Nucleic Acids Research, 1994, Vol. 22, No. 22 4779-4788
© 1994
MOLECULAR BIOLOGY |
Adenovirus 12-mediated down-regulation of the major histocompatibility complex (MHC) class I promoter: identification of a negative regulatory element responsive to Ad12 E1A
Department of Biochemistry and Molecular Biology, University of Leeds Leeds LS2 9JT, UK
*To whom correpsondence should be addressed
Received June 20, 1994. Revised October 13, 1994. Accepted October 13, 1994.
In highly oncogenic adenovirus (Ad) 12transformed cells, major histocompatibility complex (MHC) class I gene expression is down-regulated by the products of the viral E1A oncogene at the level of initiation of transcription. However, class I gene expression is unaltered or elevated in non-oncogenic Ad2- or Ad5-transformed cells. These changes in class I expression may permit Ad12-transformed cells to escape host immune0 surveillance and elicit tumour formation. Here we show that the 2kb of 5' flanking region of the mouse H-2Kb class I gene is sufficient to mediate down-regulation of transcription driven from homologous or heterologous (HSV thymidine kinase) basal promoter elements in cells expressing Ad12 E1 A, but not in Ad2 E1 A-expressing cells. Deletion analysis of the 2kb region showed that sequences from –1.18 to –1.44kb (relative to the cap site) were a target for Ad12 E1A-mediated transcriptional down-regulation. Deletion of this entire region from the 2kb flanking sequence of the H-2Kb gene abolished Ad12 E1Amediated down-regulation of transcription. Computer analysis of the –1.18 to –1.44kb sequence identified two 6/7bp matches with the AP–1 transcription factor consensus sequence and two matches with the pig MHC class I PD1 repressor element. Gel retardation analysis using overlapping DNA fragments derived from the –1.18 to –1.44kb sequence revealed several DNA: protein complexes formed using nuclear extract derived from Ad12-, but not from Ad2- or Ad5-transformed cells. Some of these DNA: protein complexes were also present, but at lower levels, in nuclear extracts from untransformed rat cells suggesting the possible involvement of cellular factors in the mechanism of down-regulation mediated by Ad12 E1 A. A binding site for the AP-1 factor failed to compete for protein binding to fragments within the –1.18 to –1.44 sequence, while the PD1 site competed for binding only in the –1.15 to –1.23 region. These results indicate that novel factors (as well as a previously identified class I repressor, PD1) may be involved in Ad12 E1A-mediated down-regulation of MHC class I transcription.
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