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Gene Review

PSMD4  -  proteasome (prosome, macropain) 26S...

Homo sapiens

Synonyms: 26S proteasome non-ATPase regulatory subunit 4, 26S proteasome regulatory subunit RPN10, 26S proteasome regulatory subunit S5A, AF, AF-1, ...
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Disease relevance of PSMD4

  • To identify activation function-1 (AF-1)-dependent cofactors involved in the transcriptional function of ERRgamma, we screened for human cDNAs coding for proteins that bind to the bacterial expressed AF-1 by biopanning of a phage display library [1].
  • The abrogation of the SF2/ASF-dependent ESE is the basis for inefficient inclusion of exon 7 in SMN2, resulting in the spinal muscular atrophy phenotype [2].
  • This demonstrates a direct link between SF2/ASF-regulated splicing and cell motility, an activity important for embryogenesis, tissue formation, and tumor metastasis [3].
  • Supernates of tetanus toxoid (TT) antigen-stimulated human T cells were studied for the presence of an antigen-specific T-cell helper factor (ASF) [4].
  • Furthermore, SF2/ASF stimulates exon 16 inclusion in both in vitro complementation assays and minigene-transfected mouse erythroleukemia cells (MELCs) [5].

Psychiatry related information on PSMD4

  • Endogenous AF production can be induced by dietary modifications in several animal species, and this feed has been shown to reduce the incidence of diarrhoeal disease in weaning piglets [6].
  • The fluid that covers the surface of conducting airways (airway surface fluid, ASF) is a critical component of one of the first defense mechanisms of the lung against microbial and other environmental insults [7].

High impact information on PSMD4

  • ASF/SF2-regulated CaMKIIdelta alternative splicing temporally reprograms excitation-contraction coupling in cardiac muscle [8].
  • Cardiomyocytes deficient in ASF/SF2 display an unexpected hypercontraction phenotype due to a defect in postnatal splicing switch of the Ca(2+)/calmodulin-dependent kinase IIdelta (CaMKIIdelta) transcript [8].
  • Using ESE motif-prediction tools, mutational analysis and in vivo and in vitro splicing assays, we show that this single-nucleotide change occurs within a heptamer motif of an exonic splicing enhancer, which in SMN1 is recognized directly by SF2/ASF [2].
  • The activity of the N-terminal activation function AF-1 of RAR alpha1 is abrogated upon mutation of a phosphorylatable serine residue (Ser-77) [9].
  • Here, we show that shuttling SR proteins, in particular SF2/ASF, associate with translating ribosomes and stimulate translation when tethered to a reporter mRNA in Xenopus oocytes [10].

Chemical compound and disease context of PSMD4


Biological context of PSMD4

  • One aim of this study was to elucidate whether AF is also synthesized in the intestine or if AF produced in the pituitary is transported to the intestinal tract for its function there. cDNA clones encoding a protein proposed to be AF were isolated from rat pituitary gland and intestinal mucosa cDNA libraries [14].
  • Developmentally regulated, alternative splicing of the Rpn10 gene generates multiple forms of 26S proteasomes [15].
  • Together these data indicate a novel, direct effect of ASF/SF2 on PKCI-r mRNA stability [16].
  • Overexpression and RNAi experiments demonstrate that SF2/ASF, by controlling the production of DeltaRon, activates epithelial to mesenchymal transition leading to cell locomotion [3].
  • This article describes a conserved protein motif, based on a sequence of the proteasomal component Rpn10/S5a, that is known to recognize ubiquitin [17].

Anatomical context of PSMD4

  • Analyses of somatic cell hybrid panel (SCHP) and radiation hybrid (IMpRH) panel revealed that PSMD4 gene maps to SSC 4q21-q23 and closely linked the SW512 (14 cR, LOD = 19.47) [18].
  • Both recombinant AF and AF extracted from pituitary gland appeared in SDS-polyacrylamide to have a molecular mass of 60 kDa, although the renal value was 41 kDa [19].
  • Purification and characterization of the antisecretory factor: a protein in the central nervous system and in the gut which inhibits intestinal hypersecretion induced by cholera toxin [20].
  • Moreover, SF2/ASF enhances translation of reporter mRNAs in HeLa cells, and this activity is dependent on its ability to shuttle from the nucleus to the cytoplasm and is increased by the presence of an exonic-splicing enhancer [10].
  • We used an embryonic chicken cDNA library to screen for differential mRNA expression in the chicken B-cell line DT40-ASF, expressing or not expressing ASF/SF2 [16].

Associations of PSMD4 with chemical compounds

  • The induction is strictly hormone dependent and requires the DNA binding domain as well as both AF-1 and AF-2 domains of the estrogen receptor (ER) alpha [21].
  • In these studies, we demonstrate a functional interaction of the two AF-containing regions of ER, when expressed as separate polypeptides in mammalian cells, in response to 17 beta-estradiol (E2) and antiestrogen binding [22].
  • The transcriptional activity of nuclear retinoic acid receptors (RARs), which act as RAR/retinoid X receptor (RXR) heterodimers, depends on two activation functions, AF-1 and AF-2, which are targets for phosphorylations and synergize for the activation of retinoic acid target genes [23].
  • We have previously shown that a ligand-dependent interaction between the two AF-containing regions of ER was promoted by E2 and the antiestrogen trans-hydroxytamoxifen (TOT) [24].
  • This strategy identified a 29-nucleotide SF2/ASF binding region in the middle of the FP sequence containing the 7-nucleotide purine-rich motif described previously [25].

Other interactions of PSMD4


Analytical, diagnostic and therapeutic context of PSMD4


  1. Identification of PNRC2 and TLE1 as activation function-1 cofactors of the orphan nuclear receptor ERRgamma. Hentschke, M., Borgmeyer, U. Biochem. Biophys. Res. Commun. (2003) [Pubmed]
  2. Disruption of an SF2/ASF-dependent exonic splicing enhancer in SMN2 causes spinal muscular atrophy in the absence of SMN1. Cartegni, L., Krainer, A.R. Nat. Genet. (2002) [Pubmed]
  3. Cell motility is controlled by SF2/ASF through alternative splicing of the Ron protooncogene. Ghigna, C., Giordano, S., Shen, H., Benvenuto, F., Castiglioni, F., Comoglio, P.M., Green, M.R., Riva, S., Biamonti, G. Mol. Cell (2005) [Pubmed]
  4. Antigen-specific helper factor in man. Mudawwar, F.B., Yunis, E.J., Geha, R.S. J. Exp. Med. (1978) [Pubmed]
  5. An erythroid differentiation-specific splicing switch in protein 4.1R mediated by the interaction of SF2/ASF with an exonic splicing enhancer. Yang, G., Huang, S.C., Wu, J.Y., Benz, E.J. Blood (2005) [Pubmed]
  6. Food induced stimulation of the antisecretory factor can improve symptoms in human inflammatory bowel disease: a study of a concept. Björck, S., Bosaeus, I., Ek, E., Jennische, E., Lönnroth, I., Johansson, E., Lange, S. Gut (2000) [Pubmed]
  7. Elemental composition of human airway surface fluid in healthy and diseased airways. Joris, L., Dab, I., Quinton, P.M. Am. Rev. Respir. Dis. (1993) [Pubmed]
  8. ASF/SF2-regulated CaMKIIdelta alternative splicing temporally reprograms excitation-contraction coupling in cardiac muscle. Xu, X., Yang, D., Ding, J.H., Wang, W., Chu, P.H., Dalton, N.D., Wang, H.Y., Bermingham, J.R., Ye, Z., Liu, F., Rosenfeld, M.G., Manley, J.L., Ross, J., Chen, J., Xiao, R.P., Cheng, H., Fu, X.D. Cell (2005) [Pubmed]
  9. Stimulation of RAR alpha activation function AF-1 through binding to the general transcription factor TFIIH and phosphorylation by CDK7. Rochette-Egly, C., Adam, S., Rossignol, M., Egly, J.M., Chambon, P. Cell (1997) [Pubmed]
  10. A novel role for shuttling SR proteins in mRNA translation. Sanford, J.R., Gray, N.K., Beckmann, K., Cáceres, J.F. Genes Dev. (2004) [Pubmed]
  11. Binding sites for Rev and ASF/SF2 map to a 55-nucleotide purine-rich exonic element in equine infectious anemia virus RNA. Chung H, n.u.l.l., Derse, D. J. Biol. Chem. (2001) [Pubmed]
  12. The epidermal basement membrane zone--structure, ontogeny, and role in disease. Katz, S.I. J. Am. Acad. Dermatol. (1984) [Pubmed]
  13. The effect on early plaque formation, gingivitis and salivary bacterial counts of mouthwashes containing hexetidine/zinc, aminefluoride/tin or chlorhexidine. Hefti, A.F., Huber, B. Journal of clinical periodontology. (1987) [Pubmed]
  14. Molecular cloning and expression of rat antisecretory factor and its intracellular localization. Tateishi, K., Misumi, Y., Ikehara, Y., Miyasaka, K., Funakoshi, A. Biochem. Cell Biol. (1999) [Pubmed]
  15. Developmentally regulated, alternative splicing of the Rpn10 gene generates multiple forms of 26S proteasomes. Kawahara, H., Kasahara, M., Nishiyama, A., Ohsumi, K., Goto, T., Kishimoto, T., Saeki, Y., Yokosawa, H., Shimbara, N., Murata, S., Chiba, T., Suzuki, K., Tanaka, K. EMBO J. (2000) [Pubmed]
  16. Stability of a PKCI-1-related mRNA is controlled by the splicing factor ASF/SF2: a novel function for SR proteins. Lemaire, R., Prasad, J., Kashima, T., Gustafson, J., Manley, J.L., Lafyatis, R. Genes Dev. (2002) [Pubmed]
  17. A ubiquitin-interacting motif conserved in components of the proteasomal and lysosomal protein degradation systems. Hofmann, K., Falquet, L. Trends Biochem. Sci. (2001) [Pubmed]
  18. Partial molecular characterization, polymorphism and chromosomal localization of the porcine PSMD4 gene. Wang, Y.F., Li, Y., Liu, B., Yu, M., Fan, B., Zhu, M.J., Xiong, T.A., Li, K. J. Anim. Breed. Genet. (2005) [Pubmed]
  19. Molecular cloning and expression of a pituitary gland protein modulating intestinal fluid secretion. Johansson, E., Lönnroth, I., Lange, S., Jonson, I., Jennische, E., Lönnroth, C. J. Biol. Chem. (1995) [Pubmed]
  20. Purification and characterization of the antisecretory factor: a protein in the central nervous system and in the gut which inhibits intestinal hypersecretion induced by cholera toxin. Lönnroth, I., Lange, S. Biochim. Biophys. Acta (1986) [Pubmed]
  21. Estrogen induction of the cyclin D1 promoter: involvement of a cAMP response-like element. Sabbah, M., Courilleau, D., Mester, J., Redeuilh, G. Proc. Natl. Acad. Sci. U.S.A. (1999) [Pubmed]
  22. Ligand-dependent, transcriptionally productive association of the amino- and carboxyl-terminal regions of a steroid hormone nuclear receptor. Kraus, W.L., McInerney, E.M., Katzenellenbogen, B.S. Proc. Natl. Acad. Sci. U.S.A. (1995) [Pubmed]
  23. Cyclin H binding to the RARalpha activation function (AF)-2 domain directs phosphorylation of the AF-1 domain by cyclin-dependent kinase 7. Bour, G., Gaillard, E., Bruck, N., Lalevée, S., Plassat, J.L., Busso, D., Samama, J.P., Rochette-Egly, C. Proc. Natl. Acad. Sci. U.S.A. (2005) [Pubmed]
  24. Analysis of estrogen receptor transcriptional enhancement by a nuclear hormone receptor coactivator. McInerney, E.M., Tsai, M.J., O'Malley, B.W., Katzenellenbogen, B.S. Proc. Natl. Acad. Sci. U.S.A. (1996) [Pubmed]
  25. Mapping the SF2/ASF binding sites in the bovine growth hormone exonic splicing enhancer. Dirksen, W.P., Li, X., Mayeda, A., Krainer, A.R., Rottman, F.M. J. Biol. Chem. (2000) [Pubmed]
  26. Immediate early response of the p62 gene encoding a non-proteasomal multiubiquitin chain binding protein. Lee, Y.H., Ko, J., Joung, I., Kim, J.H., Shin, J. FEBS Lett. (1998) [Pubmed]
  27. Enhanced expression of mRNAs of antisecretory factor-1, gp96, DAD1 and CDC34 in human hepatocellular carcinomas. Tanaka, K., Kondoh, N., Shuda, M., Matsubara, O., Imazeki, N., Ryo, A., Wakatsuki, T., Hada, A., Goseki, N., Igari, T., Hatsuse, K., Aihara, T., Horiuchi, S., Yamamoto, N., Yamamoto, M. Biochim. Biophys. Acta (2001) [Pubmed]
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