New Protein Regulates Important Tumor Suppressor

November 16, 2000

PID protein modulates p53’s ability to slow the growth of cells

New York, N.Y., November 16, 2000 - Researchers in the Institute of Cancer Genetics and the Department of Pathology of Columbia University’s College of Physicians and Surgeons have identified a new protein called PID, a novel cellular target protein for p53, a pivotal protein that slows growth of tissues. Because boosting p53 activity is the goal of many anti-tumor therapies, the finding may help in developing new tools to fight cancer. Says Dr. Wei Gu, assistant professor of pathology, “PID clearly represses p53 function. If you abrogate the effect of PID, you can enhance p53’s function. Hopefully, we’ll be able to reactivate p53 in tumor cells.” The tumor suppressor p53 normally keeps down cell numbers both by stalling cell division and by triggering cell death. At the node of a complex network of controls, the p53 “brake” on cell growth is, in turn, controlled by several different “switches.” One way of regulating p53 activity is by chemical attachment of acetyl groups, termed acetylation, which makes the protein more efficient at turning on genes to slow cell division and hasten cell death. (Dr. Gu was the first person to discover that p53 can be acetylated and functionally regulated by protein acetylation, in 1997. This discovery opens a door for acetylation as a general protein modification for many other transcriptional factors that have been reported since). In the Nov. 16 issue of Nature, Dr. Gu, and researchers Jianyuan Luo, Fei Su, Delin Chen and Ariel Shiloh report finding PID (p53 target protein in the deacetylase complexes), which weakens p53’s grip on growth. PID trims down p53 acetylation, thus easing up on the p53 “brake.” By deacetylating p53, PID undermines p53’s ability to turn on genes that hinder progression of the cell cycle, thereby slowing cell division. It also keeps p53 from activating genes that initiate programmed cell death, or apoptosis. In this way, PID boosts cell proliferation and slows cell death. The accelerated growth that comes with diminished p53 function is a hallmark of cancers, and many tumors involve mutations in the p53 gene itself; others may involve binding of viral proteins to p53, or damage to either the downstream effectors of its function or some of the regulatory proteins that impinge on it. Identifying PID as a regulator of p53 activity might help explain the genetic basis of some tumors. “PID is overexpressed in certain cancers, such as breast cancers,” says Dr. Gu. Likewise, metastasis-associated protein 1, a protein similar to PID, was first discovered in metastatic cancer cells. PID may be a good target for anti-tumor drugs. Says Dr. Gu: “Inhibiting deacetylase activity has been a goal of a lot of anti-tumor therapies. But if you inhibit all deacetylases, you can harm normal cells too. By identifying a specific target, we can selectively enhance p53 activity to fight tumor growth without hurting normal cells.” The research was funded by the National Cancer Institute at the National Institutes of Health, the American Cancer Society, and the Herbert Irving Comprehensive Cancer Center at Columbia-Presbyterian Medical Center.

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Jianyuan Luo, PID, Says Dr, Wei Gu