Disease relevance of XBP1

• After exposure to hypoxia, apoptosis increased and clonogenic survival decreased in XBP1-deficient cells [1].
• Several recent studies have demonstrated that XBP-1 mRNA expression is associated with ERalpha status in breast tumors [2].
• Overall, flaviviruses trigger the XBP1 signaling pathway and take advantage of this cellular response to alleviate virus-induced cytotoxicity [3].
• Analysis in mouse insulinoma MIN6 cells revealed that methoxyflavones mildly activated the eukaryotic initiation factor 2alpha and nuclear factor erythroid 2-related factor pathways, but not the XBP1 pathway, and induced downstream genes, including glucose-regulated protein (GRP) 78, a molecular chaperone in the ER [4].
• Identification of compounds that target the activity of IRE1 alpha/XBP-1 may yield novel therapies for the treatment of multiple myeloma and other malignancies that rely on an intact UPR [5].

Psychiatry related information on XBP1

• Impaired feedback regulation of XBP1 as a genetic risk factor for bipolar disorder [6].
• Recently, a polymorphism of the XBP1 gene (-116 C/G) was observed to play a significant role in the development of bipolar mood disorder from the Japanese population [7].

High impact information on XBP1

• Lack of support for a genetic association of the XBP1 promoter polymorphism with bipolar disorder in probands of European origin [8].
• Valproate, one of three mood stabilizers, rescued the impaired response by inducing ATF6, the gene upstream of XBP1 [6].
• Here we identified XBP1, a pivotal gene in the endoplasmic reticulum (ER) stress response, as contributing to the genetic risk factor for bipolar disorder [6].
• A polymorphism (-116C-->G) in the promoter region of XBP1, affecting the putative binding site of XBP1, was significantly more common in Japanese patients (odds ratio = 4.6) and overtransmitted to affected offspring in trio samples of the NIMH Bipolar Disorder Genetics Initiative [6].
• One of these proteins, defined as an X box binding protein (RF-X), is specifically missing in cells from class II deficient SCID patients [9].

Chemical compound and disease context of XBP1

• A possible association between the [minus sign]116C/G single nucleotide polymorphism of the XBP1 gene and lithium prophylaxis in bipolar disorder [10].

Biological context of XBP1

• We show that pXBP1 unspliced (U) encoded in XBP1 pre-mRNA was constitutively expressed and markedly accumulated at the recovery phase of ER stress. pXBP1(U) contained the nuclear exclusion signal instead of the transcriptional activation domain and shuttled between the nucleus and the cytoplasm [11].
• We show here that XBP1 expression is elevated in cells carrying HCV subgenomic replicons, but XBP1 trans-activating activity is repressed [12].
• X-box binding protein 1 (XBP1), a critical gene in the endoplasmic reticulum stress response, is located on chromosome 22q12, which has been linked with bipolar disorders in several studies [13].
• XBP1 promoter might drive gene expression with cell-type specificity [14].
• The activity of chloramphenicol acetyltransferase(CAT), which reflects the transcription activation of the XBP1 gene promoter, was detected by ELISA after 48 hours of transfection [14].

Anatomical context of XBP1

• XBP1 is required for the terminal differentiation of B lymphocytes into plasma cells, and IRE1 also participates in this differentiation event [15].
• IRE1alpha-null MEFs, a cell line with a defective IRE1-XBP1 pathway, show elevated levels of HCV IRES-mediated translation [12].
• Therefore, HCV may suppress the IRE1-XBP1 pathway to not only promote HCV expression but also to contribute to the persistence of the virus in infected hepatocytes [12].
• Whereas, in human tissues, weak splicing of XBP1 mRNA was detected only in the C1264R mutant, all rat thyroids including wild-type contained significant amounts of the spliced form of XBP1 as opposed to human liver and rat brain tissues, implying the existence of a previously unknown tissue-specific regulation of XBP1 processing [16].
• BACKGROUND: Human X-box binding protein 1 (hXBP-1) is a transcription factor essential for hepatocyte growth as well as for plasma cell differentiation. hXBP-1 also binds to cis-elements of human T cell leukemia virus and human major histocompatibility complex genes [17].

Associations of XBP1 with chemical compounds

• Upon the accumulation of unfolded proteins in the mammalian endoplasmic reticulum (ER), X-box binding protein 1 (XBP1) premessenger RNA (premRNA) is converted to mature mRNA by unconventional splicing that is mediated by the endonuclease inositol-requiring enzyme 1 [11].
• VST also inhibited the production of the UPR transcriptional activators XBP1 and ATF4 during glucose deprivation [18].
• We investigated the association between the -116C/G polymorphism of the XBP1 gene and lithium response in Japanese patients with BPD [10].
• Further, the transactivation domain of hXBP-1 encompasses a large C-terminal region of the protein, containing domains rich in glutamine, serine and threonine, and proline and glutamine residues, as shown in transient transfection experiments using hXBP-1-GAL4 fusion proteins and a reporter gene under the control of GAL4-binding sites [19].
• The X-box binding protein 1 (XBP1) gene is not associated with methamphetamine dependence [20].

Physical interactions of XBP1

• Further gel-retardation analysis has demonstrated that hXBP-1 also binds to HLA-DPB X2 but not to other X2 sequences [21].

Regulatory relationships of XBP1

• Spliced XBP1 mRNA induced by activated IRE1 is translated to the protein, a potent transcription factor that induces BiP expression [22].
• CD72-mediated suppression of human naive B cell differentiation by down-regulating X-box binding protein 1 [23].
• IL-6 as well as IL-10 up-regulate XBP-1 [24].
• XBP1 induces WFS1 through an endoplasmic reticulum stress response element-like motif in SH-SY5Y cells [25].

Other interactions of XBP1

• Key moleculars as XBP1 and GRP78/Bip were activated and up-regulated, which suggested the UPR pathway was activated [26].
• HCV NS4B activated the IRE1 pathway, as indicated by splicing of X box-binding protein (Xbp-1) mRNA [27].
• Key regulatory factors and their target genes are differentially expressed among these subgroups, including BCL-6, Blimp-1, and XBP1 [28].
• In CHEC cells where Derlin-1 was down-regulated, increased expression of the immunoglobulin heavy chain-binding protein (Bip) and UPR-specific splicing of X-box DNAbinding protein 1 (XBP1) mRNA were detected, as compared with that in other tested cells, indicating that UPR was activated [29].
• TREB7 and TREB36 protected all three repeats of the 21 bp, but TREB5 protected only the second repeat [30].

Analytical, diagnostic and therapeutic context of XBP1

• A case-control study provides evidence of association for a functional polymorphism -197C/G in XBP1 to schizophrenia and suggests a sex-dependent effect [31].
• We present microbiological growth assays for the UPR, reporter assays for UPR signaling, direct techniques to measure UPR activation in vivo, methods to study translation of HAC1 mRNA, and in vitro cleavage and ligation of HAC1 and XBP1 mRNA [32].
• We have developed a new method to detect the spliced XBP1 mRNA by means of real-time PCR and we compared the result with measurements of the expression of the ER stress inducible gene BiP [22].
• An electrophoretic mobility shift assay suggested that XBP1 does not directly bind to this sequence [25].
• Here we examined the target genes of XBP1, using DNA microarray analysis in SH-SY5Y cells transfected with an XBP1-expressing vector [25].

References