X-box binding protein 1, also known as XBP1, is a human
gene.cite web | title = Entrez Gene: XBP1 X-box binding protein 1| url = http://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=7494| accessdate = ] cite journal | author = Liou HC, Boothby MR, Finn PW, Davidon R, Nabavi N, Zeleznik-Le NJ, Ting JP, Glimcher LH | title = A new member of the leucine zipper class of proteins that binds to the HLA DR alpha promoter | journal = Science (journal) | volume = 247 | issue = 4950 | pages = 1581–4 | year = 1990 | month = March | pmid = 2321018 | doi = 10.1126/science.2321018 | url = | issn = ] The XBP1 gene is located on chromosome22 while a pseudogenehas been identified and localized to chromosome 5.cite journal | author = Liou HC, Eddy R, Shows T, Lisowska-Grospierre B, Griscelli C, Doyle C, Mannhalter J, Eibl M, Glimcher LH | title = An HLA-DR alpha promoter DNA-binding protein is expressed ubiquitously and maps to human chromosomes 22 and 5 | journal = Immunogenetics | volume = 34 | issue = 5 | pages = 286–92 | year = 1991 | pmid = 1718857 | doi = | url = | issn = ]
The X-box binding protein 1 (XBP-1) is a
transcription factorcontaining a bZIP domain. It was first identified by its ability to bind to the X-box, a conserved transcriptional element in the promoterof the human leukocyte antigen(HLA) DR alpha.
MHC class II gene regulation
The expression of this protein is required for the transcription of a subset of class II major histocompatibility genes.cite journal | author = Ono SJ, Liou HC, Davidon R, Strominger JL, Glimcher LH | title = Human X-box-binding protein 1 is required for the transcription of a subset of human class II major histocompatibility genes and forms a heterodimer with c-fos | journal = Proc. Natl. Acad. Sci. U.S.A. | volume = 88 | issue = 10 | pages = 4309–12 | year = 1991 | month = May | pmid = 1903538 | pmc = 51648 | url = http://www.pnas.org/content/88/10/4309.abstract | issn = ] Furthermore Xbp1 heterodimerizes with other bZIP transcription factors such as
Xbp1 expression is controlled by the
cytokineIL-4 and the antibody IGHM.cite journal | author = Iwakoshi NN, Lee AH, Vallabhajosyula P, Otipoby KL, Rajewsky K, Glimcher LH | title = Plasma cell differentiation and the unfolded protein response intersect at the transcription factor XBP-1 | journal = Nat. Immunol. | volume = 4 | issue = 4 | pages = 321–9 | year = 2003 | month = April | pmid = 12612580 | doi = 10.1038/ni907 | url = | issn = ] Xbp1 in turn controls the expression of IL-6 which promotes plasma cell growth and of immunoglobulins in B lymphocytes.
Plasma cell differentiation
XBP-1 is also essential for differentiation of
plasma cells (a type of antibody secreting immune cell). This differentiation requires not only the expression of XBP-1 but the expression of the spliced isoform of XBP-1s.
This protein has also been identified as a cellular transcription factor that binds to an enhancer in the promoter of the
T cell leukemia virustype 1 promoter. The generation of XBP-1s during plasma cell differentiation also seems to be the cue for Kaposi's sarcoma-associated herpesvirusand Epstein Barr virusreactivation from latency.
Endoplasmic reticulum stress response
XBP-1 is upregulated as part of the
endoplasmic reticulum(ER) stress response, the unfolded protein response(UPR). This increase in transcription requires an ER stress response consensus binding element in the promoter. XBP-1u is ubiquitously expressed but under conditions of ER-stress, the XBP-1u mRNAis processed by IRE1. Activated IRE1 oligomerises and activates its ribonucleasedomain through auto (self) phosphorylation. Because the lumen of the ER is continuous with the perinuclear space, the activated ribonucleasedomains can penetrate the inner leaflet of the nuclear envelope. Within the nucleus, activated IRE1 catalyses the excision of a 26 nucleotide unconventional intronfrom XBP-1 mRNA, in a manner mechanistically similar to pre-tRNA splicing. Removal of this intron causes a frame shift in the XBP-1 coding sequence resulting in the translation of a 371 amino acid, 54 kDa, XBP-1s isoformrather than the 261 amino acid, 33 kDa, XBP-1u isoform.
single nucleotide polymorphism, C-116G, in the promoter region of "XBP1" has been examined for possible association with personality traits. None was found.cite journal | author = Kusumi I, Masui T, Kakiuchi C, Suzuki K, Akimoto T, Hashimoto R, Kunugi H, Kato T, Koyama T | title = Relationship between XBP1 genotype and personality traits assessed by TCI and NEO-FFI | journal = Neurosci. Lett. | volume = 391 | issue = 1-2 | pages = 7–10 | year = 2005 | month = December | pmid = 16154272 | doi = 10.1016/j.neulet.2005.08.023 | url = | issn = ]
Abnormalities in XBP1 lead to a heightened ER stress and subsequently causes a heightened susceptibility for inflammatory processes.
Specifically in the colon, XBP1 anomalies have been linked to
Crohn's disease.cite journal | author = Kaser A, Lee AH, Franke A, Glickman JN, Zeissig S, Tilg H, Nieuwenhuis EE, Higgins DE, Schreiber S, Glimcher LH, Blumberg RS | title = XBP1 links ER stress to intestinal inflammation and confers genetic risk for human inflammatory bowel disease | journal = Cell | volume = 134 | issue = 5 | pages = 743–56 | year = 2008 | month = September | pmid = 18775308 | doi = 10.1016/j.cell.2008.07.021 | url = | issn = ]
*cite journal | author=Clarke R, Liu MC, Bouker KB, "et al." |title=Antiestrogen resistance in breast cancer and the role of estrogen receptor signaling. |journal=Oncogene |volume=22 |issue= 47 |pages= 7316–39 |year= 2003 |pmid= 14576841 |doi= 10.1038/sj.onc.1206937
*cite journal | author=Nekrutenko A, He J |title=Functionality of unspliced XBP1 is required to explain evolution of overlapping reading frames. |journal=Trends Genet. |volume=22 |issue= 12 |pages= 645–8 |year= 2007 |pmid= 17034899 |doi= 10.1016/j.tig.2006.09.012
*cite journal | author=Liou HC, Eddy R, Shows T, "et al." |title=An HLA-DR alpha promoter DNA-binding protein is expressed ubiquitously and maps to human chromosomes 22 and 5. |journal=Immunogenetics |volume=34 |issue= 5 |pages= 286–92 |year= 1991 |pmid= 1718857 |doi=
*cite journal | author=Ono SJ, Liou HC, Davidon R, "et al." |title=Human X-box-binding protein 1 is required for the transcription of a subset of human class II major histocompatibility genes and forms a heterodimer with c-fos. |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=88 |issue= 10 |pages= 4309–12 |year= 1991 |pmid= 1903538 |doi=
*cite journal | author=Yoshimura T, Fujisawa J, Yoshida M |title=Multiple cDNA clones encoding nuclear proteins that bind to the tax-dependent enhancer of HTLV-1: all contain a leucine zipper structure and basic amino acid domain. |journal=EMBO J. |volume=9 |issue= 8 |pages= 2537–42 |year= 1990 |pmid= 2196176 |doi=
*cite journal | author=Liou HC, Boothby MR, Finn PW, "et al." |title=A new member of the leucine zipper class of proteins that binds to the HLA DR alpha promoter. |journal=Science |volume=247 |issue= 4950 |pages= 1581–4 |year= 1990 |pmid= 2321018 |doi=
*cite journal | author=Ponath PD, Fass D, Liou HC, "et al." |title=The regulatory gene, hXBP-1, and its target, HLA-DRA, utilize both common and distinct regulatory elements and protein complexes. |journal=J. Biol. Chem. |volume=268 |issue= 23 |pages= 17074–82 |year= 1993 |pmid= 8349596 |doi=
*cite journal | author=Clauss IM, Chu M, Zhao JL, Glimcher LH |title=The basic domain/leucine zipper protein hXBP-1 preferentially binds to and transactivates CRE-like sequences containing an ACGT core. |journal=Nucleic Acids Res. |volume=24 |issue= 10 |pages= 1855–64 |year= 1996 |pmid= 8657566 |doi=
*cite journal | author=Kishimoto T, Kokura K, Ohkawa N, "et al." |title=Enhanced expression of a new class of liver-enriched b-Zip transcription factors, hepatocarcinogenesis-related transcription factor, in hepatocellular carcinomas of rats and humans. |journal=Cell Growth Differ. |volume=9 |issue= 4 |pages= 337–44 |year= 1998 |pmid= 9563853 |doi=
*cite journal | author=Dunham I, Shimizu N, Roe BA, "et al." |title=The DNA sequence of human chromosome 22. |journal=Nature |volume=402 |issue= 6761 |pages= 489–95 |year= 1999 |pmid= 10591208 |doi= 10.1038/990031
*cite journal | author=Reimold AM, Etkin A, Clauss I, "et al." |title=An essential role in liver development for transcription factor XBP-1. |journal=Genes Dev. |volume=14 |issue= 2 |pages= 152–7 |year= 2000 |pmid= 10652269 |doi=
*cite journal | author=Hartley JL, Temple GF, Brasch MA |title=DNA cloning using in vitro site-specific recombination. |journal=Genome Res. |volume=10 |issue= 11 |pages= 1788–95 |year= 2001 |pmid= 11076863 |doi=
*cite journal | author=Yoshida H, Matsui T, Yamamoto A, "et al." |title=XBP1 mRNA is induced by ATF6 and spliced by IRE1 in response to ER stress to produce a highly active transcription factor. |journal=Cell |volume=107 |issue= 7 |pages= 881–91 |year= 2002 |pmid= 11779464 |doi=
*cite journal | author=Takahashi S, Suzuki S, Inaguma S, "et al." |title=Down-regulation of human X-box binding protein 1 (hXBP-1) expression correlates with tumor progression in human prostate cancers. |journal=Prostate |volume=50 |issue= 3 |pages= 154–61 |year= 2002 |pmid= 11813207 |doi=
*cite journal | author=Gu Z, Lee RY, Skaar TC, "et al." |title=Association of interferon regulatory factor-1, nucleophosmin, nuclear factor-kappaB, and cyclic AMP response element binding with acquired resistance to Faslodex (ICI 182,780). |journal=Cancer Res. |volume=62 |issue= 12 |pages= 3428–37 |year= 2002 |pmid= 12067985 |doi=
*cite journal | author=Strausberg RL, Feingold EA, Grouse LH, "et al." |title=Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences. |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=99 |issue= 26 |pages= 16899–903 |year= 2003 |pmid= 12477932 |doi= 10.1073/pnas.242603899
*cite journal | author=Yoshida H, Matsui T, Hosokawa N, "et al." |title=A time-dependent phase shift in the mammalian unfolded protein response. |journal=Dev. Cell |volume=4 |issue= 2 |pages= 265–71 |year= 2003 |pmid= 12586069 |doi=
*cite journal | author=Shuda M, Kondoh N, Imazeki N, "et al." |title=Activation of the ATF6, XBP1 and grp78 genes in human hepatocellular carcinoma: a possible involvement of the ER stress pathway in hepatocarcinogenesis. |journal=J. Hepatol. |volume=38 |issue= 5 |pages= 605–14 |year= 2004 |pmid= 12713871 |doi=
*cite journal | author=Newman JR, Keating AE |title=Comprehensive identification of human bZIP interactions with coiled-coil arrays. |journal=Science |volume=300 |issue= 5628 |pages= 2097–101 |year= 2003 |pmid= 12805554 |doi= 10.1126/science.1084648
*cite journal | author=Kakiuchi C, Iwamoto K, Ishiwata M, "et al." |title=Impaired feedback regulation of XBP1 as a genetic risk factor for bipolar disorder. |journal=Nat. Genet. |volume=35 |issue= 2 |pages= 171–5 |year= 2003 |pmid= 12949534 |doi= 10.1038/ng1235
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