Loss of one p53 allele results in four-fold reduction of p53 mRNA and protein: a basis for p53 haplo-insufficiency

Abstract

A haploid genotype may be insufficient to support normal wild-type function. Such haplo-insufficiency has recently been documented for numerous tumour suppressor genes. p53 is a crucial tumour suppressor governing DNA repair, cell cycle arrest and apoptosis via its role as a stressresponsive transcription factor. p53 haplo-insufficiency has been observed in vivo with human familial cancer in Li-Fraumeni Syndrome (LFS) and in mouse p53-knockout models of LFS. The increased tumorigenesis associated with loss of one p53 allele has been attributed to reduced p53-dependent stress responses. However, the underlying biochemical basis for such attenuated responses in p53 þ /À cells remains unclear. Here we have determined basal p53 messenger RNA (mRNA) and protein levels, and compared the p53 stress response in p53 þ / þ , p53 þ /À and p53À/À isogenic clones derived from HCT116 cells. Basal expression of p53 in p53 þ /À cells was 25% relative to p53 þ / þ cells, and this differential was maintained following oncogenic stress. This deficiency was manifested at both p53 mRNA and protein levels and resulted in attenuated p53 stress responses, in particular for p21 waf1 upregulation and survivin downregulation, and reduced G1 arrest and apoptosis. These observations identify a molecular basis for wild-type p53 haplo-insufficiency, which may explain the attenuated tumour-suppressive phenotype observed in cells with a single wild-type p53 allele and in humans with LFS.

New Cancer Stochastic Models Involving Both Hereditary and Nonhereditary Cancer Cases: A New Approach

“…Specifically, we mention using Model-1). This confirms that the stage-1 limiting gene is a tumor suppressor gene, and unlike the p53 gene in chromosome 17p (see [33]), there is little or no haploid insufficiency for this gene in cells with genotype 1 . Using models and methods of this paper, one can easily predict future cancer cases for human eye cancer.…”

Detection of the 113p53 protein isoform: A p53-induced protein that feeds back on the p53 pathway to modulate the p53 response in zebrafish

“…seen in mouse models of haplo-insufficency at the locus, 21 hypomorphoic alleles of the negative regulator MDM2, 22,23 and the affect of polymorphisms in the MDM2 promoter in man. A further exciting form of regulation has been suggested by the discovery of p53 isoforms in all vertebrates tested.…”

A Deacetylase-Deficient SIRT1 Variant Opposes Full-Length SIRT1 in Regulating Tumor Suppressor p53 and Governs Expression of Cancer-Related Genes

“…Nonetheless, the basal levels of p53 protein are important. This is evident in p53 ϩ/Ϫ cells in which the basal expression level of p53 protein is 25% of that in p53 ϩ/ϩ cells (32). Interestingly, this differential is maintained following oncogenic stress, resulting in an attenuated p53 stress response and reduced p53-dependent apoptosis (32).…”

“…Previously we demonstrated that the basal levels of p53 protein are critical for the ability of p53 to mount a stress response, with upregulation of target genes such as CDKN1A (p21) and MDM2, and that below a certain concentration threshold p53 protein may be activated in terms of posttranslational modifications but nonetheless be deficient for activating downstream stress response mediators (32). Our discovery that, in the absence of applied stress, SIRT1-⌬2/9 maintains basal p53 protein levels in cells (see above and Fig.…”