Item – Theses Canada

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OCLC number
691738369
Link(s) to full text
LAC copy
LAC copy
Author
Assaily, Wissam.
Title
Lpin1 : a new p53 regulated gene induced by DNA damage and glucose withdrawal and its involvement in fatty acid oxidation.
Degree
Ph. D. -- University of Toronto, 2008
Publisher
Ottawa : Library and Archives Canada = Bibliothèque et Archives Canada, [2009]
Description
2 microfiches
Notes
Includes bibliographical references.
Abstract
The upregulation and activation of the p53 tumour suppressor gene in response to a variety of stress signals leads to cell cycle arrest and DNA repair, senescence or apoptosis. In addition to these functions, emerging evidence indicates a role for p53 in regulating metabolism. p53 was recently shown to be phosphorylated by AMPK in response to glucose withdrawal. p53 has also been shown to regulate expression of genes involved in mitochondrial respiration as well as glycolysis. In this study, we provide further evidence for a role of p53 in metabolism. We show that p53 protein is phosphorylated and accumulates in myoblasts cultured under low glucose conditions. Surprisingly, phosphorylation of p53 at Ser-15 in this context occurs in an ATM-dependent but AMPK-independent manner. Furthermore, we identify a new p53-regulated gene, Lpin1, which encodes lipin1. Lpin1 is essential for fat metabolism and mutation in this gene is responsible for the lypodystrophy phenotype in 'fld' mice. Lpin1 was also demonstrated to regulate fatty acid oxidation in transgenic mice. We show that Lpin1 is induced in response to DNA damage and glucose deprivation in a p53-dependent manner in cell lines as well as tissues. In addition, we show that Lpin1 regulates fatty acid oxidation under normal and reduced glucose conditions. Lpin1 provides another link between p53 and metabolism. The fact that this connection exists under DNA damage as well as a nutritionally relevant stress suggests at least two things. First, DNA damage mediated regulation of metabolism may be an important biological process and may have significance in cancer. Second, the upregulation of p53 and Lpin 1 under glucose withdrawal in a muscle cell line potentially expands the role of p53 from a tumour suppressor to a metabolic regulator. Thus, p53 may be important in disease and non-disease contexts.
ISBN
9780494447697
0494447699