The genome guardian turns to the dark side: Opportunity for drug discovery against cancer?

June 1, 2018, Publicase Comunicação Científica
Under normal conditions, native p53 protein is folded but when chemicals and/or high pressure are applied the protein may unfold and loose its 3D structure. During the unfolding process, p53 acquires the molten globule conformation that is very prone to aggregation. The presence of p53 aggregates is very harmful for the cell and is associated with cancer development and progression. Credit: Guilherme A. de Oliveira

Abnormal changes in the p53 protein are associated with many cancers. In fact, the gene that codes the p53 protein is the one most frequently mutated in human cancers. The protein, known as the guardian of the genome, has the main role of suppressing tumor formation and in so doing it blocks cancer development. But once mutated, the p53 protein not only stops working as expected, it also acquires new functions and characteristics that are catastrophic for the cell.

One of the characteristics observed in mutated p53 is the tendency to form amyloid aggregates, which are structures that no longer display the original 3-D conformation, stick together, and are resistant to degradation. These amyloid aggregates build up in the tissue, are very harmful, and present a pathogen-like behavior where mutants highjack normal counterparts and convert them into the amyloid form. These aggregates have been found in many cancer patients and in other protein-misfolding diseases such as Alzheimer's and Parkinson's.

Somewhere along its transition from its native protein state to the deleterious amyloid form, p53 assumes a transient state as a molten globule (MG). MG-state p53, or pre-aggregate MG conformers, have not yet formed aggregates but are nevertheless very prone to doing so, which makes them a promising drug target. Thus, understanding the behavior of MG-state p53s and what prompts them into this conformation in the first place is crucial.

Targeting MG- has been a real challenge because these states have a very short lifetime before they aggregate into amyloid structures. However, using a combination of techniques that include fluorescence spectroscopy, chemical and physical approaches, a research group led by Jerson Lima Silva at the Federal University of Rio de Janeiro, Brazil, has developed a new strategy that traps p53 conformers in solution so they can be observed before turning into amyloid oligomers and fibers. The group used the technique to study p53 and two other related proteins, p63 and p73. Of the three, p53 is the one that is least stable and most prone to aggregation.

While in real life the native state of p53 may be disrupted by the action of viruses (such as HPV), ultraviolet radiation (such as sun light) or exposure to carcinogens (tobacco smoke, nitropyrene emitted in diesel combustion, among many others), the research group applied different concentrations of chemicals and/or high hydrostatic pressure to disrupt the equilibrium of native proteins in the lab, as detected by fluorescence and nuclear magnetic resonance. The strategy is believed to recapitulate the same unfolding and aggregation processes that take place inside the body of cancer patients and allows researchers to get a closer look at the conformational changes suffered by individual amino acid residues before the molecule undergoes unfolding. This stage is a main step towards the amyloid state.

"A clear understanding of all the changes that occur in the molecule before it assumes the amyloid state may allow us to manipulate this process and have the option of either rescuing the native state of the or blocking its transformation into amyloid oligomers and fibrils," says Guilherme A. de Oliveira, one of the study's co-authors.

In fact, both strategies have been previously used against mutated p53 by different groups but no clear results have been produced. With this study, the group presents a new technique for trapping p53 conformers in solution and claims that the p53 pre-amyloidogenic form is a promising alternative target for drug discovery.

The paper entitled "Aggregation-primed molten globule conformers of the p53 core domain provide potential tools for studying p53C aggregation in cancer" is published online in The Journal of Biological Chemistry.

Explore further: Prions and cancer: A story unfolding

Related Stories

Prions and cancer: A story unfolding

June 25, 2012
Prions, the causal agents of Mad Cow and other diseases, are very unique infectious particles. They are proteins in which the complex molecular three-dimensional folding process just went astray. For reasons not yet understood, ...

Brain cholesterol associated with increased risk of Alzheimer's disease

May 7, 2018
Researchers have shown how cholesterol—a molecule normally linked with cardiovascular diseases—may also play an important role in the onset and progression of Alzheimer's disease.

Computer simulation reveals p53 weak spots and opens new avenues against cancer

September 7, 2016
Using microsecond timescale molecular dynamics simulations, a new study published in Scientific Reports reveals p53 weak spots and sheds light on the protein instability, which is linked to its tendency to aggregate and form ...

A human enzyme can reduce neurotoxic amyloids in a mouse model of dementia

June 27, 2017
A naturally occurring human enzyme -called cyclophilin 40 or CyP40- can unravel protein aggregates that contribute to both Alzheimer's disease and Parkinson's disease, according to a study publishing June 27 in the open access ...

Recommended for you

New screening tool could help diagnose early cognitive decline in dementia from home

June 19, 2018
An international team of scientists have developed a new way to screen for age-related cognitive decline at home using a test which asks people to detect sounds and flashes on their laptop or phone.

Genes linked to Alzheimer's contribute to damage in different ways

June 12, 2018
Multiple genes are implicated in Alzheimer's disease. Some are linked to early-onset Alzheimer's, a condition that develops in one's 30s, 40s and 50s, while others are associated with the more common late-onset form of the ...

Researchers reverse cognitive impairments in mice with dementia

June 8, 2018
Reversing memory deficits and impairments in spatial learning is a major goal in the field of dementia research. A lack of knowledge about cellular pathways critical to the development of dementia, however, has stood in the ...

As mystery deepens over the cause of Alzheimer's, researchers seek new answers

June 6, 2018
For more than 20 years, much of the leading research on Alzheimer's disease has been guided by the "amyloid hypothesis."

Research reveals how Tau aggregates can contribute to cell death in Alzheimer's disease

June 5, 2018
New evidence suggests a mechanism by which progressive accumulation of Tau protein in brain cells may lead to Alzheimer's disease. Scientists studied more than 600 human brains and fruit fly models of Alzheimer's disease ...

How does alcohol influence the development of Alzheimer's disease?

June 4, 2018
Research from the University of Illinois at Chicago has found that some of the genes affected by alcohol and inflammation are also implicated in processes that clear amyloid beta—the protein that forms globs of plaques ...

1 comment

Adjust slider to filter visible comments by rank

Display comments: newest first

Squirrel
not rated yet Jun 01, 2018
The paper is "Aggregation-primed molten globule conformers of the p53 core domain provide potential tools for studying p53C aggregation in cancer "
http://www.jbc.or...abstract

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.