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（由申请人提供）：抗TGF生长抑制作用的肿瘤细胞？仍然可以通过TGF的旁分泌作用来分泌TGF？，这可以增强肿瘤发生吗？在肿瘤微环境中。阻止这个分泌的TGF是有利的吗？在失去TGF的后期肿瘤中？生长抑制信号。我们已经确定了在未转化的上皮细胞（UEC）和人类结肠癌细胞（HCCC）中介导TGF？1产生的信号通路。差异之一涉及与TGF？1启动子相关区域结合的AP-1转录因子（TFS）的切换。在这里，我们将探讨该TF开关的基础机制，包括通过改变信号复合物的隔室化所起的作用。此外，我们还确定了新型TGF？信号中间KM23，它也是运动蛋白动力蛋白（DLC）的轻链。动力蛋白运动复合物可以运输含有TGF的膜囊泡（即内体隔室）？受体（T？r）和TGF？在核转运和信号激活之前，沿着微管沿微管沿微管的信号传导成分。在其他运动亚基中，诸如KM23之类的DLC指定了在受体内吞作用后将附着在电机上的货物，以进行细胞内转运。因此，KM23在维持TGF的适当定位中起着关键作用？信号复合物。此外，我们已经证明了UEC和HCCC中TGF？1产生所必需的KM23。因此，本文提出的研究还将研究KM23调节TGF？1产量所需的MAPK途径的基础机制，包括鉴定HCCC和UEC之间的差异在KM23控制km23的空间和时间调节中，专门介导TGF？1产生的信号和时间调节。将尝试阻止在晚期结肠癌中TGF？1的本构（IE，而不是TGF？调节）的产生，以降低体外和体内的肿瘤性潜力。结果应该导致设计新方法，以抑制TGF？耐药性HCC中的肿瘤进展，这是对在TGF？1生产途径信号传导的空间和时间调节中重要的特定成分的阻断。因此，拟议的研究将研究一种新成分在使用一种新型多维方法控制TGF？1生产中的作用。研究的结果应揭示HCCC和UEC之间的显着差异在信号传导复合物的隔离区域以及信号传导组件的差异利用中，从而促进了在晚期人类结肠癌中有选择性地阻止组成型TGF？1的努力。该提案的目的是减少生长因子的产生，从而增强结肠癌的传播。结果应导致新的治疗结肠癌方法的发展。

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.