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.

Screening of the Human Kinome Identifies MSK1/2-CREB1 as an Essential Pathway Mediating Kaposi's Sarcoma-Associated Herpesvirus Lytic Replication during Primary Infection

“…*, **, and ***, P values of Ͻ0.05, Ͻ0.01, and Ͻ0.001, respectively; NS, not significant. neurons as well as reactivation from latency (30). KSHV has been shown to activate a number of signaling pathways, such as MAPK and NF-B pathways, at the early stage of primary infection, and these pathways in return facilitate KSHV infection and gene expression (9,10,15,52).…”

Role of basic leucine zipper proteins in transcriptional regulation of the steroidogenic acute regulatory protein gene

“…Analyses of the human genome have identified 53 genes that contain bZIP motifs with the potential to form over 2700 dimers (Poels and Vanden Broeck, 2004; Vinson et al, 2006; Kehat et al, 2006). As such, many forms of CREB/ATF-1, Fos/Jun and C/EBP have the potential to dimerize with either themselves or each other, which can result in a continuum of transcription factors with varied activities (Hai and Curran, 1991; Masquilier and Sassone-Corsi, 1992; Meyer and Habener, 1993; Millhouse et al, 1998; Rutberg et al, 1999). Several examples of dimer combinations that are known to form among CREB/CREM/ATF-1, Fos/Jun and C/EBPs are provided in Table 1.…”

“…The CRE/ATF (TGACGTGA) and AP-1/TRE (TGA(C/G)TCA) sequence motifs are two of the major classes of regulatory elements that contribute to transcriptional regulation by recruiting bZIP proteins in response to a variety of extracellular signals (Sassone-Corsi et al, 1990; Hai and Curran, 1991; Montminy, 1997). The difference between the CRE and AP-1 consensus sequences is only one nucleotide, and thus overlap and/or crosstalk can occur affecting the versatility of the transcriptional response to signal transduction (Hai and Curran, 1991; Masquilier and Sassone-Corsi, 1992; Millhouse et al, 1998; Rutberg et al, 1999). Indeed, CREB/CREM/ATF-1, Fos/Jun and C/EBPβ families of proteins bind to an overlapping motif in the StAR promoter, and confer the potential for multiple effects in regulating transcription of the StAR gene (Manna et al, 2002, 2003a,b, 2004; Hiroi et al, 2004a; Clem et al, 2005; Silverman et al, 2006; Sugawara et al, 2006; Manna and Stocco, 2007, 2008; Yivgi-Ohana et al, 2008).…”

“…Indeed, CREB/CREM/ATF-1, Fos/Jun and C/EBPβ families of proteins bind to an overlapping motif in the StAR promoter, and confer the potential for multiple effects in regulating transcription of the StAR gene (Manna et al, 2002, 2003a,b, 2004; Hiroi et al, 2004a; Clem et al, 2005; Silverman et al, 2006; Sugawara et al, 2006; Manna and Stocco, 2007, 2008; Yivgi-Ohana et al, 2008). Several lines of evidence indicate that CRE DNA binding proteins heterodimerize with Fos/Jun and repress AP-1 transcriptional activity (Masquilier and Sassone-Corsi, 1992; Millhouse et al, 1998; Rutberg et al, 1999). On the other hand, heterodimers formed between C/EBPs and CREB/ATF can bind to CRE site(s) and activate transcription (Ross et al, 2001).…”

“…We have recently demonstrated that CREB and c-Fos/c-Jun can form heterodimers that bind to the closely related CRE2/AP-1 sequence with an altered DNA binding affinity that results in the repression of StAR gene transcription (Manna and Stocco, 2007). It has been demonstrated that bZIP heterodimers have distinct binding activities and functional specificities than those of their parental homodimers, and that they can bind to related CRE and/or AP-1 site depending on the dimer composition (Hai and Curran, 1991; Masquilier and Sassone-Corsi, 1992; Millhouse et al, 1998; Ross et al, 2001; Ramji, 2002 #1400). Whereas CREB/ATF and C/EBP and/or Fos/Jun and C/EBP dimers influence transcription of many genes, the role of these events in the regulation of StAR gene expression requires further investigation (Fig.…”