This proposal explores how the beta-catenin pathway regulates growth control and tissue modeling during embryonic skin formation, with objectives to manage this pathway in cancer. This pathway is frequently altered in malignancies. Normally beta-catenin binds to E-cadherin, a cell adhesion molecule lost in mammary tumors and to APC (adenomatous polyposis coli), a tumor suppressor lost in colon cancer. APC targets beta-catenin for degradation. Wnt signaling or mutations in the pathway block APC from binding beta-catenin and lead to the accumulation of beta-catenin in the nucleus. Here it associates with LEFs/TCFs to control transcription of c-myc, cyclin D1 other cell proliferation regulatory molecules as well as metalloproteinases involved in tissue modeling. When the molecular pathway is intact, growth control is kept in check. Alterations in the pathway lead to loss of growth control, changes in cell morphology and metastasis. A powerful approach to understanding and managing the pathogenesis of the beta-catenin pathway in cancer is to examine how it is regulated and functions in development. Here we take this approach to learn its physiological function in the skin new growth model. The growth of skin appendages is an established model system for the study of rapid new growth. Beta-catenin is expressed in these regions. Preliminary data showed that beta-catenin expression levels are low in apteric and scale producing regions and higher in feather producing regions. Over-expression of beta-catenin induces new feather growth from apteric and scale forming regions and abnormal growth in feather producing regions, suggesting that higher beta-catenin expression levels lead to the formation of more complex structures. Skin sections showed multiple areas of activated epidermal thickening with high cell proliferation activity preceding new feather growth. We hypothesize that the beta-catenin pathway plays pivotal roles in the control of new growth through interactions with Lef-1 and that subsequent transcriptional activation leads to changes at the level of cell proliferation and tissue modeling. We will study the function of beta-catenin, LEFs/TcFs and cadherin in this new growth using retroviral mediated gene delivery of mutated forms, missing domain-specific functions. The morphological and molecular phenotypes will be assayed in the scale - feather new growth assay. We will also study the cellular mechanisms through which this pathway regulates growth control focusing on cell proliferation and migration and tissue modeling. Knowledge gained from these studies will be useful in the diagnosis and treatment of many forms of cancer.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA083716-03
Application #
6514213
Study Section
Metabolic Pathology Study Section (MEP)
Program Officer
Mohla, Suresh
Project Start
2000-07-01
Project End
2004-06-30
Budget Start
2002-07-01
Budget End
2003-06-30
Support Year
3
Fiscal Year
2002
Total Cost
$255,938
Indirect Cost
Name
University of Southern California
Department
Pathology
Type
Schools of Medicine
DUNS #
041544081
City
Los Angeles
State
CA
Country
United States
Zip Code
90089
Chuong, Cheng-Ming; Wu, Ping; Plikus, Maksim et al. (2006) Engineering stem cells into organs: topobiological transformations demonstrated by beak, feather, and other ectodermal organ morphogenesis. Curr Top Dev Biol 72:237-74
Wu, Ping; Jiang, Ting-Xin; Shen, Jen-Yee et al. (2006) Morphoregulation of avian beaks: comparative mapping of growth zone activities and morphological evolution. Dev Dyn 235:1400-12
Wu, Ping; Jiang, Ting-Xin; Suksaweang, Sanong et al. (2004) Molecular shaping of the beak. Science 305:1465-6
Suksaweang, Sanong; Lin, Chih-Min; Jiang, Ting-Xin et al. (2004) Morphogenesis of chicken liver: identification of localized growth zones and the role of beta-catenin/Wnt in size regulation. Dev Biol 266:109-22
Widelitz, Randall B; Jiang, Ting Xin; Yu, Mingke et al. (2003) Molecular biology of feather morphogenesis: a testable model for evo-devo research. J Exp Zool B Mol Dev Evol 298:109-22
Chodankar, Rajas; Chang, Chung-Hsing; Yue, Zhicao et al. (2003) Shift of localized growth zones contributes to skin appendage morphogenesis: role of the Wnt/beta-catenin pathway. J Invest Dermatol 120:20-6
Chuong, Cheng-Ming; Wu, Ping; Zhang, Fu-Cheng et al. (2003) Adaptation to the sky: Defining the feather with integument fossils from mesozoic China and experimental evidence from molecular laboratories. J Exp Zool B Mol Dev Evol 298:42-56
Koh, Stephen S; Li, Hongwei; Lee, Young-Ho et al. (2002) Synergistic coactivator function by coactivator-associated arginine methyltransferase (CARM) 1 and beta-catenin with two different classes of DNA-binding transcriptional activators. J Biol Chem 277:26031-5