Harvard Researchers Report P53 Doppelganger

August 20, 1997

BOSTON--August 20--The famous p53, considered the single most important tumor suppressor gene, is single no more.

Researchers at Harvard Medical School, working in close collaboration with French scientists, have discovered a novel gene that closely resembles p53, a critical factor in tumor development that is mutated in 60% of all human cancers. The new gene, called p73, is deleted in at least one type of cancer and resides in an area of the genome that researchers worldwide have for years scoured for suspected tumor suppressor genes.

The researchers are publishing their discovery and an initial analysis of p73 in the August 22 Cell, but cancer researchers across the country and abroad are already testing whether it is altered in other human tumors.

It is too early to tell whether p73 will come to rival the central role in cancer genetics that 20 years of research have established for p53, or whether it will become the target of industrial drug design, as is p53. But the similarity of p73 to its famous relative, as well as other findings, make it an intriguing gene, says Frank McKeon, associate professor of cell biology at Harvard Medical School, who conducted this study with Daniel Caput of the pharmaceutical company Sanofi Recherche in Labege Cedex, France.

Although dozens of groups are studying p53--the Medline database lists more than 9000 citations since 1977--none of them ever spotted its brother. And the authors are not long-standing participants in the high-powered field of tumor genetics. Caput first discovered p73 serendipitously while pursuing research into growth factors called cytokines. To analyze it, he quickly teamed up with McKeon, who had studied genes involved in DNA replication and cell division.

The researchers knew they were on to something because the gene resides in the very tip of chromosome 1. This area is missing in many cancers, including those of the skin, colon, breast and liver, as well as neuroblastoma, a childhood cancer thatDwhile relatively rareDhas yielded much insight into the molecular workings of cancer cells.

"P73 lies in one of the most interesting hot spots for putative tumor suppressors," says McKeon. "This has been a suspicious area for cancer for a long time." He cautions, however, that this danger zone probably contains many genes and that only future work will clarify if and how p73 contributes to disease.

While it has long been known that the tip of chromosome 1 is missing in these cancers, researchers wonder why affected people cannot compensate for the loss simply by using genes on their second chromosome 1. McKeon, Caput, and colleagues do not fully understand this paradox, but they found that the p73 gene gets expressed from one chromosome only, possibly that of the mother. This finding suggests that having one faulty copy of p73 might suffice to lose all function. It also forges a connection to the separate field of genetic imprinting, which studies why and how organisms permanently "silence" certain genes just because they derive from a particular parent.

And the research suggests a possible approach to future treatments: trying to awaken a silenced gene may prove easier than trying to supply a damaged gene by gene therapy, says McKeon.

When the researchers analyzed p73, they found that it is a sibling, but no twin of p53's. Its overall structure is similar, as are important regions of the geneDthose enabling the p53 protein to bind DNA, to stick to other p53 proteins, and to activate particular genes. p73 also contains the fateful ten or so amino acids that are most frequently mutated in p53, predisposing the carrier to cancer. Finally, p73 behaves like p53 in some of the experimental tests routinely used to study tumor suppressor genes.

But that is where the resemblance ends. Unlike p53, p73 does not respond when the cell's DNA sustains damage from ultraviolet light, the researchers report. This is important because the major function of p53 that is currently known is to sense DNA damage and put the cell cycle on hold while enzymes restore the DNA. If the damage is irreparable, p53 commits the cell to destroy itself. These functions have earned p53 the sobriquet "guardian of the genome," and p73's failure to react to DNA damage suggests that its main functions, at least in part, lie elsewhere, McKeon says.

His group is working to delete the gene in mice and indeed, early indications of that work suggest that p73 acts in the development of the brain and the immune system. By contrast, mice lacking p53 show almost no embryological defects.

Next, McKeon's group and others will try to understand exactly what p73 does. They will ask what role p73 plays in the gradual process that scientists believe leads from an initial disturbance of the cell's internal controls through a series of exacerbating mutations to full-blown, metastatic cancer.

Will the arrival of p73 dethrone p53 as the most prominent cancer gene? On the contrary, says McKeon, 3I think p73 makes p53 much more interesting." Part of the reason is that p73 and p53 seem to interact. Another part may lie in evolution. McKeon suspects that a primitive p73-like gene may have evolved first, a generalist that served many functions in the growth and maturation of prehistoric cells. From this, p53 might later have evolved as a specialized offshoot concerned solely with tumor suppression.

McKeon points to work by other researchers suggesting that key genes quadrupled in number at the time vertebrate animals arose. This strategy might have been a way for nature to realize biochemically the demands of the increasing complexity of species. Based on these observations, McKeon says, there should be two more, as yet undiscovered, siblings of p53, hinting at an entire network of related proteins that interact and regulate each other. The search, he adds, is on.

Annie Yang, a student in McKeon's laboratory, is a co-author on the Cell paper.


Harvard Medical School

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