STAT3 Acetylation and Deacetylation in Metastasis

转移中的 STAT3 乙酰化和脱乙酰化

• 批准号: 7071872
• 负责人: Y. Eugene Chin
• 金额: $ 28.93万
• 依托单位: RHODE ISLAND HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-06-01 至 2010-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7071872
• 关键词: acetylation; clinical research; genetic regulation; human subject; laboratory mouse; mass spectrometry; metastasis; neoplasm /cancer genetics; neoplasm /cancer invasiveness

DESCRIPTION (provided by applicant): Signal transducer and activator of transcription (STAT) activation and inactivation are controlled by protein tyrosine kinase (i.e., JAK) and protein tyrosine phosphatase (i.e., SHP-2) activities, respectively. C-terminal region phosphorylated STAT dimerize and translocate into nuclei where it binds to DNA for transcriptional activation. To achieve maximum transcriptional activity, STAT needs to interact with other nuclear factors. Evidence from our laboratory shows that both p300/CBP and HDAC family members are capable of forming complexes with STAT3 but exert opposite effects on STAT3-dependent transcription: while p300/CBP enhances STATS's activity in transcription, overexpression of the HDAC family member HDAC3 in 293T cells was highly effective in blocking STAT3-dependent transcription. Thus, p300/CBP and HDAC activities may play key roles in regulating STAT3 activity. Recently, STAT3 has been found to play an important role in regulating cell migration and tumor metastasis although the mechanism has yet to be determined. In this regard, STAT3 constitutive phosphorylation has been widely detected in both metastatic and non-metastatic cells. Thus, an additional post-translational modification event seems to be required for STAT3 to regulate gene transcription relevant to acquisition of the metastatic phenotype. The overarching hypothesis to be tested in this proposal is that STAT activity is under the control of acetylation and deacetylation mediated by HAT and HDAC, respectively. It is hypothesized further that constitutive STAT3 acetylation may play a central role in development of metastasis. To fully test these hypotheses, experiments will use our antibody array technology, specific gene-deficiency and/or down regulation, and mass-spectroscopy in order to: (1) explore HAT/HDAC as components of STAT3 signaling complex; (2) test STAT3 acetylation in STAT3 dimerization and resisting to inactivation/degradation; and (3) test the hypothesis that STAT3 acetylation plays a role in metastasis-related gene regulation and constitutive STAT3 acetylation is responsible for metastatic phenotype in vivo. These complimentary approaches will elucidate the role of uncontrolled STAT3 acetylation/deacetylation in causing cancer cell invasion and metasasis.

描述（由申请人提供）：信号转导器和转录激活子（STAT）的激活和失活分别由蛋白酪氨酸激酶（即，JAK）和蛋白酪氨酸磷酸酶（即，SHP-2）活性控制。 C 末端区域磷酸化 STAT 二聚化并易位到细胞核中，与 DNA 结合以实现转录激活。为了实现最大的转录活性，STAT 需要与其他核因子相互作用。我们实验室的证据表明，p300/CBP 和 HDAC 家族成员都能够与 STAT3 形成复合物，但对 STAT3 依赖性转录产生相反的影响：虽然 p300/CBP 增强 STATS 的转录活性，但 HDAC 家族成员 HDAC3 在 293T 细胞中的过表达在阻断 STAT3 依赖性转录方面非常有效。因此，p300/CBP 和 HDAC 活性可能在调节 STAT3 活性中发挥关键作用。最近发现STAT3在调节细胞迁移和肿瘤转移中发挥重要作用，但其机制尚未确定。在这方面，STAT3组成型磷酸化已在转移性和非转移性细胞中广泛检测到。因此，STAT3 似乎需要额外的翻译后修饰事件来调节与获得转移表型相关的基因转录。本提案要测试的总体假设是 STAT 活性分别受到 HAT 和 HDAC 介导的乙酰化和脱乙酰化的控制。进一步假设 STAT3 乙酰化可能在转移的发生中发挥核心作用。为了充分检验这些假设，实验将使用我们的抗体阵列技术、特定基因缺陷和/或下调以及质谱，以便：（1）探索 HAT/HDAC 作为 STAT3 信号复合物的组成部分； (2)测试STAT3二聚化中的STAT3乙酰化和抵抗失活/降解； (3)检验STAT3乙酰化在转移相关基因调控中发挥作用以及组成型STAT3乙酰化负责体内转移表型的假设。这些补充方法将阐明不受控制的 STAT3 乙酰化/脱乙酰化在引起癌细胞侵袭和转移中的作用。