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)

Malfolded protein formation and perturbance of calcium homoeostasis results in the induction of the endoplasmic reticulum (ER) chaperone protein, namely the 78 kDa glucose-regulated protein (GRP78)/immunoglobulin heavy-chain binding protein. Various ER stress inducers can activate grp78, but signal transduction mechanisms are not well understood. We report in the present study that the induction of endogenous grp78 mRNA by the amino acid analogue azetidine (AzC) requires the integrity of a signal transduction pathway mediated by p38 mitogen-activated protein kinase (p38 MAPK). In contrast, induction of grp78 by thapsigargin that depletes the ER calcium storage can occur even when the p38 MAPK pathway is blocked. Treatment of cells with AzC results in the sustained activation of p38 MAPK. We identified an ER transmembrane activating transcription factor 6 (ATF6) as a target of p38 MAPK phosphorylation in AzC-treated cells. ATF6 undergoes proteolytic cleavage on AzC treatment, releasing a nuclear form that is an activator of the grp78 promoter. We show here that constitutively active mitogen-activated protein kinase kinase 6, a selective p38 MAPK activator, enhances the ability of the nuclear form of ATF6 to transactivate the grp78 promoter. Our results provide direct evidence that different ER stress inducers use diverse pathways to activate grp78 and that in addition to activation by proteolytic cleavage, ATF6 undergoes specific ER stress-induced phosphorylation. We propose that phosphorylation of ATF6 is a novel mechanism for augmenting its potential as a transcription activator.
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PMID:Requirement of the p38 mitogen-activated protein kinase signalling pathway for the induction of the 78 kDa glucose-regulated protein/immunoglobulin heavy-chain binding protein by azetidine stress: activating transcription factor 6 as a target for stress-induced phosphorylation. 1207 52

X-box binding protein 1 (XBP-1) is a key regulator required for cellular unfolded protein response (UPR) and plasma cell differentiation. In addition, involvement of XBP-1 in host cell-virus interaction and transcriptional regulation of viruses, such as human T-lymphotropic virus type 1 (HTLV-1), has been revealed recently. Two XBP-1 isoforms, XBP-1U and XBP-1S, which share an identical N-terminal domain, are present in cells. XBP-1S is a transcription activator while XBP-1U is the inactive isoform. Although the transactivation domain of XBP-1S has been identified within the XBP-1S-specific C-terminus, molecular mechanism of the transcriptional activation by XBP-1S still remains unknown. Here we report the interaction between p300/CBP-associated factor (PCAF) and XBP-1S through the C-terminal domain of XBP-1S. No binding between XBP-1U and PCAF is detected. In a cell-based reporter assay, overexpression of PCAF further stimulates the XBP-1S-mediated cellular and HTLV-1 transcription while knockdown of PCAF exhibits the opposite effect. Expression of endogenous XBP-1S cellular target genes, such as BiP and CHOP, is significantly inhibited when PCAF is knocked down. Furthermore, PCAF is recruited to the promoters of XBP-1S target genes in vivo, in a XBP-1S-dependent manner. Collectively, our results demonstrate that PCAF mediates the XBP-1S-dependent transcription through the interaction with XBP-1S.
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PMID:PCAF interacts with XBP-1S and mediates XBP-1S-dependent transcription. 2081 29