Regulated expression of certain genes in the intestinal epithelial cells is controlled at the posttranscriptional levels of mRNA stability and mRNA translation. Dysregulation in either one could lead to various pathophysiological conditions including colon cancer and inflammatory bowel disease. An important cis-acting element controlling these functions is the AU-rich sequence elements, which is present in the 3'untranslated region of many tightly regulated genes. We have recently identified a novel AU-rich RNA binding protein, CUGBP2, which is induced in intestinal epithelial cells after radiation injury, coincident with the cells undergoing apoptosis. Furthermore COX-2 mRNA rapidly accumulates in the intestine after radiation injury, however, COX-2 mRNA translation is inhibited. We have now determined that CUGBP2 binds 3' untranslated region of COX-2 mRNA and stabilizes the mRNA, but inhibits its translation. Accordingly, the three aims of the current application are (a) to investigate the mechanism by which CUGBP2 binds and stabilizes AU-rich mRNAs, (b) to determine the mechanism by which CUGBP2 affects mRNA translation, and (c) to determine the effects of CUGBP2 expression on intestinal epithelial cell apoptosis. These experimental approaches should lead to a better understanding and significance of mucosal gene expression induced by injury, and advance our knowledge of posttranscriptional control of gene expression in intestine.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
1R01DK062265-01
Application #
6531958
Study Section
Special Emphasis Panel (ZRG1-SSS-3 (01))
Program Officer
Hamilton, Frank A
Project Start
2002-06-01
Project End
2007-05-31
Budget Start
2002-06-01
Budget End
2003-05-31
Support Year
1
Fiscal Year
2002
Total Cost
$259,859
Indirect Cost
Name
Washington University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
062761671
City
Saint Louis
State
MO
Country
United States
Zip Code
63130
Kwatra, Deep; Subramaniam, Dharmalingam; Ramamoorthy, Prabhu et al. (2013) Methanolic extracts of bitter melon inhibit colon cancer stem cells by affecting energy homeostasis and autophagy. Evid Based Complement Alternat Med 2013:702869
He, Zhiyun; Subramaniam, Dharmalingam; Zhang, Zhongtao et al. (2013) Honokiol as a Radiosensitizing Agent for Colorectal cancers. Curr Colorectal Cancer Rep 9:
Subramaniam, Dharmalingam; Periyasamy, Giridharan; Ponnurangam, Sivapriya et al. (2012) CDK-4 inhibitor P276 sensitizes pancreatic cancer cells to gemcitabine-induced apoptosis. Mol Cancer Ther 11:1598-608
Sahoo, Kaustuv; Dozmorov, Mikhail G; Anant, Shrikant et al. (2012) The curcuminoid CLEFMA selectively induces cell death in H441 lung adenocarcinoma cells via oxidative stress. Invest New Drugs 30:558-67
Gutheil, William G; Reed, Gregory; Ray, Amitabha et al. (2012) Crocetin: an agent derived from saffron for prevention and therapy for cancer. Curr Pharm Biotechnol 13:173-9
Ponnurangam, Sivapriya; Mammen, Joshua M V; Ramalingam, Satish et al. (2012) Honokiol in combination with radiation targets notch signaling to inhibit colon cancer stem cells. Mol Cancer Ther 11:963-72
Ramalingam, Satish; Ramamoorthy, Prabhu; Subramaniam, Dharmalingam et al. (2012) Reduced Expression of RNA Binding Protein CELF2, a Putative Tumor Suppressor Gene in Colon Cancer. Immunogastroenterology 1:27-33
Subramaniam, Dharmalingam; Nicholes, Nathan D; Dhar, Animesh et al. (2011) 3,5-bis(2,4-difluorobenzylidene)-4-piperidone, a novel compound that affects pancreatic cancer growth and angiogenesis. Mol Cancer Ther 10:2146-56
He, Zhiyun; Subramaniam, Dharmalingam; Ramalingam, Satish et al. (2011) Honokiol radiosensitizes colorectal cancer cells: enhanced activity in cells with mismatch repair defects. Am J Physiol Gastrointest Liver Physiol 301:G929-37
Subramaniam, Dharmalingam; Ramalingam, Satish; Linehan, David C et al. (2011) RNA binding protein CUGBP2/CELF2 mediates curcumin-induced mitotic catastrophe of pancreatic cancer cells. PLoS One 6:e16958

Showing the most recent 10 out of 37 publications