Differentially Regulating Apoptosis by AR: Activating Bax or Inhibiting JNK MAPK

AR 差异调节细胞凋亡：激活 Bax 或抑制 JNK MAPK

• 批准号: 7810533
• 负责人: JIALING XIANG
• 金额: $ 30.08万
• 依托单位: ILLINOIS INSTITUTE OF TECHNOLOGY
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-06-01 至 2013-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7810533
• 关键词: Androgen Receptor; Androgens; Animal Model; Apoptosis; Apoptotic; Bax protein; Binding; Biological Process; Cell Death; Cell Proliferation; Cessation of life; Cultured Cells; Death Domain; Development; Family member; Gene Targeting; Genes; Genetic Transcription; Goals; Growth; JUN gene; Ligands; Light; MAP Kinase Gene; Malignant neoplasm of prostate; Mediating; Mitogen-Activated Protein Kinases; Molecular; N-terminal; Neurodegenerative Disorders; Noxae; Physiological; Prevention; Prostatic Neoplasms; Protein Family; Protein Kinase; Proteins; Regulation; Role; Stimulus; TNF gene; Testing; Time; Tumor Necrosis Factor-alpha; Tumor Necrosis Factors; UV induced; Work; base; human disease; in vivo; killings; member; novel strategies; receptor function; response; spinal and bulbar muscular atrophy; steroid hormone; steroid hormone receptor; transcription factor; tumorigenesis

DESCRIPTION (provided by applicant): The androgen receptor (AR) is member of the steroid hormone receptor superfamily. Upon binding to its ligand androgen, AR functions as a transcription factor to induce expression of numerous genes, thereby regulating many physiological or pathological activities, from cell proliferation, tumorigenesis, to neurodegenerative disorders. However, the ligand-independent function of AR was unknown and the role of AR in programmed cell death is also incompletely understood. Recently, we uncovered that AR can promote UV-induced pro-death activity of the Bcl-2 family protein Bax through its non-transcription activity, but inhibits tumor necrosis factor (TNF1)-induced pro-death activity of the MAP kinase JNK through its transcription activity. We hypothesize that AR has dual regulatory role in programmed cell death: promoting or inhibiting apoptosis in a death stimulus-dependent manner. In this proposal, we will first determine the mechanism by which AR promotes Bax-dependent cell death through its non-transcription activity. To this end, we will define the AR pro-death domain(s) that is sufficient to promote Bax pro-death activity and determine whether AR regulates the interaction between Bax and other Bcl-2 family members, thereby promoting Bax activation. Finally, we will study whether specific AR-dependent Bax-associated proteins are involved in AR-mediated cell death, and determine whether the promotion of Bax activity by AR sensitizes cell death in animal model. Next, we will determine the mechanism by which AR inhibits TNF1-induced, JNK-dependent cell death through its transcription activity. To this end, we will determine how androgen/AR via induction of p21 inhibits TNF1-induced JNK activation and whether inhibition of JNK activity by androgen/AR occurs in animal model. We will determine whether in addition to inhibition of JNK, androgen/AR suppresses TNF1-induced cell death through inhibition of other component(s) in the death machinery. Finally, we will determine how differential regulation of JNK and Bax by AR is integrated for suppressing TNF1- induced cell death. Our long-term goal is to uncover the molecular mechanism underlying the ligand-independent function of AR and its differential regulation of programmed cell death, thereby providing molecular basis for developing novel strategies to treat human diseases related to dysregulation of AR function. PROJECT NARRATIVE: The androgen receptor involves many physiological or pathological activities, from cell proliferation, tumorigenesis, to neurodegenerative diseases. In this proposal, we will study molecular mechanisms underlying the non-transcription function of AR and its dual regulatory roles in cell death in response to different death stimuli. This study should provide invaluable information for developing novel strategies for prevention and treatment of human diseases, such as prostate cancer and spinal and bulbar muscular atrophy.

描述（由申请人提供）：雄激素受体（AR）是类固醇激素受体超家族的成员。与其配体雄激素结合后，AR充当转录因子诱导许多基因的表达，从而调节从细胞增殖，肿瘤发生到神经退行性疾病的许多生理或病理活性。然而，AR的配体无依赖性功能尚不清楚，并且AR在程序性细胞死亡中的作用也不完全理解。最近，我们发现AR可以通过其非转录活性来促进Bcl-2家族蛋白BAX的紫外线促hote tar活性，但通过其转录活性抑制了MAP激酶JNK的肿瘤坏死因子（TNF1）诱导的促肿瘤坏死因子。我们假设AR在程序性细胞死亡中具有双重调节作用：以死亡刺激依赖性方式促进或抑制凋亡。在此提案中，我们将首先确定AR通过其非转录活性促进Bax依赖性细胞死亡的机制。为此，我们将定义足以促进Bax pro Death活性并确定AR是否调节BAX与其他Bcl-2家族成员之间的相互作用，从而促进Bax激活的AR。最后，我们将研究特定的AR依赖性BAX相关蛋白是否参与AR介导的细胞死亡，并确定AR通过AR促进Bax活性是否会使动物模型中的细胞死亡敏感。接下来，我们将通过其转录活性来确定AR抑制TNF1诱导的JNK依赖性细胞死亡的机制。为此，我们将通过诱导P21来确定雄激素/AR如何抑制TNF1诱导的JNK激活，以及在动物模型中抑制雄激素/AR对JNK活性的抑制。我们还将确定除了抑制JNK外，雄激素/AR是否还通过抑制死亡机械中其他成分抑制TNF1诱导的细胞死亡。最后，我们将确定如何整合AR对JNK和BAX的差异调节，以抑制TNF1诱导的细胞死亡。我们的长期目标是发现AR的配体无关功能的分子机制及其对程序性细胞死亡的差异调节，从而为制定了治疗与AR功能失调相关的人类疾病的新型策略提供了分子基础。项目叙述：雄激素受体涉及许多生理或病理活性，从细胞增殖，肿瘤发生到神经退行性疾病。在此提案中，我们将研究AR的非转录功能及其双重调节作用在细胞死亡中的分子机制，以响应不同的死亡刺激。这项研究应提供宝贵的信息，以制定预防和治疗人类疾病的新型策略，例如前列腺癌，脊柱和鳞茎肌肉萎缩。