p53 isoform Δ113p53 is a p53 target gene that antagonizes p53 apoptotic activity via BclxL activation in zebrafish

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 D133p53 and its zebrafish counterpart D113p53. 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 D113p53 is directly transactivated by full-length p53 in response to developmental and DNA-damaging signals. More importantly, we show that D113p53 functions to antagonize p53-induced apoptosis via activating bcl2L (closest to human Bcl-x L ), and knockdown of D113p53 enhances p53-mediated apoptosis under stress conditions. Thus, we demonstrate that the p53 genetic locus contains a new p53 response gene and that D113p53 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: p53 isoforms; D113p53; Bcl2; apoptosis; zebrafish] Supplemental material is available at http://www.genesdev.org.

The p53 isoform, Δ133p53α, stimulates angiogenesis and tumour progression

“…We and others have shown that p53 transactivates, in response to stress, the internal p53 promoter giving rise to D133p53 isoforms, thus providing a negative feedback regulation of the p53 response. 3,4,18,23 Altogether, it suggests that p53 and D133p53 isoforms regulate each other's expression in U87 cells. Further experiments will be required to decipher the D133p53-mediated repression of p53 in U87 cells.…”

“…21 Moreover, D133p53a inhibits replicative senescence, p53-mediated apoptosis and G1 cell cycle arrest, without preventing p53-promoted G2 cell cycle arrest by regulating gene expression. [2][3][4][5] Altogether, it suggests that p53 isoforms have a key role in carcinogenesis. However, the role of p53 isoforms in angiogenesis was unknown.…”

“…However, it is important to note that several studies have reported that p53 protein isoforms are biologically active at low expression level. [3][4][5]18,22 By a knockdown approach using siRNAs specific of TAp53 isoforms or of D133p53 isoforms, we have noticed that siD133p53 concomitantly represses D133p53mRNAs and induces p53 at the mRNA and protein levels in U87 cells, whereas siTAp53 represses p53 expression at the mRNA and protein level without altering expression of D133p53 mRNAs. Interestingly, co-transfection of siD133p53 and siTAp53 represses D133p53 mRNAs expression without inducing p53 expression.…”

“…2,3 A gain of expression of D133p53 mRNAs in human breast tumours versus normal breast tissue suggests a protumoural role of these isoforms. 2 Indeed, D113p53, the zebrafish ortholog of human D133p53a, is able to regulate wild-type p53 (WTp53) proapoptotic function.…”

“…2 Indeed, D113p53, the zebrafish ortholog of human D133p53a, is able to regulate wild-type p53 (WTp53) proapoptotic function. 3 This activity is conserved in human cells, as D133p53a can inhibit p53-mediated apoptosis and G1 cell cycle arrest without inhibiting p53-mediated G2 cell cycle arrest. 4 Furthermore, increased expression of D133p53a is associated with inhibition of replicative senescence in normal human fibroblasts and colon carcinoma.…”