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.

The Addition of Tumor Necrosis Factor plus Beta Interferon Induces a Novel Synergistic Antiviral State against Poxviruses in Primary Human Fibroblasts

“…Both of these proteins repress transcription from promoters containing a consensus cAMP response element (CRE) (5Ј-GTGACGT [AC][AG]-3Ј) (12). The CRE is found in a wide variety of both cellular and viral promoters (26,44,49). The altered kinetic expression of IL-8 and IFNAR2 (Fig.…”

Crosstalk of CREB and Fos/Jun on a single cis-element: transcriptional repression of the steroidogenic acute regulatory protein gene

“…CREB/ATF and Fos/Jun are members of the activator proteins (APs), which interact with themselves or each other to form selective dimers that bind to closely related CRE and AP-1 sequences and result in varied transcriptional responses (Dwarki et al 1990, Hai & Curran 1991, Millhouse et al 1998, Rutberg et al 1999. CREB binds to DNA as a homodimer, is activated upon phosphorylation at Ser133 by several kinases including protein kinase A, and interacts with the CREB-binding protein (CBP; Chrivia et al 1993, Parker et al 1996, Shaywitz & Greenberg 1999, Richards 2001.…”

Inducible Cyclic AMP Early Repressor Produces Reactivation of Latent Herpes Simplex Virus Type 1 in Neurons In Vitro

“…ICER may have an important function in second-messengermediated HSV-1 reactivation, which appears to involve the downregulation of LAT expression. CREs in the LAT promoter appear to be important for reactivation (4,13,15,17,24). The results suggest that signals that induce phosphorylation of CREB have a role in the mechanism of reactivation, which may include repression of LAT promoter activity.…”

“…The CRE at Ϫ43 has been shown to be cAMP responsive in transient-transfection assays, and mutagenesis of this CRE results in reduced reactivation in rabbits latently infected with the recombinant virus (4). Characterization of the CRE at Ϫ85 is primarily limited to the observation that members of the CREB/ATF family can interact with the promoter in electrophoretic mobility shift assays (13,17). Based on this evidence, it is possible that CREs in the LAT promoter may have a role in signaling that results in the reactivation of latent HSV-1.…”