Modulation of Tax and PKA-mediated expression of HTLV-I promoter via cAMP response element binding and modulator proteins CREB and CREM.
Nuclear proteins of the human peripheral blood T lymphocytes that bind to the CREs located within three 21-bp repeat enhancers of the HTLV-I promoter belong to the CREB/CREM family of bZIP transcription factors. It has been shown previously that Tax enhances transactivation of these CREs by direct interactions with the bZIP domain of the transcription factors to stabilize DNA-binding. We show that CREB and CREM bind all three CRE sequences of the HTLV-I promoter which are important determinants in Tax-elicited transactivation as well as PKA-mediated activation of the HTLV-I promoter. Tax and PKA activate transcription from a HTLV-I-LTR CAT reporter plasmid transfected to NIH 3T3 cells, and CREM attenuates the activation. In the context of a GAL4 CREB fusion protein in which the DNA-binding bZIP domain of CREB is replaced by GAL4 binding domain, a single amino acid substitution of serine-133, phosphorylated by PKA and critical for the transactivation function of CREB, attenuates both Tax and PKA-mediated transcriptional responses. These observations suggest that Tax enhances CREB-mediated transactivation of the HTLV-I promoter by a mechanism apart from, and/or in addition to, the reported stabilization of DNA-binding by interaction with the bZIP domain of CREB.
Laboratory of Molecular Endocrinology, Massachusetts General Hospital (WEL320), Howard Hughes Medical Institute, Boston 02114, USA.
J
J
Bodor
W
W
Walker
E
E
Flemington
A L
AL
Spetz
J F
JF
Habener
D016475:3T3 Cells; D000818:Animals; D001483:Base Sequence; D001665:Binding Sites; D051786:Cyclic AMP Response Element Modulator; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism; D015368:Human T-lymphotropic virus 1 / Q000235:genetics*; D006801:Humans; D051379:Mice; D008969:Molecular Sequence Data; D009687:Nuclear Proteins / Q000378:metabolism; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D011506:Proteins / Q000378:metabolism; D012091:Repetitive Sequences, Nucleic Acid; D012097:Repressor Proteins; D013601:T-Lymphocytes / Q000378:metabolism; D014158:Transcription, Genetic; D015533:Transcriptional Activation; D014162:Transfection
D017362:Cyclic AMP Response Element-Binding Protein; D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; D011506:Proteins; D012097:Repressor Proteins; D051786:Cyclic AMP Response Element Modulator; D017868:Cyclic AMP-Dependent Protein Kinases