗传学和内分泌学的方法来实现这一目标。预计拟议研究的结果将为女性生殖和乳腺癌以及其他内分泌疾病中类固醇受体功能的潜在分子机制提供新的见解。雌激素等激素在女性生殖组织的生长和功能以及乳腺癌中起着至关重要的作用。这些生物学效应主要由控制特定基因表达的激素受体介导。雌激素受体介导的基因转录激活过程受到核辅因子蛋白功能的高度调节。这项研究将探讨核辅因子如何与受体和其他核蛋白一起控制基因表达和雌激素的生物学效应。了解这一过程将为女性生殖和乳腺癌以及其他内分泌疾病中类固醇受体功能的潜在分子机制提供新的见解。

DESCRIPTION (provided by applicant): Hormone signaling such as estrogen-stimulated cell proliferation and differentiation in female reproductive tissues involves dynamic processes of gene expression. In mouse uterus, as well as in human endometrial cancer and breast cancer cells, estrogen stimulation results in cascades of gene expression that leads to marked cell proliferation. In addition, estrogen receptor-alpha (ERa) mediated activation of gene transcription also entails a dynamic assembly of nuclear cofactors that are required for facilitating the transcriptional regulation. Among all the protein factors involved in the dynamic regulation processes, nuclear cofactors may play a key role. Indeed our previous studies indicate that ACTR, one of the p160/SRC cofactors, can function as a coactivator for both ERa and the activator E2Fs, therefore linking closer the transcriptional programs of estrogen signaling and cell cycle control. During the course of our study, we found that a novel nuclear cofactor ATAAB is highly induced by estrogen in ERa-positive cancer cells as well as in the epithelium of mouse uterus and mammary gland. Consistent with its critical role in estrogen signaling, we found that ATAAB can act as an ERa coactivator. These and other findings led to the hypothesis that estrogen stimulation of cell proliferation involves the activation of a novel nuclear factor ATAAB, which functions by directing ER to specific target genes and subsequently remodeling the ER- coactivator complexes. We will test the hypothesis in the following Specific Aims: in Aim 1, we will determine the role of ATAAB in directing and integration of E2-induced transcription program for cell proliferation. In Aim 2, we will determine the functional mechanism of ATAAB in mediating ER-ACTR control of gene transcription. In Aim 3, we will examine the physiological and pathological function of ATAAB. We will apply biochemistry, molecular genetics and endocrinology approaches to achieve the goals. It is anticipated that results from the proposed study will provide novel insights to the underlying molecular mechanisms of steroid receptor function in female reproduction and breast cancers as well as other endocrine disorders. Hormones such as estrogen play crucial roles in the growth and function of female reproductive tissues and in breast cancer. These biological effects are largely mediated by the hormone receptor which controls specific gene expression. The process of estrogen receptor mediated activation of gene transcription is highly regulated by the function of nuclear cofactor proteins. This proposed study will examine how the nuclear cofactors work together with the receptor and other nuclear protein to control gene expression and the biological effects of estrogen. Understanding the process will provide novel insights to the underlying molecular mechanisms of steroid receptor function in female reproduction and breast cancers as well as other endocrine disorders.