The cancer gene p53 is famous for being mutated in over half of all human cancers, and for this reason has been dubbed "the guardian of the genome."Researchers are still working out the role that p53 plays in healthy people, and understanding its functions will be very valuable in designing effective cancer treatments.
Two papers in today's issue of Cell make an important step towards this, by uncovering a new aspect of p53 regulation that links it to normal metabolism and perhaps also to aging.
Researchers have known for almost ten years that normal p53 prompts stressed and damaged cells to commit suicide, thereby reducing the risk that they continue to grow in a damaged state and become cancerous. p53 acts as a transcription factor, which means it controls the activity of other genes.
Anything that interferes with the normal activity of p53 can reduce its ability to regulate transcription, and thus its capacity for killing aberrant cells.
In the new studies, Bob Weinberg and colleagues at MIT's Whitehead Institute and Wei Gu and colleagues at Columbia University discovered a link between p53 and genes in the “silent information regulator” family (SIR2).
Sir proteins exist in many organisms and are involved in a variety of processes, including aging and damage responses. Both teams found that Sir2 alpha mouse protein and the human protein SIR2 directly bind to p53 and remove acetyl groups from it.
Removing these acetyl groups reduces the activity of p53 and thereby its ability to respond to stress and damage. Conversely, the researchers found that inhibiting SIR2 increased the sensitivity of the cells to the same insults.
Thus, SIR2 plays an important role in p53-mediated cancer protection. It could also even be important in cancers that do not feature p53 mutations or a decrease in p53 levels. It is possible that some such tumors instead contain an excess of SIR2, which prevents p53 from doing its normal work.
There may be some immediate lessons from this for doctors who are treating cancer patients. The results suggest that drugs that inhibit SIR2 could increase the effectiveness of existing cancer therapy procedures.
"Agents that inhibit SIR2 or its ability to bind to p53 would be obvious candidates for therapy," says Weinberg. Furthermore, because SIR2's activity is affected by the rate of metabolism, the work makes a connection between metabolism and sensitivity to DNA damage.
“Everyone has a different metabolic rate and possibly that's why they have a different sensitivity to chemotherapy,” says Gu.
(Reference: Volume 107 Number 2 October 19, 2001 Cell)
[Contact: Bob Weinberg, Wei Gu]
19-Oct-2001
