title: ATF/CREB elements in the herpes simplex virus type 1 latency-associated transcript promoter interact with members of the ATF/CREB and AP-1 transcription factor families.
abstract: The herpes simplex virus type 1 (HSV-1) latency-associated transcript (LAT) promoter 1 (LP1) is an inducible and cell type-specific promoter involved in regulating the production of an 8.3-kb primary LAT transcript during acute and latent infection of peripheral sensory neurons and during subsequent virus reactivation. A number of cis-acting regulatory elements have been identified in LP1, including two cyclic-AMP (cAMP) response element (CRE)-like sequences, designated CRE-1 and CRE-2. CRE-1 has previously been shown to confer cAMP responsiveness to LP1 and to regulate reactivation of HSV-1 from latency in vivo. A role for CRE-2 in modulating inducible activity is not yet as clear; however, it has been shown to support basal expression in neuronal cells in vitro. Electrophoretic mobility shift (EMS) analyses demonstrate that the LP1 CRE-like elements interact with distinct subsets of neuronal ATF/CREB and Jun/Fos proteins including CREB-1, CREB-2, ATF-1, and JunD. The factor-binding properties of each LP1 CRE element distinguish them from each other and from a highly related canonical CRE binding site and the TPA response element (TRE). LP1 CRE-1 shares binding characteristics of both a canonical CRE and a TRE. LP1 CRE-2 is more unusual in that it shares more features of a canonical CRE site than a TRE with two notable exceptions: it does not bind CREB-1 very well and it binds CREB-2 better than the canonical CRE. Interestingly, a substantial proportion of the C1300 neuroblastoma factors that bind to CRE-1 and CRE-2 have been shown to be immunologically related to JunD, suggesting that the AP-1 family of transcription factors may be important in regulating CRE-dependent LP1 transcriptional activity. In addition, we have demonstrated the two HSV-1 LP1 CRE sites to be unique with respect to their ability to bind neuronal AP1-related factors that are regulated by cAMP. These studies suggest that both factor binding and activation of bound factors may be involved in cAMP regulation of HSV-1 LP1 through the CRE elements, and indicate the necessity of investigating the expression and posttranslational modification of a variety of ATF/CREB and AP-1 factors during latency and reactivation.
authors.affiliation: Department of Microbiology and Immunology, The Pennsylvania State University College of Medicine, Hershey, PA 17033, USA. bwigdahl@psu.edu
authors.forename: S
authors.initials: S
authors.lastname: Millhouse
authors.forename: J J
authors.initials: JJ
authors.lastname: Kenny
authors.forename: P G
authors.initials: PG
authors.lastname: Quinn
authors.forename: V
authors.initials: V
authors.lastname: Lee
authors.forename: B
authors.initials: B
authors.lastname: Wigdahl
mesh_terms: D051697:Activating Transcription Factor 1; D002460:Cell Line; D004268:DNA-Binding Proteins; D015967:Gene Expression Regulation, Viral; D018259:Herpesvirus 1, Human / Q000502:physiology*; D006801:Humans; D010446:Peptide Fragments; D011401:Promoter Regions, Genetic; D011498:Protein Precursors; D011506:Proteins / Q000235:genetics*; D018808:Transcription Factor AP-1 / Q000235:genetics*; D014157:Transcription Factors / Q000235:genetics*; D053773:Transforming Growth Factor beta1; D017735:Virus Latency / Q000235:genetics*; D014779:Virus Replication / Q000235:genetics
chemical_list: D051697:Activating Transcription Factor 1; D004268:DNA-Binding Proteins; D010446:Peptide Fragments; D011498:Protein Precursors; D011506:Proteins; D018808:Transcription Factor AP-1; D014157:Transcription Factors; D053773:Transforming Growth Factor beta1