The development of cancer involves the inactivation of specific genes involved in growth regulation. Recent work from our laboratory and others have identified two tumor suppressor genes that belong to the Protein 4.1 family of molecules (the NF2 gene product, merlin, and Protein 4.1B) and are deleted in brain, breast, and lung cancers. In specific brain tumors (meningiomas), Protein 4.1B expression is lost early in tumor development and may represent an initiating event in brain tumorigenesis. We have previously shown that (a) Protein 4.1B suppresses meningioma cell growth in vitro, (b) Protein 4.1B associates with both CD44 and 14-3-3, and (c) the minimal growth suppressor domain of Protein 4.1 B maps to a region that mediates binding to both CD44 and 14-3-3. In this proposal, I plan to test the hypothesis that the ability of Protein 4.1B to suppress meningioma cell growth requires regulated interactions with both CD44 and 14-3-3. Specifically, I wish to (1) identify and characterize the minimal domain of Protein 4.1B required for growth suppression, (2) define the molecular determinants within the Protein 4.1B growth suppressor domain that mediate interactions with CD44 and 14-3-3, and (3) determine whether the binding of Protein 4.1B to CD44 and 14-3-3 is critical for Protein 4.1B growth suppression. These studies are focused on elucidating the mechanism(s) underlying tumor suppression of one of the critical growth regulators important in brain tumor formation.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Postdoctoral Individual National Research Service Award (F32)
Project #
5F32CA097816-02
Application #
6613878
Study Section
Special Emphasis Panel (ZRG1-F09 (20))
Program Officer
Lohrey, Nancy
Project Start
2002-07-17
Project End
Budget Start
2003-07-17
Budget End
2004-07-16
Support Year
2
Fiscal Year
2003
Total Cost
$46,420
Indirect Cost
Name
Washington University
Department
Neurology
Type
Schools of Medicine
DUNS #
068552207
City
Saint Louis
State
MO
Country
United States
Zip Code
63130
Robb, Victoria A; Gerber, Mark A; Hart-Mahon, Elizabeth K et al. (2005) Membrane localization of the U2 domain of Protein 4.1B is necessary and sufficient for meningioma growth suppression. Oncogene 24:1946-57
Robb, Victoria A; Li, Wen; Gutmann, David H (2004) Disruption of 14-3-3 binding does not impair Protein 4.1B growth suppression. Oncogene 23:3589-96
Singh, Vinita; Miranda, Tina Branscombe; Jiang, Wei et al. (2004) DAL-1/4.1B tumor suppressor interacts with protein arginine N-methyltransferase 3 (PRMT3) and inhibits its ability to methylate substrates in vitro and in vivo. Oncogene 23:7761-71
Robb, Victoria A; Li, Wen; Gascard, Philippe et al. (2003) Identification of a third Protein 4.1 tumor suppressor, Protein 4.1R, in meningioma pathogenesis. Neurobiol Dis 13:191-202