APOPTOSIS AND TUMOR SUPPRESSOR p53
GROUP LEADER
| PATRICK DUMONT |
Profile |
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Dr. Patrick Dumont received his Ph.D. in biology in January 2001 from the Facultés Universitaires Notre-Dame de la Paix (Namur, Belgium). From 1995 until 2000 (Laboratory of Professor José Remacle), his research focused on cellular aging and, more specifically, on the process of Stress-Induced Premature Senescence (SIPS), an irreversible growth arrest that can be triggered by various agents including oxidative stresses and diverse anticancer drugs. Following his thesis, he did a four-year postdoc at the Fox Chase Cancer Center (Philadelphia, USA) in the laboratory of Prof. Maureen Murphy. During this postdoc, he performed a functional characterization of two polymorphisms (P/R 72 and P/S 47) in the coding sequence of the tumor suppressor p53. He is also involved in the elucidation of the transcription-independent pathway of p53-mediated apoptosis. Back in Belgium, he joined Unibioscreen SA as R&D project manager and subsequently the Erasme University Hospital (Brussels, Belgium) where he studied the tumor-host interactions in colon cancer.
Since September 2008, Patrick Dumont is Associate Professor in the Department of Biology at the Université catholique de Louvain. His main interest is the study of cancer cell biology, with a focus on the molecular mechanisms of apoptosis.
Fields of expertise:
- Tumor suppressor p53
- Apoptosis / programmed cell deaths
- Cancer cell biology
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Unité de Biologie Animale
Bt.Carnoy (a.112)
5 Croix du Sud
B-1348 Louvain-la-Neuve-Belgium
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Email :
Tel. +32 10 47 35 24
Fax. +32 10 47 35 15
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RESEARCH OVERVIEW
The tumor suppressor p53 carries the distinction of being the most frequently mutated gene in human cancer, with an overall mutation rate of 50%. p53 is a short-lived protein, maintained at low levels in cells. In response to various detrimental stimuli such as DNA damage or oncogene activation, p53 is activated and accumulates into the nucleus where it acts as a sequence-specific transcription factor. Subsequently to its activation, p53 can trigger cell cycle arrest or apoptosis, which explains the strong selection for its mutation in tumor cells.
Following an apoptotic stimulus, we have found that a fraction of p53 relocalizes to the mitochondria where it interacts with Bak, a pro-apoptotic Bcl-2 family member. Formation of the p53–Bak complex coincides with loss of an interaction between Bak and the anti-apoptotic Bcl-2 family member Mcl1. The interaction causes BAK oligomerization, the formation of pores in the mitochondrial outer membrane and the release of the mitochondrial effectors of apoptosis such as cytochrome c, into the cytoplasm. We showed that a common polymorphism at codon 72 (P/R) markedly affects the mitochondrial trafficking of p53, and this determines the ability of the two polymorphic variants to induce apoptosis.
Our current studies aim to characterize the transcription-independent pathway of p53-mediated apoptosis:
- Contribution of post-translational modifications of p53 to its mitochondrial trafficking and to its apoptosis-inducing activity at the mitochondria.
- Functional characterization of new interactions between p53 and mitochondrial proteins.
- Influence of the anti-apoptotic Bcl-2 family members on the ability of p53 to localize to the mitochondria and trigger BAK oligomerization.
