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Mechanisms of TGF-Beta Production in Human Cancer Cells

人类癌细胞中 TGF-β 产生的机制

基本信息

批准号：
8073200
负责人：
Kathleen M Mulder
金额：
$ 30.08万
依托单位：
PENNSYLVANIA STATE UNIV HERSHEY MED CTR
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-08-01 至 2014-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8073200
关键词：
Abbreviations Appendiceal Neoplasms Area Attenuated Binding Cells Colon Carcinoma Combined Modality Therapy Complex Development Diagnostic Neoplasm Staging Dynein ATPase Endocytosis Endothelial Cells Epithelial Cells Event FOS gene Fibroblasts Goals Growth Growth Factor Human Immune In Vitro Intracellular Transport Lead Ligands Light Link Malignant Epithelial Cell Malignant Neoplasms Mediating Microtubules Mitogen-Activated Protein Kinases Motor Movement Nature Nuclear Translocation Oncogenic Pathway interactions Peptides Phosphorylation Play Production Proteins Refractory Regulation Relative (related person)Research Resistance Role Signal Pathway Signal Transduction Site Specific qualifier value Staging TGFB1 gene Testing Time Transcription Factor AP-1 Transforming Growth Factor beta Transmembrane Transport Tumor stage Vesicle acronyms autocrine cancer cell cancer therapy design dynein light chain human RIPK1 protein in vivo inhibitor/antagonist innovation neoplastic cell novel novel strategies paracrine promoter receptor response small molecule trafficking transcription factor tumor tumor progression tumorigenesis tumorigenic

项目摘要

DESCRIPTION (provided by applicant): Tumor cells that are resistant to the growth inhibitory effects of TGF? can still secrete TGF?, which enhances tumorigenesis via the paracrine effects of TGF? in the tumor microenvironment. It is advantageous to block this secreted TGF? in late-stage tumors that have lost the TGF? growth inhibitory signals. We have identified the signaling pathways mediating TGF?1 production in untransformed epithelial cells (UECs) and in human colon cancer cells (HCCCs). One of the differences involves a switching of the AP-1 transcription factors (TFs) bound to the relevant region of the TGF?1 promoter. Here we will explore the mechanisms underlying this TF switching, including the role played by altered compartmentalization of signaling complexes. In addition, we have identified the novel TGF? signaling intermediate km23, which is also a light chain of the motor protein dynein (DLC). The dynein motor complex can transport membrane vesicles (ie, endosomal compartments) containing TGF? receptors (T?R's) and TGF? signaling components along the microtubules to a new vesicular compartment, prior to nuclear translocation and signal activation. Among other motor subunits, DLCs such as km23 specify the cargo that will be attached to the motor for intracellular transport after receptor endocytosis. Thus, km23 plays a key role in maintaining the appropriate localization of TGF? signaling complexes. In addition, we have shown that km23 is required for TGF?1 production in both UECs and HCCCs. Accordingly, the studies proposed herein will also investigate the mechanisms underlying the ability of km23 to regulate the MAPK pathways required for TGF?1 production, including identifying differences between HCCCs and UECs in km23 control of the spatial and temporal regulation of the signaling complexes specifically mediating TGF?1 production. Attempts will be made to block the constitutive (ie, not TGF?-regulated) production of TGF?1 in advanced-stage colon cancer, to decrease the tumorigenic potential both in vitro and in vivo. The results should lead to the design of novel approaches to suppress tumor progression in TGF?-resistant HCC, via blockade of specific components important in the spatial and temporal regulation of TGF?1 production pathway signaling. Thus, the proposed studies will investigate the role of a novel component in controlling TGF?1 production using a novel, multidimensional approach. The results of the studies should reveal significant differences between HCCC's and UEC's in the altered compartmentalization of signaling complexes, as well as in the differential utilization of signaling components, thereby facilitating efforts to selectively block constitutive TGF?1 production in late-stage human colon carcinomas. The goal of this proposal is to reduce production of a growth factor that enhances the spread of colon cancer. The results should lead to the development of novel approaches to treat colon cancer.

描述（申请人提供）：对TGF抑制生长的肿瘤细胞？还能分泌TGF吗？通过TGF?的旁分泌作用促进肿瘤发生在肿瘤微环境中。阻断这种分泌的TGF？晚期肿瘤中TGF？生长抑制信号。我们已经确定了介导TGF？1在未转化上皮细胞（UECs）和人结肠癌细胞（HCCCs）中产生。其中一个差异涉及到结合在TGF？1启动子。在这里，我们将探讨这种TF转换的机制，包括信号复合物区隔化改变所起的作用。此外，我们还发现了新的TGF？信号传导中间体km23，也是马达蛋白动力蛋白（DLC）的轻链。动力蛋白运动复合体可以运输含有TGF？受体(T ?R's)和TGF？在核易位和信号激活之前，信号成分沿着微管到达一个新的囊泡室。在其他运动亚基中，dlc如km23指定在受体内吞作用后附着在运动上进行细胞内运输的货物。因此，km23在维持TGF？信号复合物。另外，我们已经证明了TGF？uec和hccc的生产均为1。因此，本文提出的研究也将探讨km23调节TGF？1的产生，包括鉴别HCCCs和UECs在km23对特异性介导TGF？1生产。会尝试阻断本构(即TGF？-调节)TGF？1 .用于晚期结肠癌，降低体内和体外的致瘤潜能。这些结果应该会导致设计新的方法来抑制TGF？-耐药HCC，通过阻断TGF？1 .生产通路信号。因此，本研究将探讨一种新成分在控制TGF？1生产使用新颖的，多维的方法。研究结果应该揭示HCCC和UEC在信号复合物区隔化改变以及信号成分利用差异方面的显著差异，从而有助于选择性阻断构成型TGF？1在晚期人类结肠癌中的产生。

项目成果

期刊论文数量（14）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

A dynein motor attachment complex regulates TGFß/Smad3 signaling.

DOI：
10.7150/ijbs.5718
发表时间：
2013
期刊：
International journal of biological sciences
影响因子：
9.2
作者：
Jin Q;Gao G;Mulder KM
通讯作者：
Mulder KM

Role of km23-1 in RhoA/actin-based cell migration.

DOI：
10.1016/j.bbrc.2012.10.047
发表时间：
2012-11-23
期刊：
BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS
影响因子：
3.1
作者：
Jin, Qunyan;Pulipati, Nageswara R.;Zhou, Weidong;Staub, Cory M.;Liotta, Lance A.;Mulder, Kathleen M.
通讯作者：
Mulder, Kathleen M.

Overexpression of the dynein light chain km23-1 in human ovarian carcinoma cells inhibits tumor formation in vivo and causes mitotic delay at prometaphase/metaphase.

DOI：
10.1002/ijc.25954
发表时间：
2011-08-01
期刊：
INTERNATIONAL JOURNAL OF CANCER
影响因子：
6.4
作者：
Pulipati, Nageswara R.;Jin, Qunyan;Liu, Xin;Sun, Baodong;Zhao, Yan;Pandey, Manoj K.;Huber, Jonathan P.;Ding, Wei;Mulder, Kathleen M.
通讯作者：
Mulder, Kathleen M.

Requirement for protein kinase A in the phosphorylation of the TGFβ receptor-interacting protein km23-1 as a component of TGFβ downstream effects.