The win locus involved in activation of the distal N-myc2 gene upon WHV integration in woodchuck liver tumors harbors S/MAR elements.
Woodchuck hepatitis virus (WHV) and the woodchuck (Marmota monax) are models for hepatocellular carcinoma (HCC) induced by hepatitis B virus (HBV). In woodchuck liver tumors, the N-myc2 proto-oncogene is frequently activated by WHV integration either close to the gene or in the b3n and win downstream loci, located 10 and 150 kb from N-myc2, respectively. A scaffold/matrix attachment region (S/MAR) regulative element was shown to be in b3n, possibly mediating activation of the upstream N-myc2 gene upon WHV integration. To investigate if S/MAR elements are in win too, a 17-kb DNA fragment corresponding to the major region of WHV insertion in this locus was cloned and sequenced. Overlapping subcloned fragments spanning candidate S/MARs predicted by sequence analysis were tested by standard in vitro binding assays. Results showed the presence of two S/MAR elements in win. The distribution of previously described WHV insertions relative to the S/MARs reinforces the hypothesis that S/MARs nearby distal WHV insertions might be involved in long-range activation of N-myc2.
Viral Hepatitis Unit, Department of Infectious, Parasitic and Immunomediated Diseases, Istituto Superiore di Sanità, Viale Regina Elena 299, 00161 Rome, Italy.
Roberto
R
Bruni
Emilio
E
D'Ugo
Umbertina
U
Villano
Geneviève
G
Fourel
Marie-Annick
MA
Buendia
Maria
M
Rapicetta
D000818:Animals; D001483:Base Sequence; D006528:Carcinoma, Hepatocellular / Q000235:genetics* / Q000378:metabolism; D004195:Disease Models, Animal; D015972:Gene Expression Regulation, Neoplastic; D017919:Hepatitis B Virus, Woodchuck / Q000235:genetics / Q000472:pathogenicity*; D006801:Humans; D008113:Liver Neoplasms / Q000235:genetics / Q000378:metabolism; D008114:Liver Neoplasms, Experimental / Q000235:genetics* / Q000378:metabolism; D008392:Marmota; D045170:Matrix Attachment Regions / Q000235:genetics*; D008969:Molecular Sequence Data; D000090063:Proto-Oncogene Mas; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics / Q000378:metabolism*; D016662:Virus Integration
C000715470:MAS1 protein, human; D000090063:Proto-Oncogene Mas; D016271:Proto-Oncogene Proteins c-myc