The transcription factor p53 plays pivotal roles in numerous biological processes, including the suppression of tumours. The rich availability of biophysical data aimed at understanding its structure–function relatio...The transcription factor p53 plays pivotal roles in numerous biological processes, including the suppression of tumours. The rich availability of biophysical data aimed at understanding its structure–function relationships since the 1990s has enabled the application of a variety of computational modelling techniques towards the establishment of mechanistic models. Together they have provided deep insights into the structure, mechanics, energetics, and dynamics of p53. In parallel, the observation that mutations in p53 or changes in its associated pathways characterize several human cancers has resulted in a race to develop therapeutic modulators of p53, some of which have entered clinical trials. This review describes how computational modelling has played key roles in understanding structural-dynamic aspects of p53, formulating hypotheses about domains that are beyond current experimental investigations, and the development of therapeutic molecules that target the p53 pathway.展开更多
In the second volume of this special issue, we focus on the activity and function of the mutant p53 proteins. The elegant work of Nakayama and Oshima (2019) uses mouse models of colorectal cancer to directly dem on st...In the second volume of this special issue, we focus on the activity and function of the mutant p53 proteins. The elegant work of Nakayama and Oshima (2019) uses mouse models of colorectal cancer to directly dem on strate the role that expression of the R273H protein has in promoting invasion. Using both animal studies and organotypic cultures, they are able to demonstrate that the gain-of-function (GOF) is driven by high-level nuclear expression of the protein and that this high-level expression requires escaping from Mdm2-depe ndent degradation and environ mental influe nee that are especially see n at the invadi ng front of the tumor. Their studies show that wildtype p53 can inhibit the GOF of the mutant protein providing clear support for the need for loss of the wild-type allele as the tumor progresses. This elegant in vivo work shows that the dominantnegative function of mutant p53 proteins has limited penetrance and helps to clarify this controversial area.展开更多
文摘The transcription factor p53 plays pivotal roles in numerous biological processes, including the suppression of tumours. The rich availability of biophysical data aimed at understanding its structure–function relationships since the 1990s has enabled the application of a variety of computational modelling techniques towards the establishment of mechanistic models. Together they have provided deep insights into the structure, mechanics, energetics, and dynamics of p53. In parallel, the observation that mutations in p53 or changes in its associated pathways characterize several human cancers has resulted in a race to develop therapeutic modulators of p53, some of which have entered clinical trials. This review describes how computational modelling has played key roles in understanding structural-dynamic aspects of p53, formulating hypotheses about domains that are beyond current experimental investigations, and the development of therapeutic molecules that target the p53 pathway.
文摘In the second volume of this special issue, we focus on the activity and function of the mutant p53 proteins. The elegant work of Nakayama and Oshima (2019) uses mouse models of colorectal cancer to directly dem on strate the role that expression of the R273H protein has in promoting invasion. Using both animal studies and organotypic cultures, they are able to demonstrate that the gain-of-function (GOF) is driven by high-level nuclear expression of the protein and that this high-level expression requires escaping from Mdm2-depe ndent degradation and environ mental influe nee that are especially see n at the invadi ng front of the tumor. Their studies show that wildtype p53 can inhibit the GOF of the mutant protein providing clear support for the need for loss of the wild-type allele as the tumor progresses. This elegant in vivo work shows that the dominantnegative function of mutant p53 proteins has limited penetrance and helps to clarify this controversial area.
