Dominant negative activity of mutated p53 proteins

Médecine sciences : M/S
Walid DridiRégen Drouin

Abstract

Tumor suppressor gene inactivation as proposed by the Knudson model implies a sequential inactivation of two alleles of a gene. For example, the first allele is inactivated by a missense mutation, and the second one is inactivated by a deletion or insertion. The alteration of the p53 tumor suppressor gene is far to correspond only to this model. In the great majority of cancers, the mutated allele of p53 coexists with the normal allele. It is well known that the transcriptional activity is one of the most important functions of p53. The p53 protein is active as a tetramer (this complex activates the expression of targeted genes by binding to its consensus DNA sequence called the p53 response element). Experimental evidence shows that wild-type p53 interacts with mutant proteins to form heterotetramers. In association with wild-type proteins, mutant proteins drive the wild-type subunits into a mutant conformation. This association leads to a loss of trans-activating function. The capacity of mutant subunits to form heterotetramers with wild-type subunits and to commit them into a mutant conformation is called < dominant negative effect >. Many p53 mutant proteins possess this dominant negative activity. Recently, several factors...Continue Reading

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Citations

Jan 12, 2019·British Journal of Pharmacology·Yang LiKun Huang
Oct 16, 2012·Expert Review of Gastroenterology & Hepatology·Jacob A ChisholmDavid I Watson
Nov 7, 2019·Clinical & Translational Oncology : Official Publication of the Federation of Spanish Oncology Societies and of the National Cancer Institute of Mexico·P GargalloA Cañete

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