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AUTOCRINE TGF BETA AND CELL DEATH

自分泌 TGF Beta 和细胞死亡

基本信息

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
项目类别：
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

项目摘要

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（申请人提供）：该项目的总体概念是TGF？受体再生介导生存素的抑制，从而有助于与组蛋白脱乙酰酶抑制剂（HDACi）相关的抗肿瘤活性。据认为，HDACi 功效将通过减少当前可用药物抑制的 HDAC 范围的混杂性而得到改善。因此，控制 TGF 的关键 HDAC 的鉴定？受体抑制对于制定适当的策略具有重要意义。我们的初步数据表明 HDAC1 是 TGF 的调节者？癌症中的受体抑制。 TGF 的转录抑制？受体表达及其抑癌基因（TSG）活性经常出现在结肠癌细胞和乳腺癌细胞中。这与患者样本中这些受体在蛋白质和 mRNA 水平上的频繁丢失是一致的，其机制不太可能与 TGF 突变相关？信号元件。受体表达的丧失也与这些患者的不良预后相关 (3)。 TGF 缺失？ HDACi 抑制剂治疗可逆转受体和信号传导。在其他工作中，我们发现一种针对生存素表达抑制的新型内源性细胞死亡途径是 TGF? 的重要组成部分。 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 相关？具体目标 I 中通过这种新型自分泌死亡途径的 TSG 活性。HDAC1 SiRNA 的稳定表达再生了缺陷型 TGF？受体表达，因此暗示 HDAC1 负责受体的转录抑制。在这个项目周期中，我们发现 TGF 重新激活？受体转录依赖于几个 Sp1 位点的 HDAC 抑制。然而，这些位点在转录因子的使用方面有所不同。因此，对 HDAC 抑制的不同反应机制发生在 RII 启动子的不同 Sp1 位点的假设将在 Aim II 中进行测试。 HDACi 和特定 HDAC1 抑制激活异种移植模型中内在的生存素介导的死亡途径的假设将在 Specific Aim III 中进行测试。这种新的稳定 HDAC1 敲低模型的表征可能导致基于互补作用机制的合理组合方法的识别。具体目标是： 1) 确定 HDAC 1 抑制是否足以使两种 TGF 再生？ P21 和存活蛋白的受体和抑制。 2) TGF 激活和沉默机制的确定？转录 3) 确定 HDAC 1 敲低是否足以在异种移植物中获得抗肿瘤活性。

项目成果

期刊论文数量（23）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Establishment and Validation of an Orthotopic Metastatic Mouse Model of Colorectal Cancer.

DOI：
10.1155/2013/206875
发表时间：
2013
期刊：
ISRN hepatology
影响因子：
0
作者：
Rajput A;Agarwal E;Leiphrakpam P;Brattain MG;Chowdhury S
通讯作者：
Chowdhury S

Cell survival and metastasis regulation by Akt signaling in colorectal cancer.

DOI：
10.1016/j.cellsig.2013.03.025
发表时间：
2013-08
期刊：
Cellular signalling
影响因子：
4.8
作者：
Agarwal E;Brattain MG;Chowdhury S
通讯作者：
Chowdhury S

Identification of a novel TGFβ/PKA signaling transduceome in mediating control of cell survival and metastasis in colon cancer.

DOI：
10.1371/journal.pone.0019335
发表时间：
2011-05-03
期刊：
PloS one
影响因子：
3.7
作者：
Chowdhury S;Howell GM;Rajput A;Teggart CA;Brattain LE;Weber HR;Chowdhury A;Brattain MG
通讯作者：
Brattain MG

Akt inhibitor MK-2206 promotes anti-tumor activity and cell death by modulation of AIF and Ezrin in colorectal cancer.

AKT抑制剂MK-2206通过调节结直肠癌的AIF和EZRIN促进抗肿瘤活性和细胞死亡。