title: TNFalpha cooperates with the protein kinase A pathway to synergistically increase HIV-1 LTR transcription via downstream TRE-like cAMP response elements.
abstract: Activating protein-1 (AP-1) binding TPA responsive elements (TRE) are located downstream of the transcription initiation site in the U5 region of the HIV-1 long terminal repeat (LTR). These downstream sequence elements, termed DSE, can bind both AP-1 and CREB/ATF transcription factors. Recently, we demonstrated that the DSE are also cAMP-responsive elements (CRE), since they mediated activation signals elicited by cholera toxin (Ctx), a potent activator of the cAMP-dependent protein kinase A (PKA) signal transduction pathway. In the present study, we demonstrate that the HIV-1 DSE can mediate the transcriptional synergy elicited by the combination of Ctx and TNFalpha. Ctx combined with TNFalpha or IL-1beta to produce a synergistic increase in p24 antigen production in U1 promonocytic cells. Transfection studies of LTR reporter constructs indicated that mutation of the DSE sites abrogated the LTR-mediated synergy induced by Ctx and TNFalpha, whereas the synergy induced by Ctx and IL-1beta was unaffected, suggesting TNFalpha and IL-1beta cooperate differently with the cAMP/PKA activation pathway to induce HIV-1 expression in U1 cells. Because the DSE are also TRE sites, we assessed the effect of the agonist combinations on AP-1-dependent transcription. TNFalpha as well as IL-1beta cooperated with Ctx to produce a synergistic activation of AP-1-mediated transcription. These data indicate that the TRE-like cAMP-responsive DSE sites within the 5'-untranslated leader can mediate the transcriptional cooperativity between TNFalpha and the cAMP/PKA pathway. Since the DSE and TRE sites cannot bind CREB/ATF homodimers, we propose a mechanism in which the HIV-1 DSE bind heterodimers composed of both AP-1 and CREB/ATF proteins.
authors.affiliation: Department of Immunology/Microbiology, Rush-Presbyterian-St. Luke's Medical Center, 1653 West Congress Parkway, Chicago, Illinois 60612, USA.
authors.forename: M F
authors.initials: MF
authors.lastname: Rabbi
authors.forename: L
authors.initials: L
authors.lastname: Al-Harthi
authors.forename: K A
authors.initials: KA
authors.lastname: Roebuck
mesh_terms: D002460:Cell Line; D017868:Cyclic AMP-Dependent Protein Kinases / Q000502:physiology*; D016325:HIV Long Terminal Repeat / Q000235:genetics*; D015497:HIV-1 / Q000502:physiology*; D006801:Humans; D009000:Monocytes / Q000502:physiology / Q000821:virology*; D015290:Second Messenger Systems; D015398:Signal Transduction; D018808:Transcription Factor AP-1 / Q000502:physiology*; D014158:Transcription, Genetic; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology*; D014779:Virus Replication
chemical_list: D018808:Transcription Factor AP-1; D014409:Tumor Necrosis Factor-alpha; D017868:Cyclic AMP-Dependent Protein Kinases