p53 isoform Δ113p53 is a p53 target gene that antagonizes p53 apoptotic activity via BclxL activation in zebrafish
- 1 February 2009
- journal article
- Published by Cold Spring Harbor Laboratory
- Vol. 23 (3), 278-290
- https://doi.org/10.1101/gad.1761609
Abstract
P53 is a well-known tumor suppressor and is also involved in processes of organismal aging and developmental control. A recent exciting development in the p53 field is the discovery of various p53 isoforms. One p53 isoform is human Δ133p53 and its zebrafish counterpart Δ113p53. These N-terminal-truncated p53 isoforms are initiated from an alternative p53 promoter, but their expression regulation and physiological significance at the organismal level are not well understood. We show here that zebrafish Δ113p53 is directly transactivated by full-length p53 in response to developmental and DNA-damaging signals. More importantly, we show that Δ113p53 functions to antagonize p53-induced apoptosis via activating bcl2L (closest to human Bcl-xL), and knockdown of Δ113p53 enhances p53-mediated apoptosis under stress conditions. Thus, we demonstrate that the p53 genetic locus contains a new p53 response gene and that Δ113p53 does not act in a dominant-negative manner toward p53 but differentially modulates p53 target gene expression to antagonize p53 apoptotic activity at the physiological level in zebrafish. Our results establish a novel feedback pathway that modulates the p53 response and suggest that modulation of the p53 pathway by p53 isoforms might have an impact on p53 tumor suppressor activity.Keywords
This publication has 28 references indexed in Scilit:
- Expression of novel p53 isoforms in oral lichen planusOral Oncology, 2008
- p53 Activation by Knockdown TechnologiesPLoS Genetics, 2007
- p53 in health and diseaseNature Reviews Molecular Cell Biology, 2007
- Expression of p53 isoforms in squamous cell carcinoma of the head and neckEuropean Journal of Cancer, 2007
- Functional characterization of the Bcl-2 gene family in the zebrafishCell Death & Differentiation, 2006
- HNF factors form a network to regulate liver-enriched genes in zebrafishDevelopmental Biology, 2006
- Transcriptional regulation by p53: one protein, many possibilitiesCell Death & Differentiation, 2006
- Loss of function of def selectively up-regulates Δ113p53 expression to arrest expansion growth of digestive organs in zebrafishGenes & Development, 2005
- Insertional mutagenesis in zebrafish rapidly identifies genes essential for early vertebrate developmentNature Genetics, 2002
- The mdm-2 oncogene product forms a complex with the p53 protein and inhibits p53-mediated transactivationCell, 1992