| The main goal of our laboratory is to elucidate the biochemical and biological processes that underlie the ability of p53 to act as a tumor suppressor. In addition, we are also interested in
- the Mdm2 gene - an oncogene whose protein products inhibit the biochemical activity of p53 and target p53 for rapid degradation
- ARF - another tumor suppressor that can trigger p53 activation in cancer-prone cells
- p63 - a member of the p53 family
- Mutant p53 Gain of Function , by which the mutated protein acquires additional pro-oncogenic functions.
The following specific questions are being addressed by our current research: (Click on each image for an enlargement.)
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- Which genes are direct targets for specific transcriptional regulation by p53 , and what are the consequences of such regulation for cell proliferation and cell survival?
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- Which genes are direct targets for specific transcriptional regulation by p53 , and what are the consequences of such regulation for cell proliferation and cell survival? Can p53 distinguish between different target genes and regulate them differentially? If so, what is the molecular basis for such differential regulation, and can such differential regulation account for the ability of p53 to elicit diverse biological effects in different cell types ? Can oncogenes contribute to such differential regulation?
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- How does a cell decide whether or not to undergo apoptosis in response to p53 activation?
- What is the basis for the increased propensity of tumor cells to undergo apoptosis in response to p53 activation?
- Which biochemical mechanisms, transcriptional and non-transcriptional, underlie the apoptotic activity of p53 ? How is this activity of p53 regulated (positively and negatively)?
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- How is the biochemical activity of Mdm2 regulated within living cells?
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- How is the activity of ARF regulated?
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- Why do mutant p53 protein molecules accumulate in cancer cells? Does such mutant p53 possess an overt oncogenic gain of function, which contributes actively to tumor progression?
- Does the Mdm2 gene have other functions in addition to its ability to down-regulate p53 activity? Do such functions contribute to the oncogenic activity of Mdm2?
- How does the loss of p53 and ARF promote the development of cancer?
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Eventually, it is hoped that the knowledge gained through such studies will allow the identification of suitable targets for therapy and the design of better approaches to treat human disease. Work in the Oren laboatory is supported by grants from the National Cancer Institute, the Israel Science Foundation (Center of Excellence program), the German-Israeli Project Cooperation (DIP), the European Union (Fifth Framework), the Israel-USA Binational Science Foundation, the Bosch Foundation, the Kadoury Charitable Foundations, and Yad Abraham Center for Cancer Diagnosis and Therapy.
Weizmann Institute of Science, Rehovot, 76100 Israel
Tel: 972-8-934-4072; Fax: 972-8-946-5223;
Email: moshe.oren@weizmann.ac.il |
