The Function of XBP1
Isoform 2: functions as a stress-inducible potent transcriptional activator during endoplasmic reticulum (ER) stress by inducing unfolded protein response (UPR) target genes via binding to the UPR element (UPRE). Up-regulates target genes encoding ER chaperones and ER-associated degradation (ERAD) components to enhance the capacity of productive folding and degradation mechanism, respectively, in order to maintain the homeostasis of the ER under ER stress (PubMed:11779464, PubMed:25239945). Plays a role in the production of immunoglobulins and interleukin-6 in the presence of stimuli required for plasma cell differentiation (By similarity). Induces phospholipid biosynthesis and ER expansion (PubMed:15466483). Contributes to the VEGF-induced endothelial cell (EC) growth and proliferation in a Akt/GSK-dependent and/or -independent signaling pathway, respectively, leading to beta-catenin nuclear translocation and E2F2 gene expression (PubMed:23529610). Promotes umbilical vein EC apoptosis and atherosclerotisis development in a caspase-dependent signaling pathway, and contributes to VEGF-induced EC proliferation and angiogenesis in adult tissues under ischemic conditions (PubMed:19416856, PubMed:23529610). Involved in the regulation of endostatin-induced autophagy in EC through BECN1 transcriptional activation (PubMed:23184933). Plays a role as an oncogene by promoting tumor progression: stimulates zinc finger protein SNAI1 transcription to induce epithelial-to-mesenchymal (EMT) transition, cell migration and invasion of breast cancer cells (PubMed:25280941). Involved in adipocyte differentiation by regulating lipogenic gene expression during lactation. Plays a role in the survival of both dopaminergic neurons of the substantia nigra pars compacta (SNpc), by maintaining protein homeostasis and of myeloma cells. Increases insulin sensitivity in the liver as a response to a high carbohydrate diet, resulting in improved glucose tolerance. Improves also glucose homeostasis in an ER stress- and/or insulin-independent manner through both binding and proteasome-induced degradation of the transcription factor FOXO1, hence resulting in suppression of gluconeogenic genes expression and in a reduction of blood glucose levels. Controls the induction of de novo fatty acid synthesis in hepatocytes by regulating the expression of a subset of lipogenic genes in an ER stress- and UPR-independent manner (By similarity). Associates preferentially to the HDAC3 gene promoter region in a disturbed flow-dependent manner (PubMed:25190803). Binds to the BECN1 gene promoter region (PubMed:23184933). Binds to the CDH5/VE-cadherin gene promoter region (PubMed:19416856). Binds to the ER stress response element (ERSE) upon ER stress (PubMed:11779464). Binds to the 5'-CCACG-3' motif in the PPARG promoter.
Protein names
Recommended name:
X-box-binding protein 1Short name:
XBP-1Alternative name(s):
Tax-responsive element-binding protein 5TREB-5
- RS2239815 (XBP1) ??
- RS2269577 (XBP1) ??
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Top Gene-Substance Interactions
XBP1 Interacts with These Diseases
Disease | Score |
Substances That Increase XBP1
Substances | Interaction | Organism | Category |
Substances That Decrease XBP1
Substances | Interaction | Organism | Category |
Advanced Summary
From NCBI Gene: Major affective disorder 7From UniProt: Major affective disorder 7 (MAFD7): A major psychiatric disorder that is characterized by severe mood swings, with fluctuation between two abnormal mood states (manic or major depressive episode). Mania is accompanied by symptoms of euphoria, irritability, or excitation, whereas depression is associated with low mood and decreased motivation and energy. [MIM:612371]
From NCBI Gene: This gene encodes a transcription factor that regulates MHC class II genes by binding to a promoter element referred to as an X box. This gene product is a bZIP protein, which was also identified as a cellular transcription factor that binds to an enhancer in the promoter of the T cell leukemia virus type 1 promoter. It may increase expression of viral proteins by acting as the DNA binding partner of a viral transactivator. It has been found that upon accumulation of unfolded proteins in the endoplasmic reticulum (ER), the mRNA of this gene is processed to an active form by an unconventional splicing mechanism that is mediated by the endonuclease inositol-requiring enzyme 1 (IRE1). The resulting loss of 26 nt from the spliced mRNA causes a frame-shift and an isoform XBP1(S), which is the functionally active transcription factor. The isoform encoded by the unspliced mRNA, XBP1(U), is constitutively expressed, and thought to function as a negative feedback regulator of XBP1(S), which shuts off transcription of target genes during the recovery phase of ER stress. A pseudogene of XBP1 has been identified and localized to chromosome 5. [provided by RefSeq, Jul 2008] From UniProt: Isoform 2: functions as a stress-inducible potent transcriptional activator during endoplasmic reticulum (ER) stress by inducing unfolded protein response (UPR) target genes via binding to the UPR element (UPRE). Up-regulates target genes encoding ER chaperones and ER-associated degradation (ERAD) components to enhance the capacity of productive folding and degradation mechanism, respectively, in order to maintain the homeostasis of the ER under ER stress (PubMed:11779464, PubMed:25239945). Plays a role in the production of immunoglobulins and interleukin-6 in the presence of stimuli required for plasma cell differentiation (By similarity). Induces phospholipid biosynthesis and ER expansion (PubMed:15466483). Contributes to the VEGF-induced endothelial cell (EC) growth and proliferation in a Akt/GSK-dependent and/or -independent signaling pathway, respectively, leading to beta-catenin nuclear translocation and E2F2 gene expression (PubMed:23529610). Promotes umbilical vein EC apoptosis and atherosclerotisis development in a caspase-dependent signaling pathway, and contributes to VEGF-induced EC proliferation and angiogenesis in adult tissues under ischemic conditions (PubMed:19416856, PubMed:23529610). Involved in the regulation of endostatin-induced autophagy in EC through BECN1 transcriptional activation (PubMed:23184933). Plays a role as an oncogene by promoting tumor progression: stimulates zinc finger protein SNAI1 transcription to induce epithelial-to-mesenchymal (EMT) transition, cell migration and invasion of breast cancer cells (PubMed:25280941). Involved in adipocyte differentiation by regulating lipogenic gene expression during lactation. Plays a role in the survival of both dopaminergic neurons of the substantia nigra pars compacta (SNpc), by maintaining protein homeostasis and of myeloma cells. Increases insulin sensitivity in the liver as a response to a high carbohydrate diet, resulting in improved glucose tolerance. Improves also glucose homeostasis in an ER stress- and/or insulin-independent manner through both binding and proteasome-induced degradation of the transcription factor FOXO1, hence resulting in suppression of gluconeogenic genes expression and in a reduction of blood glucose levels. Controls the induction of de novo fatty acid synthesis in hepatocytes by regulating the expression of a subset of lipogenic genes in an ER stress- and UPR-independent manner (By similarity). Associates preferentially to the HDAC3 gene promoter region in a disturbed flow-dependent manner (PubMed:25190803). Binds to the BECN1 gene promoter region (PubMed:23184933). Binds to the CDH5/VE-cadherin gene promoter region (PubMed:19416856). Binds to the ER stress response element (ERSE) upon ER stress (PubMed:11779464). Binds to the 5'-CCACG-3' motif in the PPARG promoter. Functions as a transcription factor during endoplasmic reticulum (ER) stress by regulating the unfolded protein response (UPR). Required for cardiac myogenesis and hepatogenesis during embryonic development, and the development of secretory tissues such as exocrine pancreas and salivary gland (By similarity). Involved in terminal differentiation of B lymphocytes to plasma cells and production of immunoglobulins (PubMed:11460154). Modulates the cellular response to ER stress in a PIK3R-dependent manner (PubMed:20348923). Binds to the cis-acting X box present in the promoter regions of major histocompatibility complex class II genes (PubMed:8349596). Involved in VEGF-induced endothelial cell (EC) proliferation and retinal blood vessel formation during embryonic development but also for angiogenesis in adult tissues under ischemic conditions. Functions also as a major regulator of the UPR in obesity-induced insulin resistance and type 2 diabetes for the management of obesity and diabetes prevention. Isoform 1: plays a role in the unconventional cytoplasmic splicing processing of its own mRNA triggered by the endoplasmic reticulum (ER) transmembrane endoribonuclease ENR1: upon ER stress, the emerging XBP1 polypeptide chain, as part of a mRNA-ribosome-nascent chain (R-RNC) complex, cotranslationally recruits its own unprocessed mRNA through transient docking to the ER membrane and translational pausing, therefore facilitating efficient IRE1-mediated XBP1 mRNA isoform 2 production (PubMed:19394296, PubMed:21233347). In endothelial cells (EC), associated with KDR, promotes IRE1-mediated XBP1 mRNA isoform 2 productions in a vascular endothelial growth factor (VEGF)-dependent manner, leading to EC proliferation and angiogenesis (PubMed:23529610). Functions as a negative feed-back regulator of the potent transcription factor XBP1 isoform 2 protein levels through proteasome-mediated degradation, thus preventing the constitutive activation of the ER stress response signaling pathway (PubMed:16461360, PubMed:25239945). Inhibits the transactivation activity of XBP1 isoform 2 in myeloma cells (By similarity). Acts as a weak transcriptional factor (PubMed:8657566). Together with HDAC3, contributes to the activation of NFE2L2-mediated HMOX1 transcription factor gene expression in a PI(3)K/mTORC2/Akt-dependent signaling pathway leading to EC survival under disturbed flow/oxidative stress (PubMed:25190803). Binds to the ER stress response element (ERSE) upon ER stress (PubMed:11779464). Binds to the consensus 5'-GATGACGTG[TG]N(3)[AT]T-3' sequence related to cAMP responsive element (CRE)-like sequences (PubMed:8657566). Binds the Tax-responsive element (TRE) present in the long terminal repeat (LTR) of T-cell leukemia virus type 1 (HTLV-I) and to the TPA response elements (TRE) (PubMed:2321018, PubMed:2196176, PubMed:1903538, PubMed:8657566). Associates preferentially to the HDAC3 gene promoter region in a static flow-dependent manner (PubMed:25190803). Binds to the CDH5/VE-cadherin gene promoter region (PubMed:19416856).
Conditions with Increased Gene Activity
Condition | Change (log2fold) | Comparison | Species | Experimental variables | Experiment name |
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Conditions with Decreased Gene Activity
Condition | Change (log2fold) | Comparison | Species | Experimental variables | Experiment name |
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Technical
The following transcription factors affect gene expression:
Tissue specificity:
Expressed in plasma cells in rheumatoid synovium (PubMed:11460154). Over-expressed in primary breast cancer and metastatic breast cancer cells (PubMed:25280941). Isoform 1 and isoform 2 are expressed at higher level in proliferating as compared to confluent quiescent endothelial cells (PubMed:19416856).
Induction:
Isoform 1 is up-regulated at the recovery phase of the endoplasmic reticulum (ER) stress response and isoform 2 is up-regulated early during the ER stress response and gradually decreased at later phase of ER stress (PubMed:16461360). Isoform 1 and isoform 2 are down-regulated by laminar flow but up-regulated by disturbed flow in umbilical vein endothelial cells in vitro (at protein level) (PubMed:19416856). Down-regulated by the B-cell-specific transcription factor PAX5 (PubMed:8627152). Up-regulated by interleukin IL-6 in myeloma cells (PubMed:10375612). Up-regulated during plasma-cell differentiation, either through the CD40 receptor signaling pathway or mitogens such as lipopolysaccharide (LPS) (PubMed:11460154). Isoform 1 and isoform 2 are down-regulated by laminar flow but up-regulated by disturbed flow in umbilical vein endothelial cells in vitro (PubMed:25190803). Isoform 2 is up-regulated early during the ER stress response in a ATF6-dependent manner (PubMed:11779464, PubMed:17110785, PubMed:16461360). Isoform 2 is up-regulated by endostatin in a ERN1-dependent manner (PubMed:23184933). Isoform 2 is transiently up-regulated by the mitogenic vascular endothelial growth factor (VEGF) in endothelial cells (PubMed:23529610).
Molecular Function:
- Chromatin Dna Binding
- Core Promoter Binding
- Dna Binding
- Enhancer Sequence-Specific Dna Binding
- Estrogen Receptor Binding
- Protease Binding
- Protein Heterodimerization Activity
- Protein Homodimerization Activity
- Protein Kinase Binding
- Rna Polymerase Ii Regulatory Region Sequence-Specific Dna Binding
- Rna Polymerase Ii Transcription Factor Activity, Sequence-Specific Dna Binding
- Transcription Factor Activity, Sequence-Specific Dna Binding
- Transcription Regulatory Region Dna Binding
- Ubiquitin Protein Ligase Binding
Biological Processes:
- Adipose Tissue Development
- Angiogenesis
- Atf6-Mediated Unfolded Protein Response
- Autophagy
- Cell Growth
- Cellular Response To Amino Acid Stimulus
- Cellular Response To Fluid Shear Stress
- Cellular Response To Fructose Stimulus
- Cellular Response To Glucose Starvation
- Cellular Response To Glucose Stimulus
- Cellular Response To Insulin Stimulus
- Cellular Response To Interleukin-4
- Cellular Response To Laminar Fluid Shear Stress
- Cellular Response To Lipopolysaccharide
- Cellular Response To Nutrient
- Cellular Response To Oxidative Stress
- Cellular Response To Peptide Hormone Stimulus
- Cellular Response To Vascular Endothelial Growth Factor Stimulus
- Cellular Triglyceride Homeostasis
- Cholesterol Homeostasis
- Endoplasmic Reticulum Unfolded Protein Response
- Endothelial Cell Proliferation
- Epithelial Cell Maturation Involved In Salivary Gland Development
- Exocrine Pancreas Development
- Fatty Acid Biosynthetic Process
- Fatty Acid Homeostasis
- Immune Response
- Intrinsic Apoptotic Signaling Pathway In Response To Endoplasmic Reticulum Stress
- Ire1-Mediated Unfolded Protein Response
- Liver Development
- Muscle Organ Development
- Negative Regulation Of Apoptotic Process
- Negative Regulation Of Endoplasmic Reticulum Stress-Induced Intrinsic Apoptotic Signaling Pathway
- Negative Regulation Of Endoplasmic Reticulum Unfolded Protein Response
- Negative Regulation Of Erk1 And Erk2 Cascade
- Negative Regulation Of Myotube Differentiation
- Negative Regulation Of Pathway-Restricted Smad Protein Phosphorylation
- Negative Regulation Of Transcription From Rna Polymerase Ii Promoter
- Negative Regulation Of Transforming Growth Factor Beta Receptor Signaling Pathway
- Neuron Development
- Organelle Organization
- Phosphatidylinositol 3-Kinase Signaling
- Positive Regulation Of Angiogenesis
- Positive Regulation Of Autophagy
- Positive Regulation Of B Cell Differentiation
- Positive Regulation Of Cell Migration
- Positive Regulation Of Cell Proliferation
- Positive Regulation Of Endoplasmic Reticulum Unfolded Protein Response
- Positive Regulation Of Endothelial Cell Apoptotic Process
- Positive Regulation Of Er-Associated Ubiquitin-Dependent Protein Catabolic Process
- Positive Regulation Of Fat Cell Differentiation
- Positive Regulation Of Hepatocyte Proliferation
- Positive Regulation Of Histone Methylation
- Positive Regulation Of Immunoglobulin Production
- Positive Regulation Of Immunoglobulin Secretion
- Positive Regulation Of Interleukin-6 Secretion
- Positive Regulation Of Lactation
- Positive Regulation Of Mhc Class Ii Biosynthetic Process
- Positive Regulation Of Phospholipid Biosynthetic Process By Positive Regulation Of Transcription From Rna Polymerase Ii Promoter
- Positive Regulation Of Plasma Cell Differentiation
- Positive Regulation Of Proteasomal Protein Catabolic Process
- Positive Regulation Of Protein Acetylation
- Positive Regulation Of Protein Kinase B Signaling
- Positive Regulation Of Protein Phosphorylation
- Positive Regulation Of T Cell Differentiation
- Positive Regulation Of Tor Signaling
- Positive Regulation Of Transcription Factor Import Into Nucleus
- Positive Regulation Of Transcription From Rna Polymerase Ii Promoter
- Positive Regulation Of Transcription From Rna Polymerase Ii Promoter In Response To Endoplasmic Reticulum Stress
- Positive Regulation Of Transcription From Rna Polymerase Ii Promoter Involved In Unfolded Protein Response
- Positive Regulation Of Vascular Associated Smooth Muscle Cell Migration
- Positive Regulation Of Vascular Smooth Muscle Cell Proliferation
- Positive Regulation Of Vascular Wound Healing
- Protein Destabilization
- Protein Transport
- Regulation Of Autophagy
- Regulation Of Protein Stability
- Response To Endoplasmic Reticulum Stress
- Response To Insulin-Like Growth Factor Stimulus
- Sterol Homeostasis
- Transcription From Rna Polymerase Ii Promoter
- Ubiquitin-Dependent Protein Catabolic Process
- Vascular Endothelial Growth Factor Receptor Signaling Pathway