Transactivation of naturally occurring HIV-1 long terminal repeats by the JNK signaling pathway. The most frequent naturally occurring length polymorphism sequence introduces a novel binding site for AP-1 factors.
To study the role of MAPK cascades in the regulation of naturally occurring human immunodeficiency virus type 1 long terminal repeats (HIV-1 LTRs), we analyzed several HIV-1 LTRs from patients at different stages of disease progression. One of these naturally occurring HIV-1 LTRs contains an insertion termed the most frequent naturally occurring length polymorphism (MFNLP) and exhibited high inducibility upon T cell activation. We found that the protein kinase mixed lineage kinase 3/src-homology 3 domain-containing proline-rich kinase, a specific activator of the stress-activated protein kinase (SAPK)/JNK signaling pathway in T lymphocytes, induces high transcriptional activation of this promoter. Promoter inducibility is inhibited by the SAPK/JNK inhibitor, the JNK binding domain of the JNK interacting protein 1, and Tam-67 (N-terminal deletion mutant of c-Jun). In electrophoretic mobility shift assay, several protein complexes were found to bind to the MFNLP sequence in T cells. We identified AP-1 factors c-Fos and JunB as MFNLP-binding proteins, whose binding is abolished by introducing point mutations in the 3'-half of the MFNLP sequence. Introduction of these point mutations into the MFNLP containing HIV-1 LTR reduced src-homology 3 domain-containing proline-rich kinase -mediated transactivation. These data indicate that the AP-1-like binding site in the MFNLP sequence gives rise to a higher inducibility of natural HIV-LTRs by the SAPK/JNK signaling pathway.
Chen
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P
Institut für Medizinische Strahlenkunde und Zellforschung, Universität Würzburg, Versbacher Strasse 5, D-97078 Würzburg, Germany.
Flory
E
E
Avots
A
A
Jordan
B W
BW
Kirchhoff
F
F
Ludwig
S
S
Rapp
U R
UR
D001665:Binding Sites; D001667:Binding, Competitive; D004268:DNA-Binding Proteins / Q000235:genetics; D016325:HIV Long Terminal Repeat / Q000235:genetics*; D015497:HIV-1 / Q000235:genetics*; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases; D020930:MAP Kinase Kinase Kinases; D020928:Mitogen-Activated Protein Kinases / Q000235:genetics*; D009154:Mutation; D009838:Oligodeoxyribonucleotides / Q000235:genetics; D011110:Polymorphism, Genetic; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics; D013601:T-Lymphocytes / Q000378:metabolism; D018808:Transcription Factor AP-1 / Q000235:genetics; D015533:Transcriptional Activation; D014407:Tumor Cells, Cultured; D000097767:Mitogen-Activated Protein Kinase Kinase Kinase 11
D004268:DNA-Binding Proteins; D048031:JNK Mitogen-Activated Protein Kinases; D020930:MAP Kinase Kinase Kinases; D020928:Mitogen-Activated Protein Kinases; D009838:Oligodeoxyribonucleotides; D017346:Protein Serine-Threonine Kinases; D018808:Transcription Factor AP-1; D000097767:Mitogen-Activated Protein Kinase Kinase Kinase 11