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ALCOHOL MEDIATED EXPRESSION OF
CYTOPROTECTIVE ENZYME - NQO-1
AND ITS POST TRANSLATIONAL REGULATION
by
Monisha Ravichandran
A Thesis Presented to the
FACULTY OF THE USC GRADUATE SCHOOL
UNIVERSITY OF SOUTHERN CALIFORNIA
In Partial Fulfillment of the
Requirements for the Degree
MASTER OF SCIENCE
(BIOCHEMISTRY AND MOLECULAR BIOLOGY)
August 2012
Copyright 2012 Monisha Ravichandran
Object Description
| Title | Alcohol mediated expression of cyto-protective enzyme - NQO-1 and its post translational regulation |
| Author | Ravichandran, Monisha |
| Author email | mravicha@usc.edu;souravmoni42@gmail.com |
| Degree | Master of Science |
| Document type | Thesis |
| Degree program | Biochemistry and Molecular Biology |
| School | Keck School of Medicine |
| Date defended/completed | 2012-05-22 |
| Date submitted | 2012-08-02 |
| Date approved | 2012-08-02 |
| Restricted until | 2012-08-02 |
| Date published | 2012-08-02 |
| Advisor (committee chair) | Kalra, Vijay K. |
| Advisor (committee member) |
Tokes, Zoltan Tahara, Stanley |
| Abstract | Chronic alcohol consumption leads to liver injury and death. Studies have shown ethanol causes increased inflammation, which leads to liver damage and cirrhosis. To counteract this inflammatory response, cells up-regulate antioxidant response genes, e.g. hemeoxygenase-1(HO-1) and NADH-quinone oxidoreductase-1(NQO-1). These cytoprotective genes are regulated by a central transcription factor, Nrf-2. Previous studies show ethanol induced mRNA levels of both HO-1 and NQO-1 in Kupffer cells involve activation of Nrf-2. In the present study, we examined whether ethanol affected the stability of NQO-1 mRNA, and transcription factors, i.e. Nrf-2 mRNA and Keap-1 mRNA, in endothelial cells. Our studies showed that ethanol increased the net expression of NQO-1, Nrf-2 and Keap-1 mRNAs in human endothelial cells (HMEC-1) in a time-dependent manner. Moreover, ethanol increased the stability of NQO-1 mRNA and Nrf-2 mRNA, while the Keap-1 mRNA was destabilized. Thus, we examined the role of microRNAs in the post-transcriptional regulation of NQO-1mRNA and Keap-1 mRNA. ❧ Our studies showed that both miR-566 and miR-518 attenuate the NQO-1 mRNA levels under basal and ethanol-treated conditions, as determined by transfection of HMEC-1 cells with miRs (synthetic mimics) and anti-miRs. We identified miR-200a as a potential candidate miRNA, which affects the Keap-1 mRNA expression. These studies for the first time, to the best of my knowledge, identify specific miRNAs, which may be involved in binding to the 3’UTR of NQO-1 mRNA and the 3’UTR of Keap-1 mRNA. These miRNAs may play an important role in affecting expression of cyto-protective genes and inflammation as observed in chronic alcoholic individuals. |
| Keyword | NQO-1; ethanol; miR-566; miR-518; miR-642; Nrf-2; Bach-1; Keap-1 |
| Language | English |
| Part of collection | University of Southern California dissertations and theses |
| Publisher (of the original version) | University of Southern California |
| Place of publication (of the original version) | Los Angeles, California |
| Publisher (of the digital version) | University of Southern California. Libraries |
| Provenance | Electronically uploaded by the author |
| Type | texts |
| Legacy record ID | usctheses-m |
| Rights | Ravichandran, Monisha |
| Access conditions | The author retains rights to his/her dissertation, thesis or other graduate work according to U.S. copyright law. Electronic access is being provided by the USC Libraries in agreement with the author, as the original true and official version of the work, but does not grant the reader permission to use the work if the desired use is covered by copyright. It is the author, as rights holder, who must provide use permission if such use is covered by copyright. The original signature page accompanying the original submission of the work to the USC Libraries is retained by the USC Libraries and a copy of it may be obtained by authorized requesters contacting the repository e-mail address given. |
| Repository name | University of Southern California Digital Library |
| Repository address | USC Digital Library, University of Southern California, University Park Campus MC 7002, 106 University Village, Los Angeles, California 90089-7002, USA |
| Repository email | cisadmin@usc.edu |
| Archival file | uscthesesreloadpub_Volume4/etd-Ravichandr-1112.pdf |
Description
| Title | Page 1 |
| Full text | ALCOHOL MEDIATED EXPRESSION OF CYTOPROTECTIVE ENZYME - NQO-1 AND ITS POST TRANSLATIONAL REGULATION by Monisha Ravichandran A Thesis Presented to the FACULTY OF THE USC GRADUATE SCHOOL UNIVERSITY OF SOUTHERN CALIFORNIA In Partial Fulfillment of the Requirements for the Degree MASTER OF SCIENCE (BIOCHEMISTRY AND MOLECULAR BIOLOGY) August 2012 Copyright 2012 Monisha Ravichandran |
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