Abstract

The goal of this application is to determine the mechanisms leading to the overexpression of the urokinase receptor (u-PAR) in invasive colon cancer.
In Specific Aim 1, the applicant proposes to identify the role of an upstream AP-1 motif in the regulation of u-PAR expression and also identify transcription factors bound by this sequence.
Aim 2 will ascertain the role of these promoter regions in regulating u-PAR expression by determining if deletion of either region impairs u-PAR promoter activity, by identifying the nucleotides contacted by nuclear proteins, and by determining the effect of mutation of the contacted nucleotides on u-PAR promoter activity.
Aim 3 will determine the role of extracellular signal-regulated kinases 1 (ERK1) and 2 or a constitutively activated MEK1 which lies upstream of the ERKs, to modulate u-PAR expression and in vitro invasion.
Aim 4 will investigate the ability of a synthetic inhibitor of MEK1 activation to downregulate u-PAR expression and in vitro invasion, and Aim 5 will determine the role of the c-Jun aminoterminal kinase 1 (JNK1) in regulating u-PAR expression. It is hoped that these studies will benefit colon cancer patients by decreasing u-PAR expression in colon cancer and thereby reduce the metastatic spread of the disease.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
2R01CA058311-04
Application #
2393435
Study Section
Metabolic Pathology Study Section (MEP)
Project Start
1994-07-01
Project End
2002-04-30
Budget Start
1997-07-15
Budget End
1998-04-30
Support Year
4
Fiscal Year
1997
Total Cost
Indirect Cost

  Institution

Name
University of Texas MD Anderson Cancer Center
Department
Biology
Type
Other Domestic Higher Education
DUNS #
001910777
City
Houston
State
TX
Country
United States
Zip Code
77030

  Publications

Chauhan, Santosh; Goodwin, Jinesh G; Chauhan, Swati et al. (2013) ZKSCAN3 is a master transcriptional repressor of autophagy. Mol Cell 50:16-28
Chauhan, Santosh; Boyd, Douglas D (2012) Regulation of u-PAR gene expression by H2A.Z is modulated by the MEK-ERK/AP-1 pathway. Nucleic Acids Res 40:600-13
Avila, Hector; Wang, Heng; Chauhan, Santosh et al. (2011) Accelerated urokinase-receptor protein turnover triggered by interference with the addition of the glycolipid anchor. Biochem J 434:233-42
Ishiguro, T; Avila, H; Lin, S-Y et al. (2010) Gene trapping identifies chloride channel 4 as a novel inducer of colon cancer cell migration, invasion and metastases. Br J Cancer 102:774-82
Nair, Rajesh R; Avila, Hector; Ma, Xujun et al. (2008) A novel high-throughput screening system identifies a small molecule repressive for matrix metalloproteinase-9 expression. Mol Pharmacol 73:919-29
Wang, H; Yan, C; Asangani, I et al. (2007) Identification of an histone H3 acetylated/K4-methylated-bound intragenic enhancer regulatory for urokinase receptor expression. Oncogene 26:2058-70
Yan, Chunhong; Boyd, Douglas D (2007) Regulation of matrix metalloproteinase gene expression. J Cell Physiol 211:19-26
Nair, Rajesh R; Solway, Julian; Boyd, Douglas D (2006) Expression cloning identifies transgelin (SM22) as a novel repressor of 92-kDa type IV collagenase (MMP-9) expression. J Biol Chem 281:26424-36
Yang, Lin; Avila, Hector; Wang, Heng et al. (2006) Plasticity in urokinase-type plasminogen activator receptor (uPAR) display in colon cancer yields metastable subpopulations oscillating in cell surface uPAR density--implications in tumor progression. Cancer Res 66:7957-67
Yan, Chunhong; Boyd, Douglas D (2006) Histone H3 acetylation and H3 K4 methylation define distinct chromatin regions permissive for transgene expression. Mol Cell Biol 26:6357-71

Showing the most recent 10 out of 42 publications