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. ? ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
2R01CA090765-06A2
Application #
7321536
Study Section
Tumor Cell Biology Study Section (TCB)
Program Officer
Blair, Donald G
Project Start
2007-08-01
Project End
2012-05-31
Budget Start
2007-08-01
Budget End
2008-05-31
Support Year
6
Fiscal Year
2007
Total Cost
$301,958
Indirect Cost
Name
Pennsylvania State University
Department
Pharmacology
Type
Schools of Medicine
DUNS #
129348186
City
Hershey
State
PA
Country
United States
Zip Code
17033
Jin, Qunyan; Liu, Guangming; Domeier, Phillip P et al. (2013) Decreased tumor progression and invasion by a novel anti-cell motility target for human colorectal carcinoma cells. PLoS One 8:e66439
Jin, Qunyan; Gao, Guofeng; Mulder, Kathleen M (2013) A dynein motor attachment complex regulates TGFß/Smad3 signaling. Int J Biol Sci 9:531-40
Jin, Qunyan; Zhong, Yan; Mulder, Kathleen M (2013) Requirement for protein kinase A in the phosphorylation of the TGF* receptor-interacting protein km23-1 as a component of TGF* downstream effects. Exp Cell Res 319:897-907
Jin, Qunyan; Pulipati, Nageswara R; Zhou, Weidong et al. (2012) Role of km23-1 in RhoA/actin-based cell migration. Biochem Biophys Res Commun 428:333-8
Pandey, Manoj K; Liu, Guangming; Cooper, Timothy K et al. (2012) Knockdown of c-Fos suppresses the growth of human colon carcinoma cells in athymic mice. Int J Cancer 130:213-22
Jin, Qunyan; Ding, Wei; Mulder, Kathleen M (2012) The TGF? receptor-interacting protein km23-1/DYNLRB1 plays an adaptor role in TGF?1 autoinduction via its association with Ras. J Biol Chem 287:26453-63
Jin, Qunyan; Gao, Guofeng; Mulder, Kathleen M (2012) Requirement of a dynein light chain in transforming growth factor ? signaling in zebrafish ovarian follicle cells. Mol Cell Endocrinol 348:233-40
Pulipati, Nageswara R; Jin, Qunyan; Liu, Xin et al. (2011) 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. Int J Cancer 129:553-64
Jin, Qunyan; Gao, Guofeng; Mulder, Kathleen M (2009) Requirement of a dynein light chain in TGFbeta/Smad3 signaling. J Cell Physiol 221:707-15
Jin, Qunyan; Ding, Wei; Mulder, Kathleen M (2007) Requirement for the dynein light chain km23-1 in a Smad2-dependent transforming growth factor-beta signaling pathway. J Biol Chem 282:19122-32

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