AUTOCRINE TGF BETA AND CELL DEATH

自分泌 TGF Beta 和细胞死亡

• 批准号: 8101847
• 负责人: MICHAEL G BRATTAIN
• 金额: $ 24.14万
• 依托单位: UNIVERSITY OF NEBRASKA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-06-01 至 2012-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8101847
• 关键词: Apoptosis; Breast Cancer Cell; Cell Cycle Arrest; Cell Death; Cell Death Induction; Cessation of life; Colon Carcinoma; Data; Development; Elements; Equilibrium; Failure; Funding; Generations; Genes; Genetic Transcription; HDAC1 gene; Histone Deacetylase; Histone Deacetylase Inhibitor; Histone deacetylase inhibition; Lead; Link; Malignant Neoplasms; Malignant neoplasm of pancreas; Mediating; Mediator of activation protein; Messenger RNA; Modeling; Mutation; Natural regeneration; Normal Cell; Oncogene Activation; Pathway interactions; Patients; Process; Proteins; Proto-Oncogenes; Repression; Resistance; Sampling; Signal Transduction; Site; Stress; Testing; Time; Transforming Growth Factor beta; Tumor Suppression; Tumor Suppressor Genes; Tumor Suppressor Proteins; Work; Xenograft Model; Xenograft procedure; autocrine; base; chemotherapeutic agent; gene repression; human HDAC1 protein; improved; inhibitor/antagonist; malignant breast neoplasm; novel; outcome forecast; promoter; receptor; receptor expression; reconstitution; response; restoration; survivin; tissue culture; transcription factor; tumor; tumor progression; Apoptosis; Breast Cancer Cell; Cell Cycle Arrest; Cell Death; Cell Death Induction; Cessation of life; Colon Carcinoma; Data; Development; Elements; Equilibrium; Failure; Funding; Generations; Genes; Genetic Transcription; HDAC1 gene; Histone Deacetylase; Histone Deacetylase Inhibitor; Histone deacetylase inhibition; Lead; Link; Malignant Neoplasms; Malignant neoplasm of pancreas; Mediating; Mediator of activation protein; Messenger RNA; Modeling; Mutation; Natural regeneration; Normal Cell; Oncogene Activation; Pathway interactions; Patients; Process; Proteins; Proto-Oncogenes; Repression; Resistance; Sampling; Signal Transduction; Site; Stress; Testing; Time; Transforming Growth Factor beta; Tumor Suppression; Tumor Suppressor Genes; Tumor Suppressor Proteins; Work; Xenograft Model; Xenograft procedure; autocrine; base; chemotherapeutic agent; gene repression; human HDAC1 protein; improved; inhibitor/antagonist; malignant breast neoplasm; novel; outcome forecast; promoter; receptor; receptor expression; reconstitution; response; restoration; survivin; tissue culture; transcription factor; tumor; tumor progression

DESCRIPTION (provided by applicant): The overall concept of the project is that TGF? receptor regeneration mediates the repression of survivin thereby contributing to the anti tumor activity associated with histone deacetylase inhibitors (HDACi). It is thought that HDACi efficacy would be improved by less promiscuity with respect to the range of HDAC's inhibited by currently available agents. Thus, identification of a key HDAC(s) controlling TGF? receptor repression would be of consequence for the development of appropriate strategies. Our preliminary data point to HDAC1 as a mediator of TGF? receptor repression in cancer. Transcriptional repression of TGF? receptor expression and hence its tumor suppressor gene (TSG) activity occurs frequently in colon and breast cancer cells. This is consistent with the frequent loss of these receptors at both the protein and mRNA levels in patient samples by mechanisms that are unlikely to be associated with mutations of TGF? signaling components. Loss of receptor expression is associated with poor prognosis in these patients as well (3). Loss of TGF? receptors as well as signaling was reversed by treatment with HDACi inhibitors. In other work we have found that a novel endogenous cell death pathway targeting repression of survivin expression is an important element of TGF? TSG activity. Consequently, we will test the hypothesis that tumor inhibition associated with inhibition of HDAC activity is linked to TGF? TSG activity through this novel autocrine death pathway in Specific Aim I. Stable expression of HDAC1 SiRNA regenerated deficient TGF? receptor expression thus implying that HDAC1 is responsible for transcriptional repression of the receptors. During this cycle of the project we found that reactivation of the TGF? receptor transcription was dependent upon the HDAC inhibition at several Sp1 sites. However, these sites differed with respect to transcription factor usage. Consequently, the hypothesis that different mechanisms of response to HDAC inhibition occurs at different Sp1 sites in the RII promoter will be tested in Aim II. The hypotheses that HDACi and specific HDAC1 inhibition activates an intrinsic survivin mediated death pathway in xenograft models will be tested in Specific Aim III. Characterization of this new stable HDAC1 knockdown model could lead to the identification of rational combination approaches based on complementary mechanisms of action. The Specific Aims are: 1) DETERMINE WHETHER HDAC 1 INHIBITION is SUFFICIENT FOR REGENERATION OF BOTH TGF? RECEPTORS AND REPRESSION OF P21 AND SURVIVIN. 2) DETERMINATION OF THE MECHANISMS OF ACTIVATION & SILENCING OF TGF? TRANSCRIPTION 3) DETERMINE WHETHER HDAC 1 KNOCKDOWN IS SUFFICIENT TO OBTAIN ANTI-TUMOR ACTIVITY IN XENOGRAFTS.

描述（由申请人提供）：项目的总体概念是TGF？受体再生介导了Survivin的抑制，从而导致与组蛋白脱乙酰基酶抑制剂（HDACI）相关的抗肿瘤活性。人们认为，就当前可用代理的HDAC抑制范围而言，HDACI功效将通过少杂种而提高。因此，识别控制TGF的密钥HDAC？受体抑制作用将是制定适当策略的结果。我们的初步数据指向HDAC1是TGF的调解人？癌症的受体抑制。 TGF的转录抑制？受体表达及其肿瘤抑制基因（TSG）的活性经常发生在结肠和乳腺癌细胞中。这与患者样品中蛋白质和mRNA水平在患者样品中经常丢失的机制频繁丢失，而这种机制不太可能与TGF突变有关？信号传导组件。受体表达的丧失与这些患者的预后不良有关（3）。失去TGF？受体和信号传导通过HDACI抑制剂治疗逆转。在其他工作中，我们发现一种新型的内源性细胞死亡途径靶向抑制Survivin表达是TGF的重要元素？ TSG活动。因此，我们将检验以下假设：与HDAC活性抑制相关的肿瘤抑制与TGF有关？ TSG通过这种新型自分泌死亡途径在特定目标I中的活性I。HDAC1siRNA的稳定表达再生不足的TGF？因此，受体表达表明HDAC1负责受体的转录抑制。在项目的这个周期中，我们发现TGF重新激活？受体转录取决于几个SP1位点的HDAC抑制。但是，这些位点在转录因子使用方面有所不同。因此，将在AIM II中测试RII启动子中不同SP1位点发生不同的HDAC抑制反应机理的假设。 HDACI和特异性HDAC1抑制激活异种移植模型中内在的Survivin介导的死亡途径的假设将在特定的AIM III中进行测试。这种新的稳定HDAC1敲低模型的表征可以导致基于互补的作用机理的理性组合方法的识别。具体目的是：1）确定HDAC 1抑制是否足以再生两个TGF？受体和p21和survivin的抑制。 2）确定TGF激活和沉默的机制？转录3）确定HDAC 1敲低足以获得异种移植物中的抗肿瘤活性。