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MAF1 IS A NOVEL TARGET OF THE TUMOR SUPPRESSOR PTEN AND A NEGATIVE REGULATOR OF LIPID METABOLISM
by
Beth Marie Palian
A Dissertation Presented to the
FACULTY OF THE USC GRADUATE SCHOOL
UNIVERSITY OF SOUTHERN CALIFORNIA
In Partial Fulfillment of the
Requirements for the Degree
DOCTOR OF PHILOSPHY
(GENETIC, MOLECULAR AND CELLULAR BIOLOGY)
August 2012
Copyright 2012 Beth Marie Palian
Object Description
| Title | Maf1 is a novel target of the tumor suppressor PTEN and a negative regulator of lipid metabolism |
| Author | Palian, Beth Marie |
| Author email | palian@usc.edu;beth.palian@gmail.com |
| Degree | Doctor of Philosophy |
| Document type | Dissertation |
| Degree program | Genetic, Molecular and Cellular Biology |
| School | Keck School of Medicine |
| Date defended/completed | 2012-05-04 |
| Date submitted | 2012-06-22 |
| Date approved | 2012-06-22 |
| Restricted until | 2012-06-22 |
| Date published | 2012-06-22 |
| Advisor (committee chair) | Johnson, Deborah L. |
| Advisor (committee member) |
Stiles, Bangyan L. Dubeau, Louis |
| Abstract | Although Maf1 has been identified as a central negative regulator of transcription, little is known about its regulation and it is likely that many of its target genes have yet to be identified. Our finding that Maf1 can suppress cellular transformation led us to examine whether Maf1 might be regulated by the tumor suppressor, PTEN. Indeed, Pten-deficient cell lines and mouse tissues show marked decreases in Maf1 protein expression. Consistent with these results, induction of PTEN expression in human glioblastoma cells results in increased Maf1 expression. Pharmacologic inhibitors of PI3K signaling also induce Maf1 expression, and expression of a phosphatase defective mutant PTEN fails to alter Maf1 expression. These data suggest that regulation of Maf1 expression by PTEN is due, at least in part, to its ability to inhibit the PI3K signaling pathway. Loss of Akt2 in the liver of mice results in increased Maf1 protein expression. Additionally, loss of Akt2 in combination with Pten loss rescues the decreased Maf1 expression that was caused by Pten loss alone. Ectopic expression of FoxO1, a downstream target of Akt, increases Maf1 protein expression. Given the established role for the PI3K/AKT/FoxO1 pathway in regulating lipid biosynthesis, we investigated whether Maf1 could regulate these genes. We show that enzymes required for lipid biogenesis, including FASN and ACC1, are repressed by Maf1. Repressing Maf1 expression in Huh7 hepatoma cells resulted in increased lipid accumulation. A marked decrease in Maf1 staining is observed in Pten-null mouse prostate and human prostate cancer tissue. Together these studies identify Maf1 as a downstream target of PTEN and a novel regulator of lipogenic gene expression. |
| Keyword | Maf1; PTEN; FASN; de novo lipogenesis |
| 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 |
| Contributing entity | University of Southern California |
| Rights | Palian, Beth Marie |
| 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-PalianBeth-900.pdf |
Description
| Title | Page 1 |
| Contributing entity | University of Southern California |
| Full text | MAF1 IS A NOVEL TARGET OF THE TUMOR SUPPRESSOR PTEN AND A NEGATIVE REGULATOR OF LIPID METABOLISM by Beth Marie Palian A Dissertation Presented to the FACULTY OF THE USC GRADUATE SCHOOL UNIVERSITY OF SOUTHERN CALIFORNIA In Partial Fulfillment of the Requirements for the Degree DOCTOR OF PHILOSPHY (GENETIC, MOLECULAR AND CELLULAR BIOLOGY) August 2012 Copyright 2012 Beth Marie Palian |
