Abstract

The underlying hypothesis of the proposed studies is that the ability of activated Cdc42 to induce anchorage-independent growth derives from its effects on cyclin A. Thus, the proposal focuses on identifying the mechanisms by which Cdc42 induces anchorage-independent growth and how it stimulates cyclin A expression in the absence of mitogens. The application contains three specific aims. The first will be to determine the mechanism by which Cdc42 activates the cyclin A promoter. Here the goal will be to identify and characterize the cis- and trans-acting factors that confer Cdc42-responsiveness to the cyclin A promoter.
The second aim i s to identify Cdc42 effectors that are responsible for mediating cyclin A induction and anchorage-independent growth.
The third aim will be to establish whether Cdc42V12 effectors are critical mediators of adhesion-dependent signals during the normal proliferative response. The importance of these experiments is to establish whether similar pathways are used by a transforming Cdc42 mutant and wild type Cdc42 under normal physiological conditions.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA081415-03
Application #
6513557
Study Section
Cell Development and Function Integrated Review Group (CDF)
Program Officer
Woodhouse, Elizabeth
Project Start
2000-07-01
Project End
2005-06-30
Budget Start
2002-07-01
Budget End
2003-06-30
Support Year
3
Fiscal Year
2002
Total Cost
$283,507
Indirect Cost

  Institution

Name
University of Pennsylvania
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104

  Publications

Pringle, L M; Young, R; Quick, L et al. (2012) Atypical mechanism of NF-?B activation by TRE17/ubiquitin-specific protease 6 (USP6) oncogene and its requirement in tumorigenesis. Oncogene 31:3525-35
Erickson-Johnson, Michele R; Chou, Margaret M; Evers, Barbara R et al. (2011) Nodular fasciitis: a novel model of transient neoplasia induced by MYH9-USP6 gene fusion. Lab Invest 91:1427-33
Ye, Y; Pringle, L M; Lau, A W et al. (2010) TRE17/USP6 oncogene translocated in aneurysmal bone cyst induces matrix metalloproteinase production via activation of NF-kappaB. Oncogene 29:3619-29
Lau, Alan W; Pringle, Lashon M; Quick, Laura et al. (2010) TRE17/ubiquitin-specific protease 6 (USP6) oncogene translocated in aneurysmal bone cyst blocks osteoblastic maturation via an autocrine mechanism involving bone morphogenetic protein dysregulation. J Biol Chem 285:37111-20
Holloway, Beth A; Gomez de la Torre Canny, Sol; Ye, Ying et al. (2009) A novel role for MAPKAPK2 in morphogenesis during zebrafish development. PLoS Genet 5:e1000413
Lau, Alan W; Chou, Margaret M (2008) The adaptor complex AP-2 regulates post-endocytic trafficking through the non-clathrin Arf6-dependent endocytic pathway. J Cell Sci 121:4008-17
Robertson, Sarah E; Setty, Subba Rao Gangi; Sitaram, Anand et al. (2006) Extracellular signal-regulated kinase regulates clathrin-independent endosomal trafficking. Mol Biol Cell 17:645-57
Shen, Chuanlu; Ye, Ying; Robertson, Sarah E et al. (2005) Calcium/calmodulin regulates ubiquitination of the ubiquitin-specific protease TRE17/USP6. J Biol Chem 280:35967-73
Martinu, Lenka; Masuda-Robens, Jeffrey M; Robertson, Sarah E et al. (2004) The TBC (Tre-2/Bub2/Cdc16) domain protein TRE17 regulates plasma membrane-endosomal trafficking through activation of Arf6. Mol Cell Biol 24:9752-62
Baumeister, Mark A; Martinu, Lenka; Rossman, Kent L et al. (2003) Loss of phosphatidylinositol 3-phosphate binding by the C-terminal Tiam-1 pleckstrin homology domain prevents in vivo Rac1 activation without affecting membrane targeting. J Biol Chem 278:11457-64

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