Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P11021 (BiP)
 2,049 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Mammalian GRP78/BiP is a stress-inducible 78-kDa endoplasmic reticulum (ER) protein with molecular chaperone and calcium-binding properties. The transactivation of grp78 by the calcium ionophore A23187 provides a model system with which to study the signal transduction that allows mammalian cells to sense calcium depletion in intracellular stores and activate transcription of specific genes. Linker-scanning mutation analysis of the grp78 promoter reveals that the single most important regulatory element is C1, which contains a CCAAT motif most proximal to the TATA sequence. The C1 element is crucial for mediating the stimulatory effects by the upstream regulatory elements under normal and stress conditions. In this report, we establish that the heteromeric CCAAT-binding factor CBF is the major component of the C1-binding factor (C1F) in human cells. A GGAGG motif flanking the CCAAT sequence also contributes to high-affinity C1F/CBF binding. We show here that the binding of C1F in vitro is sensitive to the concentration of calcium ions. At high calcium ion concentrations, the C1F-binding activity is lower because of a higher dissociation rate. This binding characteristic correlates with the induction of grp78 transcription in response to the depletion of intracellular calcium stores. The strikingly similar behavior of C1F from nuclear extracts of control and A23187-treated cells further suggests that C1F itself does not undergo any major inherent changes after calium depletion stress. Rather, its binding property could be modulated by the immediate calcium ionic environment in stressed and nonstressed cells. On the basis of the in vitro and in vivo site occupancies of C1F and other stress-inducible changes of upstream regulatory complexes, we present a model to explain how C1F and other upstream factors can synergistically activate grp78 transcription in calcium-depleted cells.
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PMID:Transduction of calcium stress through interaction of the human transcription factor CBF with the proximal CCAAT regulatory element of the grp78/BiP promoter. 789 20

Transcription of the gene encoding GRP78/BiP, a calcium-binding molecular chaperone localized in the endoplasmic reticulum, is induced in mammalian cells through gradual depletion of the intracellular calcium stores. The multimeric CCAAT binding factor, CBF/NF-Y, binds to the most proximal CCAAT regulatory element (C1) of the grp78 promoter required for both basal level expression and stress response. Using an in vitro transcription system, we show through factor competition and immunodepletion that the grp78 C1-mediated enhancement of transcription requires primarily CBF. Correlating with the previous observation that CBF binding to the 78C1 site is enhanced by EGTA and EDTA, these divalent cation chelators specifically stimulate 78C1-directed transcription. In contrast, increasing amounts of calcium ions are inhibitory. These results provide evidence that CBF is functionally important in transactivating the grp78 C1 transcriptional activity, and suggest a possible mechanism by which grp78 transcription is stimulated by calcium depletion. We further discovered that in addition to binding CBF, both the 78C1 element and the CBF binding site of the alpha2(I) collagen promoter interact weakly with the multifunctional transcription factor YY1. Our studies show that the binding sites for CBF and YY1 are distinct for the two promoter sites, suggesting that YY1 and other interacting factors could exert differential effects on individual promoters bearing the same CBF site.
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PMID:Calcium-sensitive transcriptional activation of the proximal CCAAT regulatory element of the grp78/BiP promoter by the human nuclear factor CBF/NF-Y. 891 May 50