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Int J Cancer. 2004 Nov 10;112(3):536-40.

Transgenic overexpression of a dominant negative mutant of FADD that, although counterselected during tumor progression, cooperates in L-myc-induced tumorigenesis.

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1
Institute of Signaling, Developmental Biology and Cancer Research, Centre National de la Recherche Scientifique Unité mixte de Recherche 6543 Centre A. Lacassagne, Nice, France.

Abstract

Activation of the so-called death receptors, e.g., CD95/Fas/Apo-1, is a potent stimulus to trigger apoptosis. Overexpression of the C-terminal FADD deletion mutant FADD-DN blocks death receptor-induced apoptosis, but despite this antiapoptotic activity, lck FADD-DN transgenic mice do not develop lymphomas. To analyze whether functional inactivation of FADD cooperates with Myc overexpression in tumorigenesis, lck FADD-DN transgenic mice were crossed with Emicro L-myc transoncogenic animals. While no tumors were detected in single transgenic FADD-DN or L-myc mice within 15 months, 5 of 17 (29%) FADD-DN/L-myc double transgenic animals developed lymphomas with an average latency period of 47 weeks. Protein analysis of FADD-DN/L-myc tumors showed, however, undetectable levels of FADD-DN protein. FADD-DN protein expression was again lost in 16 of 17 FADD-DN/p53 k.o. T-cell lymphomas, though no significant acceleration of tumorigenesis in P53-deficient lck FADD-DN mice compared to p53 k.o. animals was observed. These data suggest a strong counterselection against the FADD-DN protein during tumor progression, which could be explained by the cell cycle inhibitory activity of FADD-DN. Such counterselection would have to be compensated for by other antiapoptotic mutations, and indeed, strong upregulation of the antiapoptotic Bcl-2 family member Bcl-xL was found in one of the tumors. This in vivo mouse model demonstrates that an antiapoptotic protein involved in the onset of tumorigenesis is selected against and consequently lost during tumor progression because of its additional antiproliferative activity.

PMID:
15382083
DOI:
10.1002/ijc.20422
[Indexed for MEDLINE]
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