Post-translational regulation of aromatase in aging

摘要：雌激素信号的改变导致一系列异常 从骨骼发育不良到阿尔茨海默病(AD)，都会影响生理和行为。 CYP19A1基因编码芳香酶，芳香酶是雌激素生物合成的最后一种酶 将雄激素转化为雌激素的途径。体内雌激素的合成可以 根据组织的不同在空间和时间上受到调节。雌激素的影响会扩大 除了内质网和内质网的刺激外，最近还被证明调节G- 不同组织中的蛋白质偶联雌激素受体。此外，17-雌二醇(E_2)的影响 基质细胞和免疫细胞在调节免疫系统和 信号转导功能障碍与自身免疫性疾病有关。尽管存在严重的 芳香酶在生物学中的重要作用从上皮组织到组织器官 从大脑到骨骼，关于芳香酶的调节仍然存在许多主要的知识空白 转录和翻译后水平。最近，我们的实验室有了两项重大发现。 首先，我们最近的报告首次证实，Wnt的关键调节因子--蓬乱的蛋白质 信号转导，结合多个组织特异性CYP19A1启动子并调节芳香酶 表情。这些最新的观察结果可能为我们提供重要的洞察 与衰老相关的病理。最近的报告证实了CYP19A1基因突变与 AD，并显示AD患者的神经内分泌学和类固醇激素生成改变。动物模型 进一步表明芳香酶失调在衰老相关病理中的重要性。第二, 我们的团队首次发现了新的翻译后修饰(PTM)调节性赖氨酸 控制芳香酶活性的物质。在我们的报告之前，我们对这种程度一无所知 赖氨酸乙酰化对其调节芳香酶活性。我们假设芳香酶PTM 会受到体内老化的影响。我们现在证明芳香酶PTMS调节 芳香酶抑制剂的敏感性和拟议的研究具有重要意义，因为它们将是第一个 剖析新近发现的芳香酶翻译后调控机制 使用不同的转基因小鼠模型，乳腺组织中的衰老作为年龄的函数。我们 也将通过LC-鉴定乳腺组织中新的芳香酶PTMS作为年龄的函数- MS/MS乙酰化图谱。这些研究代表了一个令人兴奋的新角度，因为 目前还不知道芳香酶PTMS在乳腺组织中的作用， 尤其是，作为年龄的函数。我们进一步假设存在新的芳香酶。 与年龄相关的乳腺微环境的特征。

Summary: Alterations in estrogen signaling contribute to a spectrum of abnormalities ranging from skeletal dysplasias to Alzheimer’s disease (AD) that impact both physiology and behavior. The CYP19A1 gene encodes aromatase which is the final enzyme in the estrogen biosynthesis pathway that converts androgens to estrogens. Synthesis of estrogen throughout the body can be regulated spatially and temporally depending on the tissue. The impact of estrogen extends beyond stimulation of ER and ER and has recently been shown to regulate the function of G- protein coupled estrogen receptors in diverse tissues. Moreover, the impact of 17-estradiol (E2) on stromal and immune cells is important in the regulation of the immune system and dysfunctional signaling has been linked with auto-immune diseases. Despite the critically important role of aromatase in biology in tissues and organs ranging from the epithelial tissue to the brain to bones, many major knowledge gaps remain regarding the regulation of aromatase at the transcriptional and post-translational level. Recently, our lab made two major discoveries. First, our recent reports were the first to establish that Dishevelled proteins, key regulators of Wnt signaling, bind to multiple CYP19A1 tissue specific promoters and modulate aromatase expression. These recent observations could provide significant insight into mechanisms of aging-related pathologies. Recent reports establish links between CYP19A1 gene alterations and AD and show altered neuroendocrinology and steroidogenesis in women with AD. Animal models further show the importance of aromatase dysregulation in aging related pathologies. Second, our group was the first to identify novel post-translational modification (PTM) regulatory lysines that control aromatase enzyme activity. Prior to our report, nothing was known about the extent to which lysine acetylation modulates aromatase activity. We hypothesize that aromatase PTMs will be influenced by aging in vivo. We now demonstrate that aromatase PTMs modulate aromatase inhibitor sensitivity and proposed studies are significant because they will be the first to dissect newly identified post-translational mechanisms of aromatase control as a function of aging in mammary gland tissue as a function of age using different transgenic mouse models. We will also identify novel aromatase PTMs in mammary gland tissue as a function of age via LC- MS/MS acetylation mapping. These studies represent an exciting new angle since virtually nothing is known about the role of aromatase PTMs in vivo in mammary gland tissue in general, and in particular, as a function of age. We further hypothesize that there are novel aromatase PTMs that are characteristic of the age-linked mammary gland microenvironments.