Induction of the Mammalian GRP78/BiP Gene by Ca²⁺ Depletion and Formation of Aberrant Proteins: Activation of the Conserved Stress-Inducible grp Core Promoter Element by the Human Nuclear Factor YY1

Abstract

Previously, we have identified a constitutive nuclear factor, p70CORE, from HeLa cell nuclear extract which interacts specifically with the stress-inducible change region (SICR) of the grp78 promoter. Here we report that p70CORE is identical to YY1, a member of the GLI zinc finger family, by criteria of biochemical properties including apparent molecular weight, binding site homology, immunoreactivity, and affinity purification. Recombinant YY1 binds the double-stranded SICR with high specificity but has no affinity for its singlestranded form. In cotransfection studies, YY1 specifically enhanced the transcriptional activation of the grp78 promoter under a variety of stress conditions: depletion of the endoplasmic reticulum calcium stores, protein glycosylation block, and formation of aberrant proteins by azetidine treatment. In contrast, YY1 has minimal effect on the stress induction of the hsp70 promoter. YY1 enhancement of the grp78 stress response is dependent on its DNA-binding domain, with little effect on the basal expression of the promoter. The effect of YY1 transactivation may be mediated by the highly conserved grp78 core element. This is the first example of the ubiquitous factor YY1 involved in regulating inducible gene expression and its involvement in mediating stress signals generated from the endoplasmic reticulum to the nucleus.

Stress signaling from the lumen of the endoplasmic reticulum: coordination of gene transcriptional and translational controls

“…Two critical cis-acting elements identified, CORE and C1, were found to bind the zinc-finger transcription factors YY1 (Li et al 1997a,b) and the histone-fold motif containing CCAAT-binding transcription factor CBF/NF-Y (Roy and Lee 1995;Roy et al 1996), respectively. Overexpression of YY1 had little effect on basal expression from the BiP promoter but enhanced induction by ER stress (Li et al 1997b). However, the binding activity of neither CBF/NF-T nor YY1 changed upon ER stress, suggesting that DNA-binding activity of these factors is not regulated by ER stress.…”

Suppression of grp78 Core Promoter Element-Mediated Stress Induction by the dbpA and dbpB (YB-1) Cold Shock Domain Proteins

“…In the accompanying paper, we show that p70CORE is identified as the human nuclear transcription factor YY1 (19). Here we report that our screening yielded two clones which encode the Y-box proteins dbpA and dbpB, the latter of which is commonly referred to as YB-1 (5,39).…”

“…The conditions used for transfection into NIH 3T3 cells were described elsewhere (19). All transfections included a simian virus 40 promoter-driven ␤-galactosidase reporter plasmid (2 g) to control for transfection efficiency (40).…”

“…As in the case of YY1/p70CORE (19), its binding site resides in the SICR. Whereas YY1 has affinity for double-stranded templates, YB-1 and dbpA much prefer the noncoding strand of the core sequence.…”

In Vivo Regulation of Grp78/BiP Transcription in the Embryonic Heart

“…The N9 GC-rich region of the ERSE binds the transcription factor TFII-I, which is autoregulated by ER stress and tyrosine phosphorylation and is known to facilitate protein-protein interactions (7,8). YY1 (Ying Yang 1), a 65-kDa zinc finger transcription factor, binds to the CCACG motif and activates the Grp78 promoter under ER stress (9,10). YY1 is ubiquitously expressed during mouse development, and homozygous deletion of YY1 is embryonically lethal (11).…”