P53 is a regulatory protein well known to cancer researchers and biotech firms alike. It is mutated in more than half of all human cancers. Even where it is not outright mutated, its functions appear compromised in most cancers. And some research has indicated that loss of p53 can turn cells into cancer stem cells. (See BioWorld Today, Sept. 21, 2009.)
P53 has two functions in cells. The protein coordinates the DNA damage response, repairing DNA that has been broken down and inducing programmed cell death or apoptosis in cells that are too damaged for repair. It also functions as a tumor suppressor.
It might be natural to assume that p53 is a tumor suppressor because it is able to respond to DNA damage. But researchers from Stanford University have shown that even when they disabled p53's DNA damage response abilities, the protein was still able to function as a tumor suppressor. Their results were published in the May 13, 2011, issue of Cell.
P53 "binds to regions throughout the genome," senior author Laura Attardi, who is an associate professor of radiation oncology and of genetics, at Stanford University School of Medicine, told BioWorld Today. But such binding by itself is not enough to get gene expression programs going. Instead, p53 recruits other proteins to initiate transcription via the so-called transactivation domain (TAD) regions.
P53 has two such TAD regions, Attardi explained, and the genes that are turned on by p53 binding depend on which TAD orchestrates gene expression after p53 binds. For their experiments, her team "made subtle alterations in each of the transactivating domains, separately or together."
When TAD1 was disabled, "the vast majority of know p53 target genes are not induced well." But there was a small subset of roughly 50 genes that was "unperturbed" by disabling TAD1.
And that subset seems to be critical for p53's tumor suppressor role: Though p53 with an altered TAD1 domain was "absolutely unable to mount a response to DNA damage," it continued to function as a tumor suppressor.
In cell culture, specifically disabling TAD2 had very little effect overall; such cells looked like wild-type cells in their gene expression profile, and so the authors focused on comparing cells with only TAD1 or both TADs disabled to normal cells.
The team tested the effects of inactivating either TAD1 or both transactivation domains in animal models. Mice with a lung cancer-causing mutation developed tumors only when both transactivating domains were disabled. Animals with TAD1 disabled, the authors wrote in their paper, "can suppress tumor growth, despite an inability to efficiently activate most known p53 target genes" – an observation they termed "remarkable."
TAD1-disabled animals were also less sensitive to the effects of high doses of radiation, such as is used in cancer treatment. Such mice did not suffer the ill effects of DNA damage that animals with either wild-type p53 or TAD2-disabled p53 did. But they did not develop tumors, either, showing that despite their lack of a DNA damage response, they were able to prevent irradiated cells from turning cancerous.
Overall, the research has yielded what Attardi termed a "gold mine – this new set of p53-associated tumor suppressor genes." That gold mine will keep her team busy for a while: "Mostly, they are very unexplored genes."
Attardi hopes that ultimately, her team's findings may point the way to improving nontargeted cancer therapies such as chemotherapy and radiation. Such therapies kill cancer cells and healthy-but-dividing cells alike, because they induce apoptosis in response to DNA damage.
Their mouse experiments suggested that if TAD1 could be selectively disabled in cells subjected to chemotherapy or radiation, the authors hope that otherwise healthy cells might be able to survive their DNA damage, while a still-active TAD2 would prevent cells that had sustained sufficient DNA damage to turn cancerous themselves from adding to the patient's woes.
The gold mine is also set to advance basic science: Despite its clear importance in human cancers, a detailed understanding of how p53 works has remained surprisingly elusive.
Her team's study, Attardi said, "provides a really important first glimpse of that."