Mechanisms of Mutant p53 Stabilization in Cancer

Abstract

p53 transactivates cell cycle inhibitory, apoptosis or senescence-related genes in response to DNA damage to protect the genetic integrity of the cell. Highlighting its critical tumor suppressor functions, p53 is mutated, lost, or functionally inactivated in nearly all cancers. When mutated within its core DNA binding domain, p53's normal instability is abrogated, and oncogenic gain-of-function properties are observed accompanied by massive accumulation of steady state mutant p53 protein levels relative to the low or undetectable steady state level of wild-type (WT) p53 in normal cells. Mutation of p53 may affect its stability through a combination of mutant p53's inherent biochemical and biophysical properties as well as pathways aberrantly activated in genetically damaged cells. The increased stability of mutant p53 proteins is key to its ability to accumulate to high levels and phenotypically exhibit "gain-of-function" properties. In this chapter we will address the multifaceted ways in which intrinsic mutant p53 properties intersect with emergent properties of cancer cells to yield the stable mutant p53 phenotype.

TP53 hot spot mutations in ovarian cancer: Selective resistance to microtubule stabilizers in vitro and differential survival outcomes from The Cancer Genome Atlas

“…These results suggest that mdm2 expression is not a significant determinant of p53 accumulation in mutant OCCs regardless of TP53 mutation status. Mdm2 is an ubiquitin ligase that targets p53 for degradation [33]. Mdm2-catalyzed ubiquitination of mutant p53 is inefficient compared to wild-type p53 ubiquitination, and ubiquitination of mutant p53 is generally low in cancer cells [33].…”

High Expressions of CUL4A and TP53 in Colorectal Cancer Predict Poor Survival

“…Mutations of TP53, which are considered to be able to bear ubiquitination, are thought to be involved in the pathogenesis of as many as 60% of colon cancers [24][25][26]. With a prolonged half-life, TP53 protein detected by immunohistochemistry assay has been widely used as a detection method for TP53 mutation [27][28][29]. Although it has been suggested that TP53 plays a critical role in cancer progression [30,31], to our knowledge no published data on the correlation between mutants TP53 and CUL4A, especially the prognostic value of their combined expression pattern exist so far.…”

A p53-independent apoptotic mechanism of adenoviral mutant E1A was involved in its selective antitumor activity for human cancer

“…As known, there is different p53 status in various type of cancer. It had been reported the cellular mutant p53 exerted oncogenic gain-of-function (GOF) properties, but the mechanisms mediating these functions remain poorly defined [24, 25]. E1A regulates a multitude of cellular proteins.…”