Export file:


  • RIS(for EndNote,Reference Manager,ProCite)
  • BibTex
  • Text


  • Citation Only
  • Citation and Abstract

The role of PSMD9 in human disease: future clinical and therapeutic implications

School of Medicine, University of Leeds, Leeds, UK

PSMD9 was first characterized as a component of the PA700 proteasomal regulator, and was found to stimulate association of PA700 with the catalytic 20S proteasomal core to form the active 26S proteasome. It was also independently identified under the name “bridge-1” as a transcriptional co-activator that modulates function of the transcription factors PDX-1, E12, and E47, and interacts with the co-activator histone acetyltransferase p300. Here, we discuss the molecular and genetic data linking PSMD9 to a diverse range of conditions including diabetes, cancer, mental health problems, polycystic ovary syndrome and neurodegenerative diseases, and thereby highlight its potential as a therapeutic target in these multiple settings.
  Article Metrics

Keywords PSMD9; proteasome; bridge-1; PDX-1; NF-κB

Citation: Joanne L. Hopper, Natasha Begum, Laura Smith, Thomas A. Hughes. The role of PSMD9 in human disease: future clinical and therapeutic implications. AIMS Molecular Science, 2015, 2(4): 476-484. doi: 10.3934/molsci.2015.4.476


  • 1. Uhlen M, Oksvold P, Fagerberg L, et al. (2010) Towards a knowledge-based Human Protein Atlas. Nat Biotechnol 28: 1248-1250.    
  • 2. Watanabe TK, Saito A, Suzuki M, et al. (1998) cDNA cloning and characterization of a human proteasomal modulator subunit, p27 (PSMD9). Genomics 50: 241-250.    
  • 3. Stanojevic V, Yao KM, Thomas MK (2005) The coactivator Bridge-1 increases transcriptional activation by pancreas duodenum homeobox-1 (PDX-1). Mol Cell Endocrinol 237: 67-74.    
  • 4. Thomas MK, Yao KM, Tenser MS, et al. (1999) Bridge-1, a novel PDZ-domain coactivator of E2A-mediated regulation of insulin gene transcription. Mol Cell Biol 19: 8492-8504.    
  • 5. Dalton WS (2004) The proteasome. Semin Oncol 31: 3-9.    
  • 6. Sahu I, Sangith N, Ramteke M, et al. (2014) A novel role for the proteasomal chaperone PSMD9 and hnRNPA1 in enhancing IkappaBalpha degradation and NF-kappaB activation - functional relevance of predicted PDZ domain-motif interaction. FEBS J 281: 2688-2709.    
  • 7. Banz-Jansen C, Munchow B, Diedrich K, et al. (2011) Bridge-1 is expressed in human breast carcinomas: silencing of Bridge-1 decreases Smad2, Smad3 and Smad4 expression in MCF-7 cells, a human breast cancer cell line. Arch Gynecol Obstet 284: 1543-1549.    
  • 8. de Kretser DM, O'Hehir RE, Hardy CL, et al. (2012) The roles of activin A and its binding protein, follistatin, in inflammation and tissue repair. Mol Cell Endocrinol 359: 101-106.    
  • 9. Hashimoto O, Funaba M (2011) Activin in glucose metabolism. Vitam Horm 85: 217-234.    
  • 10. Deli A, Kreidl E, Santifaller S, et al. (2008) Activins and activin antagonists in hepatocellular carcinoma. World J Gastroenterol 14: 1699-1709.    
  • 11. Ottley E, Gold E (2012) Insensitivity to the growth inhibitory effects of activin A: an acquired capability in prostate cancer progression. Cytokine Growth Factor Rev 23: 119-125.    
  • 12. Loomans HA, Andl CD (2014) Intertwining of Activin A and TGFbeta Signaling: Dual Roles in Cancer Progression and Cancer Cell Invasion. Cancers (Basel) 7: 70-91.    
  • 13. Langlands FE, Dodwell D, Hanby AM, et al. (2014) PSMD9 expression predicts radiotherapy response in breast cancer. Mol Cancer 13: 73.    
  • 14. Alsner J, Sorensen SB, Overgaard J (2001) TP53 mutation is related to poor prognosis after radiotherapy, but not surgery, in squamous cell carcinoma of the head and neck. Radiother Oncol 59: 179-185.    
  • 15. Abdel Raheem AM, Hameed DA, ElGanainy EO, et al. (2011) Can Bcl-XL expression predict the radio sensitivity of bilharzial-related squamous bladder carcinoma? A prospective comparative study. BMC Cancer 11: 16.
  • 16. Asanuma K, Moriai R, Yajima T, et al. (2000) Survivin as a radioresistance factor in pancreatic cancer. Jpn J Cancer Res 91: 1204-1209.    
  • 17. Crawford LJ, Walker B, Irvine AE (2011) Proteasome inhibitors in cancer therapy. J Cell Commun Signal 5: 101-110.    
  • 18. Hanis CL, Boerwinkle E, Chakraborty R, et al. (1996) A genome-wide search for human non-insulin-dependent (type 2) diabetes genes reveals a major susceptibility locus on chromosome 2. Nat Genet 13: 161-166.    
  • 19. Mahtani MM, Widen E, Lehto M, et al. (1996) Mapping of a gene for type 2 diabetes associated with an insulin secretion defect by a genome scan in Finnish families. Nat Genet 14: 90-94.    
  • 20. Gragnoli C (2010) PSMD9 gene in the NIDDM2 locus is linked to type 2 diabetes in Italians. J Cell Physiol 222: 265-267.    
  • 21. Gragnoli C, Cronsell J (2007) PSMD9 gene variants within NIDDM2 may rarely contribute to type 2 diabetes. J Cell Physiol 212: 568-571.    
  • 22. Gragnoli C (2010) PSMD9 is linked to MODY3. J Cell Physiol 223: 1-5.
  • 23. Gragnoli C (2011) PSMD9 is linked to type 2 diabetes neuropathy. J Diabetes Complications 25: 329-331.    
  • 24. Gragnoli C (2012) Proteasome modulator 9 is linked to microvascular pathology of T2D. J Cell Physiol 227: 3116-3118.    
  • 25. Gragnoli C (2011) Proteasome modulator 9 and macrovascular pathology of T2D. Cardiovasc Diabetol 10: 32.    
  • 26. Gragnoli C (2011) Proteasome modulator 9 SNPs are linked to hypertension in type 2 diabetes families. Cardiovasc Diabetol 10: 77.    
  • 27. Lee JH, Volinic JL, Banz C, et al. (2005) Interactions with p300 enhance transcriptional activation by the PDZ-domain coactivator Bridge-1. J Endocrinol 187: 283-292.    
  • 28. Thomas MK, Tsang SW, Yeung ML, et al. (2009) The roles of the PDZ-containing proteins bridge-1 and PDZD2 in the regulation of insulin production and pancreatic beta-cell mass. Curr Protein Pept Sci 10: 30-36.    
  • 29. Volinic JL, Lee JH, Eto K, et al. (2006) Overexpression of the coactivator bridge-1 results in insulin deficiency and diabetes. Mol Endocrinol 20: 167-182.    
  • 30. Donath MY (2014) Targeting inflammation in the treatment of type 2 diabetes: time to start. Nat Rev Drug Discov 13: 465-476.    
  • 31. Liu H, Yu S, Xu W, et al. (2012) Enhancement of 26S proteasome functionality connects oxidative stress and vascular endothelial inflammatory response in diabetes mellitus. Arterioscler Thromb Vasc Biol 32: 2131-2140.    
  • 32. Sullivan PF, Neale MC, Kendler KS (2000) Genetic epidemiology of major depression: review and meta-analysis. Am J Psychiatry 157: 1552-1562.    
  • 33. Millier A, Schmidt U, Angermeyer MC, et al. (2014) Humanistic burden in schizophrenia: a literature review. J Psychiatr Res 54: 85-93.    
  • 34. Cardno AG, Marshall EJ, Coid B, et al. (1999) Heritability estimates for psychotic disorders: the Maudsley twin psychosis series. Arch Gen Psychiatry 56: 162-168.    
  • 35. Mezuk B, Eaton WW, Albrecht S, et al. (2008) Depression and type 2 diabetes over the lifespan: a meta-analysis. Diabetes Care 31: 2383-2390.    
  • 36. Pan A, Lucas M, Sun Q, et al. (2010) Bidirectional association between depression and type 2 diabetes mellitus in women. Arch Intern Med 170: 1884-1891.
  • 37. Gragnoli C (2014) Proteasome modulator 9 gene SNPs, responsible for anti-depressant response, are in linkage with generalized anxiety disorder. J Cell Physiol 229: 1157-1159.    
  • 38. Gragnoli C (2012) Proteasome modulator 9 and depression in type 2 diabetes. Curr Med Chem 19: 5178-5180.    
  • 39. Wong ML, Dong C, Maestre-Mesa J, et al. (2008) Polymorphisms in inflammation-related genes are associated with susceptibility to major depression and antidepressant response. Mol Psychiatry 13: 800-812.    
  • 40. Wong ML, Dong C, Andreev V, et al. (2012) Prediction of susceptibility to major depression by a model of interactions of multiple functional genetic variants and environmental factors. Mol Psychiatry 17: 624-633.    
  • 41. Lee YH, Kim JH, Song GG (2013) Pathway analysis of a genome-wide association study in schizophrenia. Gene 525: 107-115.    
  • 42. Haase J, Brown E (2015) Integrating the monoamine, neurotrophin and cytokine hypotheses of depression--a central role for the serotonin transporter? Pharmacol Ther 147: 1-11.    
  • 43. Furtado M, Katzman MA (2015) Examining the role of neuroinflammation in major depression. Psychiatry Res 229: 27-36.    
  • 44. Uzbekov M, Maxinova N (2015) Biochemical Bases of Monoamine and Hormonal Interactions in Pathogenesis of Anxious Depression: a Hypothesis. European Psychiatry 30: 542.
  • 45. Najjar S, Pearlman DM (2015) Neuroinflammation and white matter pathology in schizophrenia: systematic review. Schizophr Res 161: 102-112.    
  • 46. Talbot K, Eidem WL, Tinsley CL, et al. (2004) Dysbindin-1 is reduced in intrinsic, glutamatergic terminals of the hippocampal formation in schizophrenia. J Clin Invest 113: 1353-1363.    
  • 47. Weickert CS, Rothmond DA, Hyde TM, et al. (2008) Reduced DTNBP1 (dysbindin-1) mRNA in the hippocampal formation of schizophrenia patients. Schizophr Res 98: 105-110.
  • 48. Saggu S, Cannon TD, Jentsch JD, et al. (2013) Potential molecular mechanisms for decreased synaptic glutamate release in dysbindin-1 mutant mice. Schizophr Res 146: 254-263.    
  • 49. Tang J, LeGros RP, Louneva N, et al. (2009) Dysbindin-1 in dorsolateral prefrontal cortex of schizophrenia cases is reduced in an isoform-specific manner unrelated to dysbindin-1 mRNA expression. Hum Mol Genet 18: 3851-3863.    
  • 50. Han MH, Hu Z, Chen CY, et al. (2014) Dysbindin-associated proteome in the p2 synaptosome fraction of mouse brain. J Proteome Res 13: 4567-4580.    
  • 51. Banz C, Munchow B, Diedrich K (2010) Bridge-1 is expressed in human granulosa cells and is involved in the activin A signaling cascade. Fertil Steril 93: 1349-1352.    
  • 52. Barber TM, Franks S (2012) The link between polycystic ovary syndrome and both Type 1 and Type 2 diabetes mellitus: what do we know today? Womens Health (Lond Engl) 8: 147-154.    
  • 53. Ehrmann DA (2005) Polycystic ovary syndrome. N Engl J Med 352: 1223-1236.    
  • 54. Marti MJ, Tolosa E, Campdelacreu J (2003) Clinical overview of the synucleinopathies. Mov Disord 18 Suppl 6: S21-27.
  • 55. Stefanova N, Klimaschewski L, Poewe W, et al. (2001) Glial cell death induced by overexpression of alpha-synuclein. J Neurosci Res 65: 432-438.    
  • 56. Xilouri M, Brekk OR, Stefanis L (2013) alpha-Synuclein and protein degradation systems: a reciprocal relationship. Mol Neurobiol 47: 537-551.    
  • 57. Stefanis L (2012) alpha-Synuclein in Parkinson's disease. Cold Spring Harb Perspect Med 2: a009399.
  • 58. Vartiainen S, Pehkonen P, Lakso M, et al. (2006) Identification of gene expression changes in transgenic C. elegans overexpressing human alpha-synuclein. Neurobiol Dis 22: 477-486.
  • 59. Rideout HJ, Dietrich P, Wang Q, et al. (2004) alpha-synuclein is required for the fibrillar nature of ubiquitinated inclusions induced by proteasomal inhibition in primary neurons. J Biol Chem 279: 46915-46920.    
  • 60. Pierre S-R, Vernace V, Wang Z, et al. (2009) Mechanisms Linking the Ubiquitin/Proteasome Pathway and Chaperones. In: Richter-Landsberg C, editor. Heat Shock Proteins in Neural Cells: Springer New York.
  • 61. Bedford L, Hay D, Devoy A, et al. (2008) Depletion of 26S proteasomes in mouse brain neurons causes neurodegeneration and Lewy-like inclusions resembling human pale bodies. J Neurosci 28: 8189-8198.    
  • 62. Sangith N, Srinivasaraghavan K, Sahu I, et al. (2014) Discovery of novel interacting partners of PSMD9, a proteasomal chaperone: Role of an Atypical and versatile PDZ-domain motif interaction and identification of putative functional modules. FEBS Open Bio 4: 571-583.    
  • 63. Geng X, Lou H, Wang J, et al. (2011) alpha-Synuclein binds the K(ATP) channel at insulin-secretory granules and inhibits insulin secretion. Am J Physiol Endocrinol Metab 300: E276-286.    
  • 64. Steneberg P, Bernardo L, Edfalk S, et al. (2013) The type 2 diabetes-associated gene ide is required for insulin secretion and suppression of alpha-synuclein levels in beta-cells. Diabetes 62: 2004-2014.    
  • 65. Hu G, Jousilahti P, Bidel S, et al. (2007) Type 2 diabetes and the risk of Parkinson's disease. Diabetes Care 30: 842-847.    
  • 66. Cereda E, Barichella M, Cassani E, et al. (2012) Clinical features of Parkinson disease when onset of diabetes came first: A case-control study. Neurology 78: 1507-1511.    
  • 67. Cereda E, Barichella M, Pedrolli C, et al. (2011) Diabetes and risk of Parkinson's disease: a systematic review and meta-analysis. Diabetes Care 34: 2614-2623.    
  • 68. Sandyk R (1993) The relationship between diabetes mellitus and Parkinson's disease. Int J Neurosci 69: 125-130.    


This article has been cited by

  • 1. Adrien Rousseau, Anne Bertolotti, Regulation of proteasome assembly and activity in health and disease, Nature Reviews Molecular Cell Biology, 2018, 10.1038/s41580-018-0040-z

Reader Comments

your name: *   your email: *  

Copyright Info: 2015, Thomas A. Hughes, et al., licensee AIMS Press. This is an open access article distributed under the terms of the Creative Commons Attribution Licese (http://creativecommons.org/licenses/by/4.0)

Download full text in PDF

Export Citation

Copyright © AIMS Press All Rights Reserved