Our growth regulation research has been concerned with oncogenes and tumor suppressor genes as positive and negative regulators of normal and neoplastic growth. The work is focused on the regulation of the Ras-superfamily of proteins and their role in cancer, as well as on the role of adhesion in cancer. Here we highlight two recent projects. 1) We are studying Sipa-1/Spa-1, which encodes a GTPase-activating protein (GAP) that negatively regulates the Rap-GTPases (a Ras-superfamily group) by enzymatically converting active Rap-GTP to inactive Rap-GDP. In collaboration with the Laboratory of Kent Hunter in CCR, we have identified Sipa-1 as a gene that can promote metastasis in a mouse breast cancer model. Consistent with this role in the mouse model, metatstatic human prostate cancer was found to be associated with Sipa-1 overexpression. Rap-GTP has several functions, including the promotion of cell adhesion and cell polarity, both of which may inhibit metastasis in many tumor systems. Our working hypothesis is that overexpression of Sipa-1 promotes metastasis at least in part by decreasing Rap-GTP-dependent adhesion and polarity. A positive role in cancer has not been reported previously for the negative regulator of a Ras-superfamily group, as most negative regulators of the Ras-superfamily groups inhibit cancer (or have no effect), rather than promote it. If a pathogenetic role is validated for Sipa-1 in human cancer, the gene and its encoded protein may represent an attractive candidate molecular target. 2) We are also investigating E-cadherin, a key cell surface adhesion protein that is a tumor suppressor frequently silenced in many epithelial cancers and melanoma, especially those with high metastatic potential. We have found that E-cadherin specifically inhibits the activation of a variety of receptor tyrosine kinases (RTKs) by their physiologic ligands. The inhibition probably results from the formation of a complex between E-cadherin and the RTKs, which restricts the ability of the ligands to bind their cognate RTK with high affinity. This inhibitory activity of E-cadherin is abrogated when E-cadherin expression is silenced in tumors, permitting more robust responses to RTKs by their ligands, a widespread phenomemon implicated in the pathogenesis of many tumors. Future studies will examine other mechanisms by which E-cadherin regulates cell growth, and the possibility of using E-cadherin as a potential cancer treatment target.

Agency
National Institute of Health (NIH)
Institute
Division of Basic Sciences - NCI (NCI)
Type
Intramural Research (Z01)
Project #
1Z01BC008905-24
Application #
7292121
Study Section
(LCO)
Project Start
Project End
Budget Start
Budget End
Support Year
24
Fiscal Year
2005
Total Cost
Indirect Cost
Name
Basic Sciences
Department
Type
DUNS #
City
State
Country
United States
Zip Code
Park, Yeong-Gwan; Zhao, Xiaohong; Lesueur, Fabienne et al. (2005) Sipa1 is a candidate for underlying the metastasis efficiency modifier locus Mtes1. Nat Genet 37:1055-62
Qian, Xiaolan; Karpova, Tatiana; Sheppard, Allan M et al. (2004) E-cadherin-mediated adhesion inhibits ligand-dependent activation of diverse receptor tyrosine kinases. EMBO J 23:1739-48
Zhang, Shuling; Qian, Xiaolan; Redman, Chanelle et al. (2003) p16 INK4a gene promoter variation and differential binding of a repressor, the ras-responsive zinc-finger transcription factor, RREB. Oncogene 22:2285-95
Li, Shaowei; Braverman, Richard; Li, Hongzhen et al. (2003) Regulation of cell morphology and adhesion by the tuberous sclerosis complex (TSC1/2) gene products in human kidney epithelial cells through increased E-cadherin/beta-catenin activity. Mol Carcinog 37:98-109
Bliskovsky, Valery; Ramsay, Edward S; Scott, John et al. (2003) Frap, FKBP12 rapamycin-associated protein, is a candidate gene for the plasmacytoma resistance locus Pctr2 and can act as a tumor suppressor gene. Proc Natl Acad Sci U S A 100:14982-7