22 Nov This is interesting
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
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
"[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.
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."
"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
"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
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."