Caspase-1 activator Ipaf is a p53-inducible gene involved in apoptosis

Abstract

The tumor suppressor protein p53 regulates transcription of many genes that mediate cell cycle arrest, apoptosis, DNA repair and other cellular responses. Here we show that Ipaf, a human CED-4 homologue and an activator of caspase-1, is induced by p53. Overexpression of p53 by transfection in U2OS and A549 cells increased Ipaf mRNA levels. Treatment of p53-positive cell lines U2OS and MCF-7 with the DNA damaging drug, doxorubicin, which increases p53 protein level, induced expression of Ipaf mRNA but similar treatment of MCF-7-mp53 (a clone of MCF-7 cells expressing mutant p53) and p53-negative K562 cells showed much less induction of Ipaf gene expression. Expression analysis for Ipaf mRNA in doxorubicin-treated human tumor cell lines suggests that p53-dependent as well as p53-independent mechanisms are involved in the regulation of Ipaf gene expression in a cell-type-specific manner. The Ipaf promoter was activated by normal p53 but not by His 273 mutant of p53. A functional p53-binding site was identified in the Ipaf promoter. A dominant-negative mutant of Ipaf inhibited p53-induced and doxorubicin-induced apoptosis by about 50%. Ipaf-directed small hairpin RNA downregulated p53-induced Ipaf gene expression and also reduced p53-induced apoptosis. Doxorubicin-induced apoptosis was also inhibited by Ipaf-directed small hairpin RNA. Our results show that p53 can directly induce Ipaf gene transcription, which contributes to p53-dependent apoptosis in at least some human cells.

Genetic and molecular alterations in olfactory neuroblastoma: implications for pathogenesis, prognosis and treatment

“…This highlights a possible role of mutations in KDR , MYC , SIN3B , NLRC4 genes for the formation of metastases in ONB. Interesting interactions may occur between products of these genes: MYC attaches to SIN3B, while p53 to the NLRC4 promoter [66, 67]. In turn, whole exome sequencing of another metastatic ONB recognized 8 candidate cancer genes: BRINP1 , CARD11 , CDKN2C , MEIS1 , MINK1 , PPP6C , TGFBR2 and TP53 [40].…”

SopB activates the Akt-YAP pathway to promote Salmonella survival within B cells

“…Yes-associated protein (YAP) is a pro-apoptotic transcriptional coactivator that acts within the Hippo pathway and regulates cell proliferation, cell differentiation, spatial organ patterning and tissue regeneration [26]. Furthermore, YAP potentiates p73 function as a transcription factor [27–29]. Additionally, YAP has been reported as a potential integrator of cell death processes and autophagy during cellular stress [30–32].…”

Role of p73 in Regulating Human Caspase-1 Gene Transcription Induced by Interferon-γ and Cisplatin

“…Construction of a Vector Expressing shRNA-The shRNA expression vector targeting p73 was constructed using the U6 promoter-based vector essentially as described (38,39). The desired synthetic oligonucleotides were annealed and cloned into the BbsI-Xba-digested U6 promoter plasmid mU6 pro.…”