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

描述(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。当AR与其配体雄激素结合后，作为一个转录因子诱导许多基因的表达，从而调节许多生理或病理活动，从细胞增殖、肿瘤发生到神经退行性疾病。然而，AR的配体非依赖性功能尚不清楚，AR在细胞程序性死亡中的作用也不完全清楚。最近，我们发现AR可以通过非转录活性促进紫外线诱导的Bcl2家族蛋白Bax的促死亡活性，但通过其转录活性抑制肿瘤坏死因子(TNF1)诱导的MAP激酶JNK的促死亡活性。我们假设AR在程序性细胞死亡中具有双重调节作用：以依赖于死亡刺激的方式促进或抑制细胞凋亡。在这个提案中，我们将首先确定AR通过其非转录活性促进Bax依赖的细胞死亡的机制。为此，我们将定义足以促进Bax致死活性的AR致死结构域(S)，并确定AR是否调节Bax与其他Bcl2家族成员之间的相互作用，从而促进Bax的激活。最后，我们将研究特定的AR依赖的Bax相关蛋白是否参与AR介导的细胞死亡，并在动物模型中确定AR对Bax活性的促进是否使细胞死亡变得敏感。接下来，我们将确定AR通过其转录活性抑制TNF1诱导的JNK依赖的细胞死亡的机制。为此，我们将确定雄激素/AR如何通过诱导p21抑制TNF1诱导的JNK活性，以及雄激素/AR是否在动物模型中抑制JNK活性。我们将确定雄激素/AR除了抑制JNK外，是否还通过抑制死亡机制中的其他成分(S)来抑制TNF1诱导的细胞死亡。最后，我们将确定AR对JNK和Bax的差异调控是如何整合到抑制TNF1诱导的细胞死亡的。我们的长期目标是揭示AR配体非依赖功能及其对程序性细胞死亡的差异调节的分子机制，从而为开发治疗与AR功能失调相关的人类疾病的新策略提供分子基础。项目简介：雄激素受体涉及许多生理或病理活动，从细胞增殖、肿瘤发生到神经退行性疾病。在这个计划中，我们将研究AR非转录功能的分子机制及其在细胞死亡中的双重调节作用，以响应不同的死亡刺激。这项研究将为开发预防和治疗人类疾病的新策略提供宝贵的信息，例如前列腺癌和脊髓和延髓肌肉萎缩。

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.