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MRC Toxicology Unit

 

Unit Programme: The p53/p73 family and cytotoxicity

Programme Leader: Dr Gerry Melino, DSc

 

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. Fortunately, several underlying molecular mechanisms, as well as a number of primary and secondary effective interventions, are available to mitigate these negative effects. There is, nonetheless, an urgent need to further expand this mechanistic knowledge. The DNA Damage Response (DDR) has been at the forefront of research in this area for the last decade, and in particular, our group has focused on the role of p53 and its family members. Indeed, while p53 is mutated, and therefore inactive, in the majority of tumours, current therapy involving DNA Damage (i.e. chemo- radio-therapy) requires a functional p53. Therefore, for chemo- or radio-therapy to be effective, requires the presence of ancillary pathways, such as the p53 family members p63 and p73. To this end, our experimental research programme utilises advances in fundamental science to refine the basic molecular events with the aim of increasing the efficacy of future interventions. Our broader approach is both in vitro and in vivo, searching for aetiology, pathogenic mechanisms, latent co-factors, effective processes and novel potential therapeutic targets. Our experimental models therefore concentrate on understanding core mechanisms and defects of the DDR and in particular of p73. The final aim would be to shape innovative interventions to modify these processes.

Figure 1.  Involvement of the p53 family in the DNA damage response. Even though the primary role is exerted by p53m the role of p63 and p73, the p53 homologues, is more evident in the often mutation and functional inactivation of p53, reaching up to 70% of all human cancers. Both p63 and p53 can substitute the p53 downstream effects, namely apoptosis and cell cycle regulation.

 

Figure 2. p73 is critically contributing to hippocampal development. a) in situ hybridisation shows expression of p73 mRNA in E18.5 mouse brain. b) depletion of p73 in mouse impairs hippocampal development. H/E of brains from 20 days old wt, heterozygous and isoform specific p73 knock-out (D13) mice.

 

Figure 3. TAp73 also interacts physically with HIF-1a. This interaction leads to reduced HIF-1a expression, which is associated with ubiquitin-dependent proteasomal degradation. MDM2 might partially contribute to this process by promoting HIF-1 ubiquitylation together with additional unknown E3- ubiquitin ligases.

 

Key Publications

GM has over 500 publications in Nature (6x), PNAS-USA (27x), Oncogene (33x), Genes Dev (5x), Nature Reviews (3x), TiBS/TCB (5x), J Cell Biol (1x), Nature Commun (2x), Nature Med (1x), Cancer Cell (2x), Embo J (3x), J Exp Med (4x), J Invest Dermatol (16x), Cancer Res (7x), Cell Death Differ (69x), Cell Death Dis (22x), Cell Cycle (29x), Oncotarget (22x), Aging (Albany NY) (8x), FEBS Lett (6x), Biochem Pharmacol (7x), Biochem J (3x), Diabetes (2x), Hum Mutat (2x), Biochem Biophys Res Commun (46x), Autophagy (3x), Stem Cells (1x), Embo Mol Med (1x), J Cell Sci (4x), Mol Neurobiol (6x), Gastroenterology (1x), Circulation (1x), J Immunol (4x), Int J Cancer (4x), …. Others

 

Amelio I, Mancini M, Petrova V, Cairns RA, Vikhreva P, Nicolai S, Marini A, Antonov AA, Le Quesne J, Acevedo JDB, Dudek K, Sozzi G, Pastorino U, Knight RA, Mak TW, Melino G.
p53 mutants co-operate with HIF-1 in transcriptional regulation of extracellular matrix components to promote tumour progression.
Proc Natl Acad Sci USA. 2018.  Submitted

 

Pieraccioli M, Nicolai S, Pitolli C, Agostini M, Antonov A, Malewicz M, Knight RA, Raschellà G, Melino G.
ZNF281 inhibits neuronal differentiation and is a prognostic marker for neuroblastoma
Proc Natl Acad Sci USA. 2018 Jul 10;115(28):7356-7361

 

Marini A, Rotblat B, Sbarrato T, Niklison-Chirou MV, Knight JRP, Dudek K, Jones C, Bushell M, Knight RA, Amelio I, Willis AE, Melino G.
TAp73 contributes to the oxidative stress response by regulating protein synthesis
Proc Natl Acad Sci USA. 2018 Jun 12;115(24):6219-6224

 

Di Rita A, Peschiaroli A, Gruber J, Dötsch V, Nygaard M, Lambrughi M, Papaleo E, Dengjel J, El Alaoui S, Youle R, Rogov VV, Melino G, Strappazzon F, Cecconi F
HUWE1 E3 ligase promotes PINK1/PARKIN-independent mitophagy by regulating AMBRA1 activation, through IKKa.
Nature Comms. 2018 Sep 14;9(1):3755

 

Sanarico AG, Ronchini C, Croce A, Memmi EM, Cammarata UA, De Antoni A, Lavorgna S, Divona M, Giacò L, Melloni GEM, Brendolan A, Simonetti G, Martinelli G, Mancuso P, Bertolini F, Coco FL, Melino G, Pelicci PG, Bernassola F.
The E3 ubiquitin ligase WWP1 sustains the growth of acute myeloid leukaemia.
Leukemia. 2018. doi: 10.1038/leu.2017.342.

 

Melino G.
Order must spring from chaos in Italy.
Nature. 2018. 436:556.

 

Compagnone M, Gatti V, Presutti D, Ruberti G, Fierro C, Markert EK, Vousden KH, Zhou H, Mauriello A, Anemone L, Bongiorno-Borbone L, Melino G, Peschiaroli A.
ΔNp63-mediated regulation of hyaluronic acid metabolism and signaling supports HNSCC tumorigenesis.
Proc Natl Acad Sci USA. 2017 Dec 12;114(50):13254-13259. doi: 10.1073/pnas.1711777114.

 

Niklison-Chirou MV, Erngren I, Engskog M, Haglöf J, Picard D, Remke M, McPolin PHR, Selby M, Williamson D, Clifford SC, Michod D, Hadjiandreou M, Arvidsson T, Pettersson C, Melino G, Marino S.
TAp73 is a marker of glutamine addiction in medulloblastoma.
Genes Dev. 2017. 31(17):1738-1753. doi: 10.1101/gad.302349.117.