Mechanisms of Cancer Initiation by TRIM32

TRIM32 引发癌症的机制

• 批准号: 7936498
• 负责人: MOLLY F. KULESZ-MARTIN
• 金额: $ 2.97万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-29 至 2013-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7936498
• 关键词: Abnormal Cell; Affect; Antibodies; Antigens; Apoptosis; Apoptotic; Biological Markers; Brain Neoplasms; Carcinogen exposure; Cell Count; Cell Nucleus; Cell Survival; Cells; Cervix carcinoma; Cessation of life; Chronic Myeloid Leukemia; Clinical; Data; Development; Disease-Free Survival; Down-Regulation; Dysmyelopoietic Syndromes; Enzymes; Epithelial; Epithelium; Event; Family; Fibroblasts; Frequencies; Future; Gene Silencing; Genetic; Genotoxic Stress; Growth; HPV-High Risk; Head and Neck Squamous Cell Carcinoma; Human; Human Development; In Vitro; Inflammatory; Inherited; Lead; Life; Ligase; Location; Malignant - descriptor; Malignant Conversion; Malignant Neoplasms; Measures; Mediating; Messenger RNA; Modeling; Molecular; Molecular Target; Mus; Muscle; Mutation; Neurologic; Normal tissue morphology; Nuclear; Oncogenes; Operative Surgical Procedures; Oxidative Stress; PTPRJ gene; Pathway interactions; Phosphorylation; Play; Post-Translational Protein Processing; Predictive Value; Prevention therapy; Prognostic Factor; Protein p53; Proteins; Protocols documentation; Radiation; Regulation; Regulator Genes; Role; Scaffolding Protein; Signal Transduction; Skin; Skin Cancer; Skin Carcinogenesis; Squamous cell carcinoma; Staging; Syndrome; TNF gene; TP53 gene; Target Populations; Testing; Time; Tissues; Transforming Growth Factor beta; Transgenic Organisms; Tumor Suppression; Tumor Suppressor Genes; UVB induced; Ultraviolet B Radiation; Work; apoptosis inducing factor; base; biological adaptation to stress; cancer initiation; carcinogenesis; cellular imaging; chemotherapy; cytokine; extracellular; human cancer mouse model; human disease; keratinocyte; member; novel; nucleocytoplasmic transport; outcome forecast; overexpression; prevent; pro-apoptotic protein; prognostic; protein expression; reconstitution; response; small molecule; stressor; therapeutic target; trafficking; tumor; tumor progression; tumorigenesis; ubiquitin-protein ligase

PROJECT SUMMARY Trim32 is an E3-ubiquitin ligase and a member of a family of scaffold proteins involved in both cancer and human development. We made the novel association of Trim32 activation with cancer through carcinogenesis studies in mouse keratinocyte models and have preliminarily confirmed this association in human squamous cell carcinoma (SCC). We have identified Piasy as a substrate protein targeted for degradation by Trim32 ubiquitylation, providing the first evidence for how Piasy is regulated in cells. Others have established that Piasy is a pro-apoptotic E3-SUMO ligase involved in regulation of tumor suppressor p53 and of NFkB cellular survival pathways. Piasy's role in cancer is evident as it is targeted for inactivation by the high-risk HPV-E6 protein implicated in human cervical carcinoma, and its downregulation is prognostic for conversion from myelodysplastic syndrome (MDS) to later stages and chronic myeloid leukemia (CML). Piasy is a pro- apoptotic factor, inducing apoptosis in CML cells, human fibroblasts and mouse keratinocytes. We show that Trim32 protects keratinocytes from apoptosis induced by UVB and synergized by TNFa. Moreover, we find an inverse correlation between Piasy and Trim32 expression levels in human SCC. These data suggest a direct role of Trim32 activation and Piasy degradation in epithelial carcinogenesis and tumor progression. We propose to define Trim32/Piasy interactions in intracellular signaling, carcinogenesis and human SCC according to the following aims: 1) define the dynamic regulation of Piasy subcellular localization by the Trim32 E3 ligase scaffold protein and the role of these interactions in survival pathways in epidermal keratinocytes; 2) examine the role of Trim32 and Piasy in initiation, promotion and malignant progression in keratinocytes during epidermal carcinogenesis; 3) explore the predictive value of Trim32/Piasy status in human skin and head and neck SCC prognosis as a basis for future strategies for molecular targeting of Trim32/Piasy interactions or downstream effectors in cancer. The expression of Trim32 and Piasy beyond epithelia, such as in hematologic, muscle and neurological tissues and the presence of Trim32 inactivating mutations in two human hereditary syndromes imply broader significance of understanding Trim32 and Piasy regulation in human disease. PROJECT NARRATIVE Trim32 and Piasy: Two enzymes with opposing roles in cancer development Trim32 is a ¿scaffold¿ protein that controls the timing and location of other proteins that must interact appropriately to cause normal tissue development and that, if abnormal, can lead to cancer. We have shown that Trim32 adds a small molecule ¿ubiquitin¿ and destroys Piasy (an enzyme that is needed for tumor suppression and cell survival mediated by important gene regulators p53, NFB, STAT and Smad/TGFbeta), providing the first evidence for how Piasy is regulated in cells. Understanding how the very earliest changes detectable in cancer, such as Trim32 activation, extend abnormal cell survival and promote further changes (activation of cancer genes and inactivation of tumor suppressor genes) provides a basis for novel selective, less toxic molecular-targeted prevention and therapy of skin cancers and perhaps cancers from other tissues where Trim32 and Piasy are expressed, such as chronic myelogenous leukemia, muscle and brain tumors.

项目摘要 Trim 32是一种E3-泛素连接酶，并且是参与癌症和肿瘤的支架蛋白家族的成员。 人类发展我们通过致癌作用将Trim 32激活与癌症联系起来， 在小鼠角质形成细胞模型中进行了研究，并初步证实了人类鳞状细胞中的这种关联 细胞癌（SCC）。我们已经将Piasy鉴定为Trim 32降解的靶向底物蛋白 泛素化，为Piasy在细胞中如何调节提供了第一个证据。其他人则认为， Piasy是一种促凋亡E3-SUMO连接酶，参与调节肿瘤抑制因子p53和NF κ B细胞凋亡。 生存之路。Piasy在癌症中的作用是显而易见的，因为它被高危HPV-E6靶向灭活。 一种与人宫颈癌有关的蛋白质，其下调是宫颈癌从 骨髓增生异常综合征（MDS）晚期和慢性髓性白血病（CML）。Piasy是一个亲- 凋亡因子，诱导CML细胞、人成纤维细胞和小鼠角质形成细胞的凋亡。我们证明了 Trim 32保护角质形成细胞免受UVB诱导的凋亡，并与TNF α协同作用。此外，我们发现一个 人SCC中Piasy和Trim 32表达水平之间的负相关性。这些数据表明， Trim 32激活和Piasy降解在上皮癌发生和肿瘤进展中的作用。我们 建议定义Trim 32/Piasy在细胞内信号传导、致癌和人类SCC中的相互作用 目的：1）明确Trim 32对Piasy亚细胞定位的动态调控 E3连接酶支架蛋白和这些相互作用在表皮角质形成细胞中的存活途径中的作用; 2） 检查Trim 32和Piasy在角质形成细胞中的启动、促进和恶性进展中的作用， 3）探索Trim 32/Piasy状态在人类皮肤和头部中的预测价值， 颈部SCC预后作为Trim 32/Piasy相互作用的分子靶向未来策略的基础， 癌症的下游效应子Trim 32和Piasy在上皮细胞以外的表达，例如在血液学中， 肌肉和神经组织以及两种人类遗传性疾病中Trim 32失活突变的存在 综合征意味着理解Trim 32和Piasy在人类疾病中的调节具有更广泛的意义。项目叙述 Trim 32和Piasy：两种在癌症发展中具有相反作用的酶 Trim 32是一种“支架”蛋白，它控制着必须相互作用的其他蛋白质的时间和位置。 适当地引起正常组织发育，如果异常，可能导致癌症。我们有 显示Trim 32增加了一个小分子泛素并破坏了Piasy（一种酶， 肿瘤抑制和细胞存活由重要的基因调节因子p53、NFB、STAT和 Smad/TGF β），为Piasy在细胞中如何调节提供了第一个证据。了解如何 在癌症中可检测到的最早期变化，如Trim 32激活，延长了异常细胞存活 并促进进一步的变化（癌症基因的激活和肿瘤抑制基因的失活） 为新的选择性、低毒的分子靶向预防和治疗皮肤提供了基础， 癌症以及可能来自表达Trim 32和Piasy的其他组织的癌症，例如 慢性骨髓性白血病，肌肉和脑肿瘤