The role of p53/p73 family members in the cytotoxic response
Lead Research Organisation:
University of Cambridge
Department Name: UNLISTED
Abstract
Toxic insult arising from environmental, occupational or therapeutic exposure, is a primary cause of disease and the treatment of these disorders has significant medical, social and economic implications for the UK population. The p53 family of proteins (p53, p63 and p73) is considered as a master regulator in vertebrates, and pathways that it controls range from developmental and homeostatic functions to the remarkable role in cancer. In particular, a predominant aspect of p53 family function in tumourigenesis is the ability to control the cellular stress response. This represents a pivotal aspect in the response to toxic insult.
The overall aim of the Laboratory is to understand the fundamental mechanisms of cellular and tissue response to injury caused by drugs, chemicals and endogenous molecules, e.g. free radicals. Therefore, using both genetically modified mouse model and high throughput analysis, we aim to investigate:
1) How environmental exposure drives tumour progression;
2) How these transcription factors regulate the response to toxic insult;
Moreover, we are dedicated to the development of chemicals compounds that can regulate expression and function of the p53 family members. This could have potential therapeutic applications.
The overall aim of the Laboratory is to understand the fundamental mechanisms of cellular and tissue response to injury caused by drugs, chemicals and endogenous molecules, e.g. free radicals. Therefore, using both genetically modified mouse model and high throughput analysis, we aim to investigate:
1) How environmental exposure drives tumour progression;
2) How these transcription factors regulate the response to toxic insult;
Moreover, we are dedicated to the development of chemicals compounds that can regulate expression and function of the p53 family members. This could have potential therapeutic applications.
Technical Summary
Environmental, occupational or therapeutic exposure to toxic insults account for a substantial proportion of cancer development both in the UK and worldwide. The p53 family (p53, p63 and p73) are transcription factors, which play a key role in several biological processes by regulating cell survival, proliferation, metabolism and stemness. In particular, a key aspect of p53 family function is the ability to control the cellular stress response, which represents a pivotal axis in the response to toxic insult.
By using a multiple scientific approaches ranging from systems biology (proteomic and genomic screenings) to the generation and characterization of genetically modified mouse models, we aim to investigate the role of the p53 family in the cellular stress response in order to understand the molecular basis underling the mechanisms for tumour transformation and progression.
The focus of this programme is on the contribution of p53 family to adaption to micro-environmental stress, investigating the role of p53 family members and isoforms to hypoxia stress and protein synthesis and to genotoxic stress response, investigating new p53 family effectors of DNA damage response machinery. Specifically we will investigate:
1) The molecular basis for cell adaptation to hypoxia: p53 family and HIF interplay
2) p53 family contribution to protein synthesis control in cell adaptation to stress
3) Novel effectors of p73 and p63 in the DNA damage response
By using a multiple scientific approaches ranging from systems biology (proteomic and genomic screenings) to the generation and characterization of genetically modified mouse models, we aim to investigate the role of the p53 family in the cellular stress response in order to understand the molecular basis underling the mechanisms for tumour transformation and progression.
The focus of this programme is on the contribution of p53 family to adaption to micro-environmental stress, investigating the role of p53 family members and isoforms to hypoxia stress and protein synthesis and to genotoxic stress response, investigating new p53 family effectors of DNA damage response machinery. Specifically we will investigate:
1) The molecular basis for cell adaptation to hypoxia: p53 family and HIF interplay
2) p53 family contribution to protein synthesis control in cell adaptation to stress
3) Novel effectors of p73 and p63 in the DNA damage response
Organisations
People |
ORCID iD |
Gerry Melino (Principal Investigator) |
Publications
Pitolli C
(2019)
p53-Mediated Tumor Suppression: DNA-Damage Response and Alternative Mechanisms.
in Cancers
Pitolli C
(2019)
Do Mutations Turn p53 into an Oncogene?
in International journal of molecular sciences
Pieraccioli M
(2018)
ZNF281 inhibits neuronal differentiation and is a prognostic marker for neuroblastoma.
in Proceedings of the National Academy of Sciences of the United States of America
Pentimalli F
(2019)
Cell death pathologies: targeting death pathways and the immune system for cancer therapy.
in Genes and immunity
Panatta E
(2018)
Kruppel-like factor 4 regulates keratinocyte senescence.
in Biochemical and biophysical research communications
Panatta E
(2020)
Long non-coding RNA uc.291 controls epithelial differentiation by interfering with the ACTL6A/BAF complex.
in EMBO reports
Orienti I
(2019)
A novel oral micellar fenretinide formulation with enhanced bioavailability and antitumour activity against multiple tumours from cancer stem cells.
in Journal of experimental & clinical cancer research : CR
Orienti I
(2019)
A new bioavailable fenretinide formulation with antiproliferative, antimetabolic, and cytotoxic effects on solid tumors.
in Cell death & disease
Nicolai S
(2020)
ZNF281/Zfp281 is a target of miR-1 and counteracts muscle differentiation.
in Molecular oncology
Nicolai S
(2020)
ZNF281 is recruited on DNA breaks to facilitate DNA repair by non-homologous end joining.
in Oncogene
Related Projects
Project Reference | Relationship | Related To | Start | End | Award Value |
---|---|---|---|---|---|
MC_UU_00025/1 | 31/03/2018 | 30/07/2020 | £1,680,000 | ||
MC_UU_00025/2 | Transfer | MC_UU_00025/1 | 31/03/2018 | 29/09/2020 | £3,488,000 |
MC_UU_00025/3 | Transfer | MC_UU_00025/2 | 31/03/2018 | 31/03/2024 | £2,873,000 |
MC_UU_00025/4 | Transfer | MC_UU_00025/3 | 31/03/2018 | 31/03/2024 | £3,108,000 |
MC_UU_00025/5 | Transfer | MC_UU_00025/4 | 31/03/2018 | 31/03/2024 | £2,200,000 |
MC_UU_00025/6 | Transfer | MC_UU_00025/5 | 31/03/2018 | 30/05/2019 | £76,000 |
MC_UU_00025/7 | Transfer | MC_UU_00025/6 | 31/03/2018 | 31/03/2024 | £2,547,000 |
MC_UU_00025/8 | Transfer | MC_UU_00025/7 | 30/09/2019 | 31/03/2024 | £2,438,000 |
MC_UU_00025/9 | Transfer | MC_UU_00025/8 | 31/08/2019 | 31/03/2024 | £1,721,000 |