- About
- Strategic Plan
- Structure
- Governance
- Scientific divisions
- ACRF Cancer Biology and Stem Cells
- ACRF Chemical Biology
- Advanced Technology and Biology
- Bioinformatics
- Blood Cells and Blood Cancer
- Clinical Translation
- Epigenetics and Development
- Immunology
- Infectious Diseases and Immune Defence
- Inflammation
- Personalised Oncology
- Population Health and Immunity
- Structural Biology
- Ubiquitin Signalling
- Laboratory operations
- Funding
- Annual reports
- Human research ethics
- Scientific integrity
- Institute life
- Career opportunities
- Business Development
- Collaborators
- Suppliers
- Publications repository
- Awards
- Discoveries
- Centenary 2015
- History
- Contact us
- Research
- Diseases
- Cancer
- Development and ageing
- Immune health and infection
- Research fields
- Research technologies
- Research centres
- People
- Alistair Brown
- Anne-Laure Puaux
- Assoc Prof Joanna Groom
- Associate Profesor Ian Majewski
- Associate Professor Aaron Jex
- Associate Professor Alyssa Barry
- Associate Professor Andrew Webb
- Associate Professor Chris Tonkin
- Associate Professor Daniel Gray
- Associate Professor Diana Hansen
- Associate Professor Edwin Hawkins
- Associate Professor Ethan Goddard-Borger
- Associate Professor Gemma Kelly
- Associate Professor Grant Dewson
- Associate Professor Isabelle Lucet
- Associate Professor James Vince
- Associate Professor Jason Tye-Din
- Associate Professor Jeanne Tie
- Associate Professor Jeff Babon
- Associate Professor Joan Heath
- Associate Professor John Wentworth
- Associate Professor Justin Boddey
- Associate Professor Kate Sutherland
- Associate Professor Marie-Liesse Asselin-Labat
- Associate Professor Matthew Ritchie
- Associate Professor Melissa Call
- Associate Professor Melissa Davis
- Associate Professor Misty Jenkins
- Associate Professor Nawaf Yassi
- Associate Professor Oliver Sieber
- Associate Professor Peter Czabotar
- Associate Professor Rachel Wong
- Associate Professor Rhys Allan
- Associate Professor Rosie Watson
- Associate Professor Ruth Kluck
- Associate Professor Sandra Nicholson
- Associate Professor Seth Masters
- Associate Professor Sumitra Ananda
- Associate Professor Tim Thomas
- Associate Professor Tracy Putoczki
- Chela Niall
- Deborah Carr
- Dr Alisa Glukhova
- Dr Anna Coussens
- Dr Ashley Ng
- Dr Belinda Phipson
- Dr Ben Tran
- Dr Bernhard Lechtenberg
- Dr Brad Sleebs
- Dr Drew Berry
- Dr Gwo Yaw Ho
- Dr Hamish King
- Dr Hui-Li Wong
- Dr Jacqui Gulbis
- Dr Kelly Rogers
- Dr Lucy Gately
- Dr Margaret Lee
- Dr Mary Ann Anderson
- Dr Maryam Rashidi
- Dr Matthew Call
- Dr Nadia Davidson
- Dr Philippe Bouillet
- Dr Rebecca Feltham
- Dr Rory Bowden
- Dr Samir Taoudi
- Dr Shabih Shakeel
- Dr Shalin Naik
- Dr Sheau Wen Lok
- Dr Stephin Vervoort
- Dr Yunshun Chen
- Guillaume Lessene
- Helene Martin
- Joh Kirby
- Kaye Wycherley
- Keely Bumsted O'Brien
- Mr Mark Eaton
- Mr Simon Monard
- Mr Steve Droste
- Ms Carolyn MacDonald
- Professor Alan Cowman
- Professor Andreas Strasser
- Professor Andrew Lew
- Professor Andrew Roberts
- Professor Anne Voss
- Professor Clare Scott
- Professor David Huang
- Professor David Komander
- Professor David Vaux
- Professor Doug Hilton
- Professor Geoff Lindeman
- Professor Gordon Smyth
- Professor Ian Wicks
- Professor Ivo Mueller
- Professor James McCarthy
- Professor James Murphy
- Professor Jane Visvader
- Professor Jerry Adams
- Professor John Silke
- Professor Ken Shortman
- Professor Leanne Robinson
- Professor Leonard C Harrison
- Professor Lynn Corcoran
- Professor Marc Pellegrini
- Professor Marco Herold
- Professor Marnie Blewitt
- Professor Melanie Bahlo
- Professor Mike Lawrence
- Professor Nicos Nicola
- Professor Peter Colman
- Professor Peter Gibbs
- Professor Phil Hodgkin
- Professor Sant-Rayn Pasricha
- Professor Stephen Nutt
- Professor Suzanne Cory
- Professor Terry Speed
- Professor Tony Papenfuss
- Professor Wai-Hong Tham
- Professor Warren Alexander
- Diseases
- Education
- PhD
- Honours
- Masters
- Clinician-scientist training
- Undergraduate
- Student research projects
- A new regulator of 'stemness' to create dendritic cell factories for immunotherapy
- Advanced imaging interrogation of pathogen induced NETosis
- Cancer driver deserts
- Cryo-electron microscopy of Wnt signalling complexes
- Deciphering the heterogeneity of breast cancer at the epigenetic and genetic levels
- Developing drugs to block malaria transmission
- Developing new computational tools for CRISPR genomics to advance cancer research
- Developing novel antibody-based methods for regulating apoptotic cell death
- Discovering novel paradigms to cure viral and bacterial infections
- Discovery and targeting of novel regulators of transcription
- Dissecting host cell invasion by the diarrhoeal pathogen Cryptosporidium
- Do membrane forces govern assembly of the deadly apoptotic pore?
- Doublecortin-like kinases, drug targets in cancer and neurological disorders
- E3 ubiquitin ligases in neurodegeneration, autoinflammation and cancer
- Engineering improved CAR-T cell therapies
- Epigenetic biomarkers of tuberculosis infection
- Exploiting cell death pathways in regulatory T cells for cancer immunotherapy
- Finding treatments for chromatin disorders of intellectual disability
- Functional epigenomics in human B cells
- Genomic rearrangement detection with third generation sequencing technology
- How does DNA damage shape disease susceptibility over a lifetime?
- How does DNA hypermutation shape the development of solid tumours?
- How platelets prevent neonatal stroke
- Human lung protective immunity to tuberculosis
- Interaction with Toxoplasma parasites and the brain
- Interactions between tumour cells and their microenvironment in non-small cell lung cancer
- Investigating the role of dysregulated Tom40 in neurodegeneration
- Investigating the role of mutant p53 in cancer
- Lupus: proteasome inhibitors and inflammation
- Machine learning methods for somatic genome rearrangement detection
- Malaria: going bananas for sex
- Measurements of malaria parasite and erythrocyte membrane interactions using cutting-edge microscopy
- Measuring susceptibility of cancer cells to BH3-mimetics
- Minimising rheumatic adverse events of checkpoint inhibitor cancer therapy
- Mutational signatures of structural variation
- Naturally acquired immune response to malaria parasites
- Predicting the effect of non-coding structural variants in cancer
- Revealing the epigenetic origins of immune disease
- Reversing antimalarial resistance in human malaria parasites
- Structural and functional analysis of DNA repair complexes
- Targeting human infective coronaviruses using alpaca antibodies
- Towards targeting altered glial biology in high-grade brain cancers
- Uncovering the real impact of persistent malaria infections
- Understanding Plasmodium falciparum invasion of red blood cells
- Understanding how malaria parasites sabotage acquisition of immunity
- Understanding malaria infection dynamics
- Understanding the mechanism of type I cytokine receptor activation
- Unveiling the heterogeneity of small cell lung cancer
- Using alpaca antibodies to understand malaria invasion and transmission
- Using combination immunotherapy to tackle heterogeneous brain tumours
- Using intravital microscopy for immunotherapy against brain tumours
- Using nanobodies to cross the blood brain barrier for drug delivery
- Using structural biology to understand programmed cell death
- School resources
- Frequently asked questions
- Student profiles
- Abebe Fola
- Andrew Baldi
- Anna Gabrielyan
- Bridget Dorizzi
- Casey Ah-Cann
- Catia Pierotti
- Emma Nolan
- Huon Wong
- Jing Deng
- Joy Liu
- Kaiseal Sarson-Lawrence
- Komal Patel
- Lilly Backshell
- Megan Kent
- Naomi Jones
- Rebecca Delconte
- Roberto Bonelli
- Rune Larsen
- Runyu Mao
- Sarah Garner
- Simona Seizova
- Wayne Cawthorne
- Wil Lehmann
- Miles Horton
- Alexandra Gurzau
- Student achievements
- Student association
- Learning Hub
- News
- Donate
- Online donation
- Ways to support
- Support outcomes
- Supporter stories
- Rotarians against breast cancer
- A partnership to improve treatments for cancer patients
- 20 years of cancer research support from the Helpman family
- A generous gift from a cancer survivor
- A gift to support excellence in Australian medical research
- An enduring friendship
- Anonymous donor helps bridge the 'valley of death'
- Renewed support for HIV eradication project
- Searching for solutions to muscular dystrophy
- Supporting research into better treatments for colon cancer
- Taking a single cell focus with the DROP-seq
- WEHI.TV
Mutant protein tackles DNA guardian to promote cancer development
7 November 2018
Melbourne scientists have discovered how tumour development is driven by mutations in the most important gene in preventing cancer, p53.
drive tumour development.
The research revealed that in the early stages of cancer, mutant p53 ‘tackles’ the normal p53 protein and blocks it from carrying out its protective role. As a result, p53 can no longer activate natural defences against cancer – such as the body’s DNA repair process – increasing the risk of cancer developing.
The research was led by Dr Brandon Aubrey, Professor Andreas Strasser and Dr Gemma Kelly together with bioinformaticians Professor Gordon Smyth and Dr Yunshun Chen. The findings are published in the journal Genes and Development.
At a glance:
- Researchers have discovered how mutations in p53 – found in half of all human cancers – drive cancer development.
- The mutant p53 protein ‘tackles’ the normal protein and prevents it from carrying out its protective role, while permitting it to activate genes driving tumour growth.
- The team is now examining whether the mutant p53 protein acts in the same way in established tumours, with important implications for cancer therapy.
Tackling DNA’s guardian
p53 is known as the ‘guardian of the genome’ due to its role in protecting cells from cancer.
“p53 plays a critical role in many pathways that prevent cancer, such as repairing DNA or killing cells if they have irreparable DNA damage,” Dr Kelly said.
Andreas Strasser and Dr Gemma Kelly have revealed how mutations
in the p53 gene drive cancer development.
“Genetic defects in p53 are found in half of all human cancers, but exactly how these changes disrupt p53 function has long been a mystery.”
Dr Kelly said that cells normally have two copies of the p53 gene in every cell.
“Early during cancer development, one copy of the gene may undergo a sudden and permanent change through mutation, while the other copy of the gene remains normal. This results in the cell making a mixture of normal and mutant versions of the p53 protein.
“We found that the mutant p53 protein can bind to and ‘tackle’ the normal p53 protein, blocking it from performing protective roles such as DNA repair. This makes the cell more likely to undergo further genetic changes that accelerate tumour development.”
The team expected the mutant proteins would block all normal p53 activity, so was surprised to find that only certain p53-dependent pathways were affected.
“The mutant proteins are cunning: while they stop p53 from activating pathways that protect against cancer, they still allow p53 to activate pathways that promote tumour growth. p53’s role in cancer is clearly more complicated than we had expected,” Dr Kelly said.
A mystery resolved
Professor Strasser said the findings inform a longstanding debate about mutant p53.
“Scientists have been debating how mutant p53 contributes to the development of cancer for decades.
“One camp argues that mutant p53 acts by ‘tackling’ the normal protein and blocking its natural protective roles. The other camp argues that mutant p53 goes ‘rogue’ and performs new roles that promote tumour development.”
“Our work clearly shows that during cancer development, the ‘tackling’ of normal p53 is most significant. This selectively disables certain but not all normal functions of p53,” Professor Strasser said.
Clinical implications
The team is now investigating whether the same is true for established tumours, with important implications for drug treatments.
“Established tumours have often lost the normal copy of their p53 gene and only produce mutant p53 protein,” Dr Kelly said.
“If mutant p53 acts by tackling normal p53, then it may no longer play a role in established tumours where no normal p53 is produced. This would mean that drugs that block mutant p53 would have no clinical benefit,” she said.
“Conversely, if mutant p53 has new, cancer-promoting activities of its own in established tumours, then a drug that specifically blocks mutant p53 could be beneficial for treating thousands of patients.”
This work was supported by the Leukaemia Foundation, the Australian National Health and Medical Research Council, the Leukemia and Lymphoma Society of America, the Cancer Council of Victoria, the Victorian Cancer Agency, the Estate of Anthony (Toni) William Redstone OAM, the Craig Perkins Cancer Research Foundation, the Victorian State Government and the Australian Government.
Media enquiries:
M: +61 475 751 811
E: communityrelations@wehi.edu.au
Super Content:
Want to hear about our latest discoveries? Subscribe to our supporter newsletter, Illuminate.
Institute scientists have discovered how the most important gene in preventing human cancer, p53, is able to stop the development of blood cancers.
Our researchers have discovered a promising strategy for treating cancers that are caused by one of the most common cancer-causing changes in cells.