Ali Tebbi's profile
I'm male and 30
What I do
We study the biological properties of nitric oxide in the context of innate immunity. NO and all its derivatives, played a key role in many physiological processes such as vascular pressure regulation, platelet aggregation, memorizing or olfaction to cite only a few examples. It is also a preserved effector of innate immunity, involved especially in defense mechanisms of the host. With reactive derivatives of oxygen, it can be produced in high concentrations by phagocytic cells. It then exerts cytotoxic and cytostatic, antimicrobic and antitumor actions. But this not very specific effector acts also on host cells and can be mutagen, genotoxic or immuno-suppressor. We are interested in these two effects, through the analysis interactions between NO and ribonucleotides reductases (RR). These ubiquitous enzymes catalyze the reduction of ribonucleotides into desoxyribonucleotides (dNTPs). Their activity is limiting for the de novo synthesis of dNTPs during DNA-replication. Most of DNA repair mechanisms require also a dNTPs-input and therefore depend consequently on RRs activities. We showed that the NO produced by the phagocytes inhibits RR activity necessary to DNA replication. This effect partly explains the anti-proliferative action with very broad spectrum of NO, against pathogens with intracellular growth, cancer cells and lymphocytes.
Affiliations
Current affiliations
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- Position
- PhD research student
- Company
- Team : Nitrogen oxides and immunity at the BBMC institute
- Further information
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Interests
The p53 tumor suppressor is frequently mutated or inactivated in human cancers. The p53R2 ribonucleotide reductase subunit is a p53-inducible protein which has a critical function in dNTPs synthesis for DNA repair and mitochondrial DNA replication. Since p53 is activated by nitric oxide, we investigated whether NO might regulate p53R2 expression. We analyzed the regulation of the expression of p53R2 in the human leukaemic lines, having a p53 functional deficit.
Projects
Ribonucleotide Reductase (RnR), is the only enzyme responsible for the de novo conversion of ribonucleosides to their corresponding deoxyribonucleosides, providing a balanced supply of precursors (dNTPs) for DNA synthesis and repair. There are two RnRs in human cells, one formed by a proteinic complex R1:R2, the other associating R1 with an R2 homologue, recently discovered, named p53R2 as a p53-inducible gene. The activity of the two enzymes depends on the expression of the two homodimeric sub-units R2 and p53R2. Expression of R2 protein is cell cycle-dependent and the RnR activity, of which it depends, ensures the synthesis of the dNTPs during DNA replication. Expression of p53R2 is controlled by the p53 tumour suppressor gene, which is inactivated in many human cancers. Previous studies of the laboratory showed that p53R2 is induced by wild-type p53 activated by DNA damages; it might take part more specifically in a p53-dependent program for the repair of damaged DNA. We examined whether other mechanisms of regulation might exist, which would able to replace p53.
Publications
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Upregulation of the p53R2 ribonucleotide reductase subunit by nitric oxide. Nitric oxide : biology and chemistry / official journal of the Nitric Oxide Society (2008) (Epub 24 Apr 2008) PubMed ID:(18474260 )
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A. Tebbi, O. Guittet, M.H. Cottet, M. Lepoivre. Upregulation of the p53 homolog p73 and induction of the p53R2 ribonucleotide reductase subunit by nitric oxide Nitric Oxide , 18 (2007)
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