MERIT Award Recipient: Moshe Oren, Ph.D.
Functional Analysis of the p53 Tumor Suppressor
Dr. Oren's research concerns the molecular mechanisms that prevent the emergence of cancer. In particular, Dr. Oren is focusing on the p53 tumor suppressor. Tumor suppressor genes serve as a built-in genetic protection device against cancer: as long as they retain their functionality, cancer is effectively aborted. Conversely, when one or more tumor suppressor genes become nonfunctional, the drift of normal cells towards a malignant state is enabled.
Of all tumor suppressor genes, p53 is the one that is altered most frequently in human cancer. Close to half of all individual human tumors carry genetic alterations in the p53 gene, which directly inactivate the gene and ablate the production of its normal protein product, the p53 protein. Understanding how p53 acts to suppress cancer and how its function is abrogated in tumor cells is thus of prime importance in elucidating the molecular mechanisms that give rise to cancer.
Dr. Oren's lab is concentrating on the biochemical and biological activities of p53, as well as on the ways in which p53 function is regulated in normal and cancer cells. Previous work has led, among other things, to the realization that one of the ways whereby p53 can suppress cancer is by triggering within cancer cells a process of programmed cell death, known as apoptosis. Subsequent work has revealed that the cellular amounts and activity of the p53 protein, as well as the ability of p53 to kill cancer cells, are largely regulated by another protein known as Mdm2. Mdm2 itself is also implicated in many types of cancer: overproduction of Mdm2 results in excessive p53 inactivation, thereby relieving the cell of p53's protective effects and facilitating the emergence of cancer.
Dr. Oren's current research attempts to elaborate how the interplay between p53 and Mdm2 is regulated, and how various incoming signals that operate either in normal or in cancer cells affect differentially the ability of p53 to become activated and the ability of Mdm2 to block this activation. Special emphasis is being placed on the role of chemical modifications that occur on Mdm2 and modulate its p53-inactivating capacity, as well as on the identification of other regulatory proteins that interact with Mdm2. The research also aims to assess how another p53-related protein, known as p63, contributes to the regulation of p53 activity and to cancer. The understanding gained from these experiments is likely to provide clues that will enable the reactivation of p53 in cancer cells, eventually triggering in such cells apoptosis or other p53-mediated inhibitory processes and contributing to the slow-down or complete elimination of the tumor.