p53-dependent apoptosis is regulated by a C-terminally alternatively spliced form of murine p53

Abstract

It is now well accepted that the p53 C-terminus plays a central role in controlling the activity of the wild-type molecule. In our previous studies, we observed that a Cterminally altered p53 protein (p53AS), generated by an alternative spliced p53 mRNA, induces an attenuated p53-dependent apoptosis, compared to that induced by the regularly spliced form (p53RS). In the present study we analysed the interrelationships between these two physiological variants of wild-type p53, and found that in cells co-expressing both forms, in contrast to the expected additive e ect on the induction of apoptosis, p53AS inhibits apoptosis induced by p53RS. This inhibitory e ect is speci®c for p53-dependent apoptosis and was not evident in a p53-independent apoptotic pathway induced by growth factor deprivation. Furthermore, the expression of p53AS in transiently transfected cells caused both inhibition of apoptosis and inhibition of the p53RS-dependent transactivation of a number of p53 target genes. These results suggest that expression of an alternatively spliced p53 form may serve as an additional level in controlling the complexity of p53 function by the C-terminal domain. Oncogene (2000) 19, 3395 ± 3403.

Changes in the expression of splicing factor transcripts and variations in alternative splicing are associated with lifespan in mice and humans

“…Cdkn2a is an important marker of cellular senescence (Tominaga, 2015) and ablation of Cdkn2a expression reverses aging phenotypes in klotho mice (Sato et al ., 2015), indicating that old animals of long‐lived strains may have lower levels of senescent cells. Young animals of longer‐lived strains also expressed profiles of Trp53 isoforms consistent with enhanced transcription and cell growth properties compared to young animals of average‐lived strains, since they express higher levels of full‐length p53 and lower levels of truncated p53AS which is thought to have antagonistic function (Wu et al ., 1997; Almog et al ., 2000; Huang et al ., 2002). Altered splicing of inflammatory genes involved in muscle remodelling produces a picture consistent with lower levels of pro‐inflammatory signalling by virtue of lower levels of Il1b and Il6 expression in young animals and reduced Tnf signalling in the older animals of long‐lived strains.…”

p53 isoforms can regulate p53 transcriptional activity

“…In mice, only one alternative splicing of intron 10-affecting the p53 C terminus-has previously been described, which leads to a p53 protein (p53AS) containing the oligomerization domain but devoid of the last 30 amino acids (Wolf et al 1985). The p53AS isoform is constitutively active for sequence-specific DNA binding, can transactivate p53 target genes, but inhibits full-length p53-mediated apoptosis (Wu et al 1994;Almog et al 2000). For the human p53 gene, two mRNA splice variants have been previously reported: (1) p53i9, alternative splicing of intron 9; and (2) ⌬40p53 (also named p47 or ⌬Np53), an alternative splicing of intron 2. p53i9 encodes a C-truncated p53 protein isoform of 341 amino acids for which no biochemical activities have been reported.…”

The Presence of a Short Form of p53 in Chicken Lymphoblastoid Cell Lines during Apoptosis

“…The functions of these alternatively spliced p53 isoforms include the regulation of p53-dependent apoptosis [2], and the control of ubiquitination, cell localization, and activity of p53 [14]. In addition, the overexpression of murine p44, a short p53 isoform which lacks a part of the transactivation domain at the N-terminus, results in p53-dependent cellular aging and reduced life span in transgenic mouse [24].…”

“…The several deleted forms of p53 mRNA are detected in MSB1-O and -cl.18 derived from MD throughout the cell cycle or during the apoptosis induced by a chemotherapeutic compound, actinomycin D [37]. In human and murine cell lines, several N-or C-terminally truncated or alternatively spliced isoforms of p53 have been identified [13], and some of them were also shown to regulate p53-dependent apoptosis and cell cycle progression [2,6,28,31]. Thus, the deleted forms of p53 present in MD and AL cell lines could also play a role in the transformation by MDV and ALV through the regulation of apoptosis or cell cycle progression.…”