Tissue and cell-specific expression of the p53-target genes: bax, fas, mdm2 and waf1/p21, before and following ionising irradiation in mice

Abstract

The mechanisms by which the p53 tumour suppressor protein would, in vivo, co-ordinate the adaptive response to genotoxic stress is poorly understood. p53 has been shown to transactivate several genes that could be involved in two main cellular responses, growth arrest and apoptosis. To get further insight into the tissuespeci®c regulation of p53 transcriptional activity, we performed an extensive study looking at the expression of four well characterized p53-responsive genes, before and after g-irradiation in p53 wild-type (p53+/+) and p53-de®cient (p537/7) mice. The waf1, bax, fas and mdm2 genes were chosen for their dierent potential roles in the cellular response to stress. Our data demonstrate the strict p53-dependence of mRNA upregulation for bax, fas and mdm2 in irradiated tissues and con®rm such ®ndings for waf1. They further highlight complex levels of regulatory mechanisms that could lead, in vivo, to selective transcriptional activation of genes by p53. In addition, our results provide arguments for the involvement of p53 in the basal mRNA expression of the four genes in some organs. Finally, in situ expression of Bax and p21Waf-1 protein suggests, at least in lymphoid organs, a direct correlation between selective p53-target gene expression and a particular response of a cell to ionising radiation.

Perp is required for tissue-specific cell survival during zebrafish development

“…The same appears to apply to other stress-induced p53 target genes, as revealed by comparative expression analysis in wild-type and p53-deficient mice, demonstrating both p53-dependent and p53-independent expression of Bax, Fas, Killer, and Mdm2 in different cell types of adult mice. 54,55 Perp and its PMP22 relatives: possible mechanisms of action During embryonic development, several important regulators, such as members of the family of Bone Morphogenetic proteins, have both pro-and antiapoptotic effects, depending on the cellular context (see for example Liu et al 56 and Israsena and Kessler 57 ). However, the molecular mechanisms underlying these contrary effects are not fully understood.…”

Transcriptional activation of caspase-6 and -7 genes by cisplatin-induced p53 and its functional significance in cisplatin nephrotoxicity

“…5,6 Upon activation, p53 binds to specific DNA sequences that promote transcription of target genes, including genes associated with apoptosis and cell cycle arrest, [6][7][8][9] in a tissue-and cell-specific manner. 10,11 Upon receiving a proapoptotic stimulus, most if not all of the signaling pathways of cell death converge into the activation of executioner caspase-3, -6, and -7. The initiator caspase-2, -8, -9, and -10, having long N-terminal prodomains, activate the downstream executioner caspases with short N-terminal prodomains by proteolytic processing.…”

Accumulation of an inactive form of p53 protein in cells treated with TNFα

“…Cells without functional p53 cannot induce p21/Waf1. 21 However, there is accumulating evidence that the expression of the p21/Waf1 gene can be induced upon stimulation through a pathway, which does not require p53 (reviewed in 20 ). Kobayashi et al showed an increased rate and accumulation of p21/ Waf1 in TNFa-treated cells expressing a transcriptioninactive p53 mutant.…”