The cancer-fighting p53 molecule has a commanding presence inside our cells, coordinating the actions of more than 60 genes to prevent a damaged cell from developing into a malignant tumor.
New findings from P&S and the National Cancer Institute should now give cancer researchers a better idea of how p53 controls the genes in its army. Led by Dr. Yuxin Yin, assistant professor of radiation oncology, the team found a previously unknown promoter sequence, a palindromic motif, that the molecule uses to activate the genes under its command.
The discovery of the new p53 binding motif only the second known to scientists should help researchers find ways to enact p53's cancer-fighting arsenal in tumors where p53 is mutated. About half of all human tumors contain the mutated molecule, impairing the effectiveness of cancer drugs that work via p53. The research was published in the April 3 issue of Nature.
The p53 molecule detects DNA damage or other deadly stress in the cell and either commands the cell to stop growing so the damage can be repaired or enacts the cell's suicide plan. Though p53 gives instructions to more than 60 genes, not all of the genes are turned on every time p53 is active. Some genes are only turned on when p53 stops cell growth; others are only turned on when p53 starts apoptosis, the cell's suicide program.
What has perplexed researchers, though, was that p53 could distinguish genes from each other even though only one binding site in the promoter was known. The promoter sequence lies in front of a gene and, as the name suggests, promotes the gene's transcription upon binding to p53. But if only one promoter sequence controlled the transcription of 60 genes, all 60 genes would be turned on every time p53 was active.
Because only selected genes are turned on when p53 is active, Dr. Yin looked for additional promoter sequences that could provide the selectivity. He found one in front of PAC1, a gene he first identified three years ago as a p53-induced molecule.
The new regulatory mechanism raises the possibility that p53 can distinguish genes from one another based on different binding sites in the promoter. The molecule could use one promoter binding site to, say, turn on genes needed after DNA is damaged by gamma-irradiation, leading to cell cycle arrest, while using another promoter site to turn on genes needed after oxidative stress, resulting in apoptosis.
Dr. Yin says the existence of two or more binding motifs may also explain why p53 is modified in so many different ways. The molecule must be phosphorylated before it's capable of turning on other genes, but phosphorylation sites vary. "Phosphorylation of p53 in different regions could control binding to different promoters," he says, "though it remains to be seen which modifications do what."
As researchers find out more about how p53 selectively turns on genes that lead to cell death, they may also discover more targets for cancer therapies. PAC1 itself may be useful, Dr. Yin says. When he and his colleagues put the PAC1 gene into human breast cancer cells, and then injected the cells into mice, the cells grew into tumors in only one-third of the mice, while cancer cells without PAC1 always grew into tumors. Tumors with PAC1 were also substantially smaller than tumors without the cancer-suppressing molecule.
"Many cancer cells have mutant p53 so they can't turn on downstream tumor-suppressing effects," Dr. Yin says. That's a problem because radiation therapy and many cancer-fighting drugs depend on normal p53 to work. "Because PAC1 can cause cell death by itself, you could kill cancer cells by overexpressing PAC1. This way, you basically mimic p53 function and wouldn't worry about p53 any more."
The research was supported by the NIH and start-up funds from Columbia University.