p53 Maintains Baseline Expression of Multiple Tumor Suppressor Genes

Abstract

TP53 is the most commonly mutated tumor suppressor gene and its mutation drives tumorigenesis. Using ChIP-seq for p53 in the absence of acute cell stress, we found that wild-type but not mutant p53 binds and activates numerous tumor suppressor genes including PTEN, STK11(LKB1), miR-34a, KDM6A(UTX), FOXO1, PHLDA3 and TNFRSF10B through consensus binding sites in enhancers and promoters. Depletion of p53 reduced expression of these target genes, and analysis across 18 tumor types showed that mutation of TP53 associated with reduced expression of many of these genes. Regarding PTEN, p53 activated expression of a luciferase reporter gene containing the p53-consensus site in the PTEN enhancer, and homozygous deletion of this region in cells decreased PTEN expression and increased growth and transformation. These findings show that p53 maintains expression of a team of tumor suppressor genes that may together with the stress-induced targets mediate the ability of p53 to suppress cancer development. p53 mutations selected during tumor initiation and progression thus inactivate multiple tumor suppressor genes in parallel, which could account for the high frequency of p53 mutations in cancer.

p53: key conductor of all anti-acne therapies

“…Increased IGF-1 signalling in acne suppresses nuclear FoxO1 [ 8 – 10 ], which is a nuclear co-suppressor of AR [ 155 ], and thus increases AR-mediated target gene expression. Recently, p53 has been identified as transcriptional inducer of FOXO1 and PTEN [ 156 ], an important observation that confirms the role of p53 in regulating multiple signalling levels of IGF-1/IGF1R/PI3K/AKT/FoxO1 signalling. AR is regarded as a sensitive marker of sebaceous differentiation [ 157 ].…”

Effect of oral isotretinoin on the nucleo‐cytoplasmic distribution of FoxO1 and FoxO3 proteins in sebaceous glands of patients with acne vulgaris

“…Only, after the addition of a second apoptosis‐inducing agent (staurosporine), DNA fragmentation in SZ95 sebocytes was induced . SV40‐mediated suppression or p53 may increase the expression of IGF‐1 receptor (IGF1R) and reduce the expression of phosphatase and tensin homolog (PTEN), which are both regulated by p53 . In fact, by using a PI3K inhibitor (LY294002) isotretinoin‐mediated upregulation of AKT‐FoxO signalling could be located to be upstream of PI3K .…”

Putting p53 in Context

“…As examples, p53 can modulate autophagy, alter metabolism, repress pluripotency and cellular plasticity, and facilitate an iron-dependent form of cell death known as ferroptosis (reviewed in Aylon and Oren, 2016). Even basal levels of p53 can reinforce multiple other tumor suppressive networks (Pappas et al, 2017). Given extensive past research, it is surprising that there is no clear and simple answer to the question of what exactly p53 does and how.…”