Cellular Interactions between TGF-B Pathway Members and TERT and c-Myc in Gastroi

胃中 TGF-B 通路成员与 TERT 和 c-Myc 之间的细胞相互作用

• 批准号: 7933853
• 负责人: BIBHUTI B MISHRA
• 金额: $ 23.83万
• 依托单位: GEORGETOWN UNIVERSITY
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7933853
• 关键词: Accounting; Adaptor Signaling Protein; Adenocarcinoma; Agonist; Animal Model; Antineoplastic Agents; Area; Beckwith-Wiedemann Syndrome; Binding; Biochemical; CDK4 gene; Cancer cell line; Carcinoma; Cell Cycle Progression; Cells; Chemical Agents; Clinical; Collaborations; Cyclin-Dependent Kinase Inhibitor 2A; DNA; Data; Dysplasia; Event; Exons; Functional disorder; Future; Genetic; Genetic Transcription; Hepatitis C virus; Hepatocyte; Human; In Vitro; Inherited; Intestines; Knockout Mice; Lesion; Liver; MADH4 gene; Malignant Neoplasms; Malignant neoplasm of gastrointestinal tract; Malignant neoplasm of pancreas; Maps; Modeling; Molecular; Mouse Strains; Mus; Mutant Strains Mice; Mutate; Mutation; Neoplasm Metastasis; Outcome; Pancreas; Pathway interactions; Patients; Pattern; Phenotype; Phosphotransferases; Prevention; Primary carcinoma of the liver cells; Primitive foregut structure; Prognostic Marker; Property; Proteins; Proteomics; Proteus Syndrome; RNA; Regulation; Role; Serial Passage; Signal Pathway; Signal Transduction; Signaling Molecule; Staging; Stomach; Telomerase; Telomere Maintenance; Testing; Therapeutic; Tissues; Transcriptional Regulation; Tumor Suppressor Proteins; Visceromegaly; Vitamin D Analog; Vitamin D3 Receptor; Work; base; c-myc Genes; cancer cell; gastrointestinal; human tissue; in vivo; inhibitor/antagonist; insight; malignant stomach neoplasm; member; molecular marker; mutant; neoplastic; new therapeutic target; novel marker; prognostic; promoter; response; telomere; therapeutic target; tumor; tumorigenesis

Escape from TGF-/3 induced antiproliferative responses is a hallmark of many cancer cells. TGF-/3 signaling molecules Smads 2, 3 and 4 inhibit G1/S cell cycle progression mostly by suppression of c-Myc and cyclindependent kinases (cdks). Myc amplification, telomere maintenance, and telomerase (TERT) reactivation are common features of human foregut cancers, such as hepatocellular carcinoma (HCC). However, the specific role(s) of h-TERT and c-MYC, and their relation to the TGF-/3 pathway, in foregut cancer formation are poorly understood. We have shown that the Smad3/4 adaptor protein ELF is an important effector of TGF-(3 tumor suppressor function. Deletion of ELF results in a dramatic and spontaneous formation of liver and gastrointestinal (Gl) cancers, with exon 15 mutations in 11% of human hepatocellular (HCC) and gastric cancer cell lines tested. E/f7"and elf^/SmadS^'mce develop visceromegaly and multiple Gl cancers (70% of mice), including metastatic pancreatic, HCC, intestinal adenocarcinomas and others spontaneously. This phenotype provides compelling evidence that elf'' and elf'/Smad3+/~ mice are a model of the hereditary human cancer, Beckwith-Wiedemann syndrome (BWS). Tert and c-Myc are markedly elevated in elf' and elf/~/Smad3*/~ mice. Interestingly, Tert levels are far higher than can be accounted for by c-Myc levels in these tumors. Ectopic ELF and SmadS suppress Tert to a greater extent than c-Myc in the absence of TGFj3. However, ELF and SmadS associate with c-Myc in TGF-jS stimulated hepatocytes, and suppress Tert. Taken together our preliminary data suggest that divergent pathways converge on ELF and SmadS that then regulate Tert expression. We hypothesize that disruption of the TGF-(3 tumor suppressor pathway (through ELF, SmadS or Smad4) leads to a proliferative potential in cells that then acquire secondary events such as activation of pathways that include telomerase as well as c-Myc, resulting in gastrointestinal cancers. This project proposes to 1) Investiage the biochemical interactions of ELF, SmadS, c-Myc and c-Myc associated proteins, and to determine the role of these proteins in transcriptional regulation of hTERT; 2) Use animal models that have predetermined mutations in elf, Smad3, Smad4 and telomerase function (mTerc) to determine their role in foregut cancer formation; 3) Develop markers and targeted therapeutics to these lethal human cancers. Our Specific Aims are to: 1. Examine the effects of ELF/SmadS on the regulation of hTERT transcription 2. Define the molecular basis for ELF/SmadS and Myc binding, and examine the effects of ELF/SmadS on Myc binding partners, towards developing new therapeutics targeted at c-Myc. 3. Investigate the collaboration between ELF, SmadS, Smad4 and telomerase dysfunction in foregut cancers by generating elf'ySmadS^'l'mTerc and elf/7Smad4+/~l mTerc mutant mice. Extend therapeutics from Project 2 and Project 4 to these models. 4. Determine whether telomerase dysfunction and c-Myc activation can be correlated temporally with loss of TGF-/3 pathway members such as ELF, SMADS and SMAD4 in BWS and human foregut cancers, from Project 1, towards developing a pathway and stage specific marker map. Inactivation of elf may greatly increase the propensity of elf'''/mTerc, elf'/SmadS^'/mTerc, and elf'' /Smad4+/'/mTerc mice to HCC and gastrointestinal tumorigenesis, compared to elf' mice. If this hypothesis is accurate, the mouse strains elf''/mTerc, elf'/SmadS^'/mTerc and elf'/SmadS^'/mTerc'' will be invaluable modes for determining efficacy of anti-cancer drugs.

从TGF-/3诱导的抗增殖反应逃脱是许多癌细胞的标志。 TGF-/3信号 分子SMADS 2、3和4分子抑制G1/s细胞周期的进展，主要是通过抑制C-Myc和环二抑制 激酶（CDK）。 MYC扩增，端粒维护和端粒酶（TERT）重新激活 是肝癌（例如肝细胞癌（HCC））的常见特征。但是， H-TERT和C-MYC的特定作用及其与TGF-/3途径的关系，在前肠癌形成中 知之甚少。我们已经表明，Smad3/4适配器蛋白ELF是 TGF-（3个肿瘤抑制功能。删除ELF会导致肝脏的戏剧性和自发形成 和胃肠道癌（GL）癌 测试的癌细胞系。 E/F7“和ELF^/SMADS^'MCE发展腹膜肿大和多种GL癌（占70％ 小鼠），包括转移性胰腺，HCC，肠道腺癌等。这 表型提供了令人信服的证据，表明精灵'和Elf'/smad3+/〜小鼠是遗传的模型 人类癌症，贝克维斯 - 威德曼综合征（BWS）。 tert和c-myc在小精灵中明显升高，并且 精灵/〜/smad3*/〜小鼠。有趣的是，TERT级别远高于C-MYC水平所占的水平 这些肿瘤。在没有TGFJ3的情况下，异位精灵和SMADS比C-MYC更大程度地抑制TERT。 然而，在TGF-JS中与C-Myc相关的小精灵和SMAD刺激了肝细胞，并抑制了TERT。 总而言之，我们的初步数据表明，不同的途径在小精灵和SMAD上汇合 调节TERT表达。 我们假设TGF-的破坏（3个肿瘤抑制途径（通过Elf，Smads或Smad4） 导致细胞中的增殖潜力，然后获得次要事件，例如激活途径 其中包括端粒酶和C-MYC，导致胃肠道癌。该项目向1提议） 投资精灵，SMADS，C-MYC和C-MYC相关蛋白质的生化相互作用，以及 确定这些蛋白质在HTERT转录调节中的作用； 2）使用具有的动物模型 ELF，SMAD3，SMAD4和端粒酶功能（MTERC）的预定突变，以确定它们在 前肠癌的形成； 3）为这些致命的人类癌症开发标记和靶向疗法。 我们的具体目的是： 1。检查小精灵/smads对HTERT转录调节的影响 2。定义精灵/smads和myc结合的分子基础，并检查精灵/smads对 MYC BINDING PARTNERS，致力于开发针对C-MYC的新治疗剂。 3。研究前癌中精灵，SMADS，SMAD4和端粒酶功能障碍之间的合作 通过生成Elf'ysmads^'l'Mterc和Elf/7smad4+/〜l mterc突变小鼠。扩展项目的治疗剂 2和项目4这些模型。 4。确定端粒酶功能障碍和C-MYC激活是否可以与丢失相关 TGF-/3途径成员，例如BWS中的ELF，SMADS和SMAD4和人类的牛肉癌 项目1，旨在开发途径和阶段特定标记图。 小精灵的失活可能会大大增加精灵''''''/mterc，Elf'/smads^'/mterc和Elf''''''''' 与小鼠相比，/smad4+/'/mTERC小鼠至HCC和胃肠道肿瘤发生。如果这个假设 是准确的，鼠标应变Elf'/mterc，Elf'/smads^'/mterc和Elf'/smads^'/mterc''将是 确定抗癌药物功效的宝贵模式。