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GEN News Highlights : Feb 4, 2014

Boosting p53 Tumor Suppressor Function to Fight Cancer

Scientists at Oregon State University say they have discovered a genetic function that helps the p53 tumor suppressor gene carry out its function and prevent cancer. Finding ways to maintain or increase the effectiveness of the gene in question—Grp1-associated scaffold protein, or Grasp—could offer an important new avenue for human cancer therapies, according to the researchers.

The study (“Grp1-associated scaffold protein regulates skin homeostasis after ultraviolet irradiation”) was published in Photochemical and Photobiological Sciences by researchers from OSU and Oregon Health & Science University.

The p53 gene is involved in repair of DNA damage and, if the damage is too great, causing a mutated cell to die before it can cause further problems, up to and including cancer. Dysfunction of p53 genetic pathways have been linked to more than half of all known cancers, particularly skin, esophageal, colon, pancreatic, lung, ovarian, and head and neck cancers.

“DNA mutations occur constantly in our bodies just by ordinary stresses, something as simple as exposure to sunlight for a few seconds,” explained Mark Leid, Ph.D., professor of pharmacology and associate dean for research in the OSU College of Pharmacy, and one of the lead authors on this study. “Just as constantly, the p53 gene and other tumor suppressors are activated to repair that damage. And in cases where the damage is too severe to be repaired, p53 will cause apoptosis of the mutated cell. Almost all of the time, when they are working right, these processes prevent the formation of cancers.”

But the activity and function of p53 can sometimes decline or fail, Dr. Leid said, and allow development of cancer. Promising approaches to cancer therapy are now based on activating or stimulating the p53 protein to do its job.

The new study has found that the Grasp gene is significantly involved in maintaining the proper function of p53. When Grasp is not being adequately expressed, the p53 protein that has entered the cell nucleus to either repair or destroy the cell comes back out of the nucleus before its work is finished.

“Grp1-associated scaffold protein (Grasp), the product of a retinoic acid-induced gene in P19 embryonal carcinoma cells, is expressed primarily in brain, heart, and lung of the mouse. We report herein that Grasp transcripts are also found in mouse skin in which the Grasp gene is robustly induced following acute ultraviolet-B (UVB) exposure,” write the investigators. “Grasp−/− mice were found to exhibit delayed epidermal proliferation and a blunted apoptotic response after acute UVB exposure. Immunohistochemical analyses revealed that the nuclear residence time of the tumor suppressor protein p53 was reduced in Grasp−/− mice after UVB exposure. Taken together, our results suggest that a physiological role of Grasp may be to regulate skin homeostasis after UVB exposure, potentially by influencing p53-mediated apoptotic responses in skin.”

“It appears that a primary function of Grasp is to form sort of a halo around the nucleus of a damaged skin cell, and act as kind of a plug to keep the p53 cell inside the nucleus until its work is done,” noted Dr. Leid. “A drug that could enhance Grasp function might also help enhance the p53 function, and give us a different way to keep this important tumor suppressor working the way that it is supposed to.”