Journal Article

Modulation of the Fas-apoptosis-signalling pathway by functional polymorphisms at <i>Fas</i>, <i>FasL</i> and <i>Fadd</i> and their implication in T-cell lymphoblastic lymphoma susceptibility

María Villa-Morales, Elena González-Gugel, Marta N. Shahbazi, Javier Santos and José Fernández-Piqueras

in Carcinogenesis

Volume 31, issue 12, pages 2165-2171
Published in print December 2010 | ISSN: 0143-3334
Published online October 2010 | e-ISSN: 1460-2180 | DOI: http://dx.doi.org/10.1093/carcin/bgq201
Modulation of the Fas-apoptosis-signalling pathway by functional polymorphisms at Fas, FasL and Fadd and their implication in T-cell lymphoblastic lymphoma susceptibility

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In previous reports, we described germ line functional polymorphisms that differentiate Fas and FasL genes in two mouse strains (SEG/Pas and C57BL/6J) exhibiting extreme differences in susceptibility to γ radiation-induced T-cell lymphomas. Here, we provide new data reinforcing the importance of the extrinsic pathway of apoptosis mediated by Fas in T-cell lymphoma development and about the functional significance of polymorphisms located at intracellular and extracellular domains of Fas and FasL. Using DNA recombinant technology, we generate chimerical Fas and FasL proteins by combination of protein regions derived from the two strains and demonstrate that any Fas–FasL interaction involving chimerical proteins drive cell apoptosis to a significant lower extent than the wild-type SEG/Pas and C57BL/6J Fas–FasL systems. In addition, we report new polymorphisms in the coding sequence of Fadd and demonstrate that the interaction between Fas and Fadd is significantly stronger if Fas and Fadd are of SEG/Pas origin compared with the C57BL/6J system. Altogether, these results suggest a model in which functional polymorphisms at the three genes collaborate on the global ability of the Fas/FasL system to induce apoptosis. A complete analysis of these three genes in the pathway appears to be a sine qua non condition to accurately predict the effectiveness of the Fas system and to estimate susceptibility to T-cell lymphoma.

Journal Article.  4713 words.  Illustrated.

Subjects: Clinical Cytogenetics and Molecular Genetics

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