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Type p53 into Pubmed and you'll get a list of 24,000 papers devoted to this guardian molecule of the cell. With that sort of attention, finding something completely unknown about the tumor suppressor, which is mutated in half of all human tumors, isn't easy.

But Dr. Wei Gu, assistant professor of pathology in the Institute for Cancer Genetics, has found a previously unknown regulator of p53 that may itself be an important tumor suppressor. Further investigations of the protein, called HAUSP, may reveal new targets for cancer drugs that could enhance p53's anti-tumor activities.

Though many genes must go bad in a cell before a tumor forms, changes in p53 seem especially important. Usually, when p53 is working, damage to other genes in the cell turns on p53, and the molecule stops the cell from dividing and proliferating the mutated gene. If the damage is extensive, p53 tells the cells to commit suicide to prevent the mutations from spreading. But if p53 itself is mutated, nothing keeps damaged cells in check and cells keep dividing even if other genes are mutated.

But because the cell constantly produces the p53 protein, it also must constantly destroy the molecule to allow the growth of normal cells. To destroy p53, the cell tags the protein with an ubiquitin molecule, which tells other molecules to degrade the protein.

When p53 is needed, the cell stops labeling the p53 proteins with ubiquitin and the proteins are stabilized. Hypothetically, removing ubiquitin from p53 molecules already slated for destruction could also boost p53 activity. But until now, ubiquitin-removing enzymes have only been confirmed in yeast.

Dr. Gu discovered p53's de-ubiquitinating protein, or HAUSP, by accident when he was looking for other regulators of p53. When an unknown protein showed up in a search for these other regulators, Dr. Gu, out of curiosity, put the protein through a mass spectrometer to find out what it was. The spectrometer read the sequence of amino acids in five regions within the protein.

After searching protein databases for the sequences, Dr. Gu's team found a protein—HAUSP—that contained all five. Though the protein is named HAUSP for herpes-associated ubiquitin-specific protease, the original discoverers of the molecule didn't really know its function, other than it resembled the yeast de-ubiquitinating enzyme.

With a protein in hand that bound to p53 and looked like a ubiquitin remover, Dr. Gu thought HAUSP might just be key in regulating cell growth. To test HAUSP's importance, he inserted the HAUSP gene into cancer cells that grew uncontrollably. The effect of HAUSP was powerful. After HAUSP was inserted, cell growth suddenly stopped and many cells committed suicide.

A look inside the cells then showed that HAUSP controls cell growth by removing ubiquitin from p53. Cells with HAUSP had far lower levels of the ubiquitinated protein than cells without HAUSP.

Besides its significance in cancer research, Dr. Gu says HAUSP is the first example of a protein in mammalian cells that can remove ubiquitin and stabilize the remaining substrate molecule.

All together, the research shows HAUSP can slow down cell growth by rescuing p53 and that it may also be a tumor suppressor. Dr. Gu is now making knock-out mice that lack the gene to better understand HAUSP's behavior. “If these mice develop tumors, then you can show this gene is really important for tumorigenesis,” Dr. Gu says.

His research team is also screening cancers to see if HAUSP plays a role in the 50 percent of tumors that don't have anything wrong with their p53. These tumors frequently have something wrong with their p53 regulators instead. “Our preliminary data show that HAUSP expression is down-regulated in tumors with functioning p53,” Dr. Gu says. “A drug that activates HAUSP could potentially restore the tumor-suppressing ability of p53.”