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
Gatti V
(2019)
?Np63 in squamous cell carcinoma: defining the oncogenic routes affecting epigenetic landscape and tumour microenvironment
in Molecular Oncology
Frezza V
(2018)
?Np63 promotes IGF1 signalling through IRS1 in squamous cell carcinoma.
in Aging
Gatti V
(2018)
?Np63 regulates the expression of hyaluronic acid-related genes in breast cancer cells.
in Oncogenesis
Orienti I
(2019)
A new bioavailable fenretinide formulation with antiproliferative, antimetabolic, and cytotoxic effects on solid tumors.
in Cell death & disease
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
Du Pré MF
(2020)
B cell tolerance and antibody production to the celiac disease autoantigen transglutaminase 2.
in The Journal of experimental medicine
Raschellà G
(2019)
Cell death in cancer in the era of precision medicine.
in Genes and immunity
Pentimalli F
(2019)
Cell death pathologies: targeting death pathways and the immune system for cancer therapy.
in Genes and immunity
Nardi P
(2018)
Cold crystalloid versus warm blood cardioplegia in patients undergoing aortic valve replacement
in Journal of Thoracic Disease
Carbone M
(2018)
Consensus report of the 8 and 9th Weinman Symposia on Gene x Environment Interaction in carcinogenesis: novel opportunities for precision medicine.
in Cell death and differentiation
Pitolli C
(2019)
Do Mutations Turn p53 into an Oncogene?
in International journal of molecular sciences
Melino G
(2019)
Emerging roles of HECT-type E3 ubiquitin ligases in autophagy regulation.
in Molecular oncology
Bufalieri F
(2019)
ERAP1 promotes Hedgehog-dependent tumorigenesis by controlling USP47-mediated degradation of ßTrCP.
in Nature communications
Aksenova V
(2018)
Erratum: Actin-binding protein alpha-actinin 4 (ACTN4) is a transcriptional co-activator of RelA/p65 sub-unit of NF-kB.
in Oncotarget
Bernassola F
(2019)
HECT-Type E3 Ubiquitin Ligases in Cancer
in Trends in Biochemical Sciences
Strappazzon F
(2020)
HUWE1 controls MCL1 stability to unleash AMBRA1-induced mitophagy.
in Cell death and differentiation
Di Rita A
(2018)
HUWE1 E3 ligase promotes PINK1/PARKIN-independent mitophagy by regulating AMBRA1 activation via IKKa.
in Nature communications
Panatta E
(2018)
Kruppel-like factor 4 regulates keratinocyte senescence.
in Biochemical and biophysical research communications
Carbone M
(2019)
Lipid metabolism offers anticancer treatment by regulating ferroptosis.
in Cell death and differentiation
Panatta E
(2020)
Long non-coding RNA uc.291 controls epithelial differentiation by interfering with the ACTL6A/BAF complex.
in EMBO reports
Michaletti A
(2019)
Multi-omics profiling of calcium-induced human keratinocytes differentiation reveals modulation of unfolded protein response signaling pathways.
in Cell cycle (Georgetown, Tex.)
Ciuffoli V
(2018)
Myoblasts rely on TAp63 to control basal mitochondria respiration.
in Aging
Fedorova O
(2018)
Novel isatin-derived molecules activate p53 via interference with Mdm2 to promote apoptosis
in Cell Cycle
Melino G
(2018)
Order must spring from chaos in Italian research.
in Nature
Fedorova O
(2019)
Orphan receptor NR4A3 is a novel target of p53 that contributes to apoptosis.
in Oncogene
Amelio I
(2018)
p53 mutants cooperate with HIF-1 in transcriptional regulation of extracellular matrix components to promote tumor progression.
in Proceedings of the National Academy of Sciences of the United States of America
Pitolli C
(2019)
p53-Mediated Tumor Suppression: DNA-Damage Response and Alternative Mechanisms.
in Cancers
Gatti V
(2019)
p63 at the Crossroads between Stemness and Metastasis in Breast Cancer
in International Journal of Molecular Sciences
Smirnov A
(2019)
p63 Is a Promising Marker in the Diagnosis of Unusual Skin Cancer.
in International journal of molecular sciences
Vikhreva P
(2018)
p73 Alternative Splicing: Exploring a Biological Role for the C-Terminal Isoforms.
in Journal of molecular biology
Zhou Q
(2018)
Pir2/Rnf144b is a potential endometrial cancer biomarker that promotes cell proliferation
in Cell Death & Disease
Terrinoni A
(2018)
Role of the keratin 1 and keratin 10 tails in the pathogenesis of ichthyosis hystrix of Curth Macklin
in PLOS ONE
Liu K
(2020)
Scd1 controls de novo beige fat biogenesis through succinate-dependent regulation of mitochondrial complex II.
in Proceedings of the National Academy of Sciences of the United States of America
Amelio I
(2018)
Similar Domains for Different Regulations of p53 Family.
in Structure (London, England : 1993)
Huang Y
(2019)
Single cell transcriptomic analysis of human mesenchymal stem cells reveals limited heterogeneity.
in Cell death & disease
Chandramouli B
(2019)
Smyd2 conformational changes in response to p53 binding: role of the C-terminal domain.
in Molecular oncology
Carbone M
(2019)
Stearoyl CoA Desaturase Regulates Ferroptosis in Ovarian Cancer Offering New Therapeutic Perspectives
in Cancer Research
Rotblat B
(2018)
Sustained protein synthesis and reduced eEF2K levels in TAp73-\- mice brain: a possible compensatory mechanism.
in Cell cycle (Georgetown, Tex.)
Marini A
(2018)
TAp73 contributes to the oxidative stress response by regulating protein synthesis.
in Proceedings of the National Academy of Sciences of the United States of America
Lopriore P
(2018)
TAp73 regulates ATP7A: possible implications for ageing-related diseases.
in Aging
Titov A
(2018)
The biological basis and clinical symptoms of CAR-T therapy-associated toxicites.
in Cell death & disease
Smirnov A
(2018)
ZNF185 is a p53 target gene following DNA damage.
in Aging
Smirnov A
(2019)
ZNF185 is a p63 target gene critical for epidermal differentiation and squamous cell carcinoma development.
in Oncogene
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
Nicolai S
(2020)
ZNF281 is recruited on DNA breaks to facilitate DNA repair by non-homologous end joining.
in Oncogene
Nicolai S
(2020)
ZNF281/Zfp281 is a target of miR-1 and counteracts muscle differentiation.
in Molecular oncology
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 |