A functional N-myc2 retroposon in ground squirrels: implications for hepadnavirus-associated carcinogenesis.
Three hepatitis B viruses infecting humans, woodchucks and ground squirrels increase the risk of hepatocellular carcinoma in their respective hosts. The woodchuck hepatitis B virus (WHV), unlike the two other viruses, induces a rapid carcinogenic process characterized by direct activation of myc proto-oncogenes by insertion of viral DNA. The highly preferred target of insertional mutagenesis in woodchucks is N-myc2, an intronless N-myc gene. Strikingly, N-myc2 has no human homolog and the homologous N-myc2 locus previously detected in the ground squirrel genome, remains silent during hepatocarcinogenesis. Therefore, N-myc2 may represent a critical host determinant in the evolution of the disease associated with hepadnavirus infection. To address this question, we performed a structural and functional analysis of the ground squirrel N-myc2 locus. We show that ground squirrel N-myc2 is highly homologous to its woodchuck counterpart and is a functional proto-oncogene. Existence of a functional N-myc2 gene as a potential target for insertional activation by viral DNA is therefore not restricted to the woodchuck species. This suggests that viral rather than host factors determine the higher oncogenic phenotype of WHV as compared to the two other mammalian hepadnaviruses.
Quignon
F
F
Unité de Recombinaison et Expression Génétique (INSERM U163), Institut Pasteur, Paris, France.
Renard
C A
CA
Tiollais
P
P
Buendia
M A
MA
Transy
C
C
D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D017124:Conserved Sequence; D004279:DNA, Viral; D016259:Genes, myc; D015613:Hepadnaviridae / Q000472:pathogenicity*; D008114:Liver Neoplasms, Experimental / Q000235:genetics / Q000821:virology*; D008969:Molecular Sequence Data; D000090063:Proto-Oncogene Mas; D051381:Rats; D011916:Rats, Inbred F344; D018626:Retroelements; D012589:Sciuridae / Q000235:genetics*; D017386:Sequence Homology, Amino Acid; D014158:Transcription, Genetic
D004279:DNA, Viral; C000715470:MAS1 protein, human; D000090063:Proto-Oncogene Mas; D018626:Retroelements