The focus of my lab is the study of secreted Frizzled-related proteins (sFRPs) and their role in regulating Wnt signaling. Particular emphasis has been placed on sFRP-1, which was independently purified and cloned in my lab. Collaborative studies with recombinant sFRP-1 indicate that it can block osteoclast formation, disrupt stereocilia orientation in developing cochlea and increase intraocular pressure. A mouse model with targeted disruption of the Sfrp1 gene has been created to explore the role of sFRP-1 in normal development and disease processes. We have broadened the investigation of Wnt regulation to include members of the Dickkopf family, proteins reported to specifically block the Wnt canonical/beta-catenin pathway. The differential effects of recombinant sFRPs and Dickkopfs should distinguish between the participation of canonical and non-canonical pathways in Wnt-dependent, biological responses. This approach has been used in a collaborative study to demonstrate the role of a non-canonical pathway in the response of multiple myeloma cells to Wnt stimulation. It also is being used to investigate the mechanism(s) of Wnt-dependent cell motility in an in vitro model system. Prior to the sFRP/Wnt studies, my research involved keratinocyte growth factor (KGF) and hepatocyte growth factor (HGF). A recent collaborative study revealed a role for KGF/KGFR signaling in thymus development and T cell maturation. Several years ago Amgen, Inc. licensed patent rights to KGF for the development of therapeutic applications. This year a phase 3 clinical trial was completed in which KGF was shown to be safe and effective in reducing the duration and incidence of severe oral mucositis in patients with hematologic malignancies who received high dose chemotherapy and radiation prior to autologous peripheral blood progenitor cell transplantation.

Agency
National Institute of Health (NIH)
Institute
Division of Basic Sciences - NCI (NCI)
Type
Intramural Research (Z01)
Project #
1Z01BC010251-08
Application #
6950937
Study Section
(LCMB)
Project Start
Project End
Budget Start
Budget End
Support Year
8
Fiscal Year
2003
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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