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How does a protein’s ‘evil twin’ promote cancer growth?

The p53 gene promotes the expression of the p53 protein, which helps maintain cellular health and has a protective role against the formation of cancer.

However, researchers have found that many forms of human cancer present mutations of the p53 protein.

Recently, specialists from the Walter and Eliza Hall Institute of Medical Research in Melbourne and the University of Melbourne, both in Australia, have been studying the role of mutated p53 in the development of cancer.

Dr. Brandon Aubrey, Prof. Andreas Strasser, Dr. Gemma Kelly, Prof. Gordon Smyth, and Dr. Yunshun Chen led this complex study, the findings of which now appear in the journal Genes and Development.

“[The protein] 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 explains.

“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,” she adds.

‘The mutant proteins are cunning’

Healthy p53 proteins protect the body against cancer either by safeguarding cell health and repairing any DNA damage that could lead to the development of cancer or by simply destroying the cells that are beyond repair.

Normally, Dr. Kelly notes, each cell carries two copies of the p53 gene. Sometimes, however, one of these copies may mutate, leading to the production of abnormal p53 proteins.

“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,” the researcher explains.

In their study, the scientists found that the mutant p53 protein blocks the protective activity of the normal 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,” says Dr. Kelly. “[This] makes the cell more likely to undergo further genetic changes that accelerate tumor development.”

However, the whole picture is much more complex. Mutant p53, it turns out, does not stop regular p53 from performing all its normal activity. Instead, the “evil twin” only blocks certain pathways, so that normal p53 is no longer able to defend cellular health but may still “feed” cancer tumors once they appear.

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 tumor growth. p53’s role in cancer is clearly more complicated than we had expected.”

Dr. Gemma Kelly

It is unclear how p53 works within tumors

“Scientists have been debating how mutant p53 contributes to the development of cancer for decades,” notes Prof. Strasser. “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 tumor development,” he says.

The study’s findings now bring the scientific community much closer to understanding how mutant p53 supports cancer growth by showing that the key factor is its interaction with its protective “double.”

“Our work,” Prof. Strasser adds, “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.”

However, the researchers admit that they will have to conduct further studies in order to understand how p53 functions within already established cancer tumors, as this will have an important bearing on developing better therapies going forward.

“Established tumors have often lost the normal copy of their p53 gene and only produce mutant p53 protein,” explains Dr. Kelly.

“If mutant p53 acts by tackling normal p53, then it may no longer play a role in established tumors where no normal p53 is produced,” she speculates, noting, “This would mean that drugs that block mutant p53 would have no clinical benefit.”

“Conversely,” she says, “if mutant p53 has new, cancer-promoting activities of its own in established tumors, then a drug that specifically blocks mutant p53 could be beneficial for treating thousands of patients.”

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