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The role of p53/p73 family members in the cytotoxic response.
Note: Many of the drugs used in cancer therapy, exert their action through the activation of the p53-family members. Indeed, loss of p53 function in cancer is associated with poor prognosis and resistance to chemotherapy. Moreover, this family of transcription factors play a key role in development of central nervous system, epidermal tissue and in overall organism metabolism. Using genetically modified mouse model and high throughput analysis, we aim to understand: 1) How these transcription factors mediate chemo sensitivity, 2) How they regulate organismal development and physiology. Technical Summary The scope of the Apoptosis & Cancer Laboratory is to understand the fundamental mechanisms of cell death (apoptosis) and tissue response to injury caused by drugs, chemicals and endogenous molecules, like free radicals. In particular, we study the physiological functions of the p53 family proteins (namely p53, p63 and p73) and their involvement in tumorigenesis and neurodegeneration triggered by toxic insults. We make use of multiple scientific approaches ranging from systems biology (proteomic and genomic screenings) to the generation and characterization of genetically modified mouse models. We are also interested to the development of chemical compounds that can regulate expression and function of these transcription factors, and that could therefore have potential therapeutic applications. Objectives Alterations of proteins that control cell proliferation, cell survival and cell death are the main causes of diseases such as cancer and neurodegenerative disorders and dictate the efficacy of drug treatment. The protein members of the p53 family, composed of TP63, TP73 and TP53 itself, are transcription factors that, by binding to the DNA, modulate the expression of multiple genes that play pivotal functions in the regulation of proliferation, differentiation, cell death, stem cell renewal and cell fate commitment. While p53 has been extensively studied over the last 32 years, p73 biology is still lagging behind despite lying at the crossroads between differentiation, cell cycle control and cell death. We aim to understand the mechanisms of p73 regulation during toxic insults and to define how it influences the outcome and severity of cellular and organism response to toxic insults. To this end, we are investigating several aspect of the p53-family biology, including: 1- p73 function in DNA damage response and cancer therapy, 2- Characterization of in vivo DNA damage models & large-scale transcriptional analysis, 3- p73, metabolism and ageing, 4- Neuronal implications of p73 deficiency, 5-Bioinformatic Evaluation of predictive value of p53 family in cancer progression and chemosensitivity in collaboration with Alexej Antonov (MRC Toxicology Unit), 6- MicroRNA and the p53 family in cancer progression in collaboration with Martin Bushell (MRC Toxicology Unit), 7- The deregulation of translation, in collaboration with Anne E. Willis (MRC Toxicology Unit), 8- Function and Pharmacological inhibition of the p73 E3 ubiquitin ligase ITCH.
| Grant period | 2002-03-31 - 2018-02-28 |
| Funding body | Medical Research Council |
| Grant number | grant.2777196 |
| Identifier | G:(Dimensions)grant.2777196 |
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Record created 2021-07-01, last modified 2021-09-24