CREB-H: a novel mammalian transcription factor belonging to the CREB/ATF family and functioning via the box-B element with a liver-specific expression

Abstract

The expression of liver-specific genes is regulated by unequivocally allocated transcription factors via proper responsible elements within their promoters. We identified a novel transcription factor, CREB-H, and found that its expression was restricted in the liver among 16 human tissues tested. A region of CREB-H exhibited significant homology to the basic leucine zipper (b-Zip) domain of members of the CREB/ATF family: mammalian LZIP and Drosophila BBF-2 that binds to box-B, a Drosophila enhancer modulating the fat-body-specific gene expression. CREB-H contained a hydrophobic region representing a putative transmembrane domain, like LZIP. Constructing a variety of CREB-H fusion proteins with the GAL4 DNA-binding domain disclosed that CREB-H functioned as a transcriptional activator and its N-terminal 149 amino acids accounted for the activation ability. Gel mobility sift assays revealed that CREB-H did not bind to the C/EBP, AP-1 and NF-kappaB elements but specifically bound to CRE and the box-B element. Luciferase reporter assays demonstrated that like BBF-2, CREB-H activated transcription via the box-B element and that a deletion of the putative transmembrane domain increased the activation of reporter expression significantly. Furthermore, a fusion protein of GFP and full-length CREB-H was localized in reticular structures surrounding the nucleus, whereas a fusion protein of GFP and a deletion mutant lacking the putative transmembrane domain was mainly in the nucleus. These findings suggest that CREB-H plays an important role in transcriptional regulation of genes specifically expressed in the liver, and that the putative transmembrane domain may be associated with modulation of its function as the transcriptional activator.

Stress hypERactivation in the β-cell

“…100 CREBH has also been identified as a hepatocyte-specific UPR transducer. 101 Together, the current research on WFS1 demonstrates that indeed there is a link between ER stress and the pathogenesis of various forms of diabetes: genetic, type 1 and type 2. Thus, WFS1 may be an important target for diabetes prevention and/or therapy.…”

Herpes simplex virus-1 disarms the unfolded protein response in the early stages of infection

“…Activation of these elements can lead to induction of chaperones, translational attenuation, ER-associated degradation (ERAD) of accumulated proteins, and ultimately cell death by apoptosis (reviewed in Bernales et al 2006;Tabas and Ron 2011;Schroder 2008;Malhotra and Kaufman 2007;Mori 2009). Recently, a family of highly similar basic region leucine zipper (bZIP) proteins exemplified by CREB3/Luman (Liang et al 2006;Raggo et al 2002;Lu et al 1997;Freiman and Herr 1997) has also been implicated in the UPR in specific cell types, including CREB3L1 (Chin et al 2005;Omori et al 2001), CREB3L2 (Storlazzi et al 2003), CREB3L3 (Honma et al 1999), and CREB3L4 (Cao et al 2002;Stirling and O'Hare 2006;Qi et al 2002;Stelzer and Don 2002;Nagamori et al 2005).…”

cAMP response element binding protein H mediates fenofibrate-induced suppression of hepatic lipogenesis

“…Cyclic AMP response element binding protein H (CREBH) is a membrane-bound transcription factor possessing a basic leucine zipper (bZIP) domain and a domain that resides within the endoplasmic reticulum (ER) [21,22]. CREBH is cleaved on ER stress and activates the expression of acute response genes [23].…”