During the past year, we have continued to focus our research efforts on the study of a secreted, Frizzled-related protein (sFRP-1) that is thought to have an important role in embryonic development and perhaps neoplasia. We developed an abundant source of recombinant sFRP-1 to demonstrate that it can bind directly to Wnt protein and exert a biphasic effect on Wnt activity. Several collaborative studies with recombinant sFRP-1 are broadening our understanding of its biological activity. In a rat embryonic kidney organ culture, sFRP-1 can block tubulogenesis presumably by inhibiting Wnt-4 activity. Our recent work with other recombinant sFRP family members indicates differences in their biological activities and functions. We also have been investigating sfrp-1 gene structure and characterizing its promoter activity to better understand how its expression is regulated. Substantial progress has been made in an ongoing collaboration concerning the structure-function analysis of HGF/SF. Experiments are in progress to confirm the identity of the amino acid residues responsible for heparin-binding, and to determine the consequences of their replacement with residues that will not mediate heparin interactions. Collaborative studies have yielded new information about the activity of keratinocyte growth factor (KGF or FGF-7). Investigations concern the role of KGF/KGFR signaling in thymus development and T cell maturation, and the mechanisms responsible for KGF's ability to ameliorate the impact of graft versus host disease associated with bone marrow transplantation.

Agency
National Institute of Health (NIH)
Institute
Division of Basic Sciences - NCI (NCI)
Type
Intramural Research (Z01)
Project #
1Z01BC010251-05
Application #
6433205
Study Section
(LCMB)
Project Start
Project End
Budget Start
Budget End
Support Year
5
Fiscal Year
2000
Total Cost
Indirect Cost
Name
Basic Sciences
Department
Type
DUNS #
City
State
Country
United States
Zip Code
Kwon, Heung-Sun; Lee, Hee-Sheung; Ji, Yun et al. (2009) Myocilin is a modulator of Wnt signaling. Mol Cell Biol 29:2139-54
Rubin, Jeffrey S; Bottaro, Donald P (2007) Loss of secreted frizzled-related protein-1 expression in renal cell carcinoma reveals a critical tumor suppressor function. Clin Cancer Res 13:4660-3
Endo, Yoshimi; Rubin, Jeffrey S (2007) Wnt signaling and neurite outgrowth: insights and questions. Cancer Sci 98:1311-7
Wang, Hong; Charles, Peter C; Wu, Yaxu et al. (2006) Gene expression profile signatures indicate a role for Wnt signaling in endothelial commitment from embryonic stem cells. Circ Res 98:1331-9
Rubin, Jeffrey S; Barshishat-Kupper, Michal; Feroze-Merzoug, Farhana et al. (2006) Secreted WNT antagonists as tumor suppressors: pro and con. Front Biosci 11:2093-105
Tchou-Wong, Kam-Meng; Fok, Sandra Y Y; Rubin, Jeffrey S et al. (2006) Rapid chemokinetic movement and the invasive potential of lung cancer cells; a functional molecular study. BMC Cancer 6:151
Qiang, Ya-Wei; Walsh, Katie; Yao, Lei et al. (2005) Wnts induce migration and invasion of myeloma plasma cells. Blood 106:1786-93
Endo, Yoshimi; Wolf, Vladimir; Muraiso, Kanae et al. (2005) Wnt-3a-dependent cell motility involves RhoA activation and is specifically regulated by dishevelled-2. J Biol Chem 280:777-86
Joesting, Margaret S; Perrin, Steve; Elenbaas, Brian et al. (2005) Identification of SFRP1 as a candidate mediator of stromal-to-epithelial signaling in prostate cancer. Cancer Res 65:10423-30
Liu, Xunxian; Rubin, Jeffrey S; Kimmel, Alan R (2005) Rapid, Wnt-induced changes in GSK3beta associations that regulate beta-catenin stabilization are mediated by Galpha proteins. Curr Biol 15:1989-97

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