Editing Proteasome (section)

== Clinical significance ==

The proteasome and its subunits are of clinical significance for at least two reasons: (1) a compromised complex assembly or a dysfunctional proteasome can be associated with the underlying pathophysiology of specific diseases, and (2) they can be exploited as drug targets for therapeutic interventions. More recently, more effort has been made to consider the proteasome for the development of novel diagnostic markers and strategies. An improved and comprehensive understanding of the pathophysiology of the proteasome should lead to clinical applications in the future.

The proteasomes form a pivotal component for the ubiquitin–proteasome system (UPS)<ref>{{cite journal | vauthors = Kleiger G, Mayor T | title = Perilous journey: a tour of the ubiquitin-proteasome system | journal = Trends in Cell Biology | volume = 24 | issue = 6 | pages = 352–9 | date = June 2014 | pmid = 24457024 | doi = 10.1016/j.tcb.2013.12.003 | pmc=4037451}}</ref> and corresponding cellular Protein Quality Control (PQC). Protein [[ubiquitination]] and subsequent [[proteolysis]] and degradation by the proteasome are important mechanisms in the regulation of the [[cell cycle]], [[cell growth]] and differentiation, gene transcription, signal transduction and [[apoptosis]].<ref>{{cite journal | vauthors = Goldberg AL, Stein R, Adams J | title = New insights into proteasome function: from archaebacteria to drug development | journal = Chemistry & Biology | volume = 2 | issue = 8 | pages = 503–8 | date = August 1995 | pmid = 9383453 | doi=10.1016/1074-5521(95)90182-5| doi-access = free }}</ref> Proteasome defects lead to reduced proteolytic activity and the accumulation of damaged or misfolded proteins, which may contribute to neurodegenerative disease,<ref>{{cite journal | vauthors = Sulistio YA, Heese K | title = The Ubiquitin–Proteasome System and Molecular Chaperone Deregulation in Alzheimer's Disease | journal = Molecular Neurobiology | date = January 2015 | pmid = 25561438 | doi = 10.1007/s12035-014-9063-4 | volume=53 | issue = 2 | pages=905–31| s2cid = 14103185 }}</ref><ref>{{cite journal | vauthors = Ortega Z, Lucas JJ | title = Ubiquitin-proteasome system involvement in Huntington's disease | journal = Frontiers in Molecular Neuroscience | volume = 7 | page = 77 | date = 2014 | pmid = 25324717 | doi = 10.3389/fnmol.2014.00077 | pmc=4179678| doi-access = free }}</ref> cardiovascular diseases,<ref>{{cite journal | vauthors = Sandri M, Robbins J | title = Proteotoxicity: an underappreciated pathology in cardiac disease | journal = Journal of Molecular and Cellular Cardiology | volume = 71 | pages = 3–10 | date = June 2014 | pmid = 24380730 | doi = 10.1016/j.yjmcc.2013.12.015 | pmc=4011959}}</ref><ref>{{cite journal | vauthors = Drews O, Taegtmeyer H | title = Targeting the ubiquitin–proteasome system in heart disease: the basis for new therapeutic strategies | journal = Antioxidants & Redox Signaling | volume = 21 | issue = 17 | pages = 2322–43 | date = December 2014 | pmid = 25133688 | doi = 10.1089/ars.2013.5823 | pmc=4241867}}</ref><ref>{{cite journal | vauthors = Wang ZV, Hill JA | title = Protein quality control and metabolism: bidirectional control in the heart | journal = Cell Metabolism | volume = 21 | issue = 2 | pages = 215–26 | date = February 2015 | pmid = 25651176 | doi = 10.1016/j.cmet.2015.01.016 | pmc=4317573}}</ref> inflammatory responses and autoimmune diseases,<ref name="Karin M 2000">{{cite journal | vauthors = Karin M, Delhase M | title = The I kappa B kinase (IKK) and NF-kappa B: key elements of proinflammatory signalling | journal = Seminars in Immunology | volume = 12 | issue = 1 | pages = 85–98 | date = February 2000 | pmid = 10723801 | doi = 10.1006/smim.2000.0210 }}</ref> and systemic DNA damage responses leading to [[malignancies]].<ref>{{cite journal | vauthors = Ermolaeva MA, Dakhovnik A, Schumacher B | title = Quality control mechanisms in cellular and systemic DNA damage responses | journal = Ageing Research Reviews | date = January 2015 | pmid = 25560147 | doi = 10.1016/j.arr.2014.12.009 | volume=23 | issue = Pt A | pages=3–11 | pmc=4886828}}</ref>

Research has implicated UPS defects in the pathogenesis of neurodegenerative and myodegenerative disorders, including [[Alzheimer's disease]],<ref>{{cite journal | vauthors = Checler F, da Costa CA, Ancolio K, Chevallier N, Lopez-Perez E, Marambaud P | title = Role of the proteasome in Alzheimer's disease | journal = Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease | volume = 1502 | issue = 1 | pages = 133–8 | date = July 2000 | pmid = 10899438 | doi=10.1016/s0925-4439(00)00039-9| doi-access = free }}</ref> [[Parkinson's disease]]<ref name="ReferenceA">{{cite journal | vauthors = Chung KK, Dawson VL, Dawson TM | title = The role of the ubiquitin-proteasomal pathway in Parkinson's disease and other neurodegenerative disorders | journal = Trends in Neurosciences | volume = 24 | issue = 11 Suppl | pages = S7–14 | date = November 2001 | pmid = 11881748 | doi=10.1016/s0166-2236(00)01998-6| s2cid = 2211658 }}</ref> and [[Pick's disease]],<ref name="ReferenceB">{{cite journal | vauthors = Ikeda K, Akiyama H, Arai T, Ueno H, Tsuchiya K, Kosaka K | title = Morphometrical reappraisal of motor neuron system of Pick's disease and amyotrophic lateral sclerosis with dementia | journal = Acta Neuropathologica | volume = 104 | issue = 1 | pages = 21–8 | date = July 2002 | pmid = 12070660 | doi = 10.1007/s00401-001-0513-5 | s2cid = 22396490 }}</ref> [[amyotrophic lateral sclerosis]] (ALS),<ref name="ReferenceB"/> [[Huntington's disease]],<ref name="ReferenceA"/> [[Creutzfeldt–Jakob disease]],<ref>{{cite journal | vauthors = Manaka H, Kato T, Kurita K, Katagiri T, Shikama Y, Kujirai K, Kawanami T, Suzuki Y, Nihei K, Sasaki H | title = Marked increase in cerebrospinal fluid ubiquitin in Creutzfeldt–Jakob disease | journal = Neuroscience Letters | volume = 139 | issue = 1 | pages = 47–9 | date = May 1992 | pmid = 1328965 | doi=10.1016/0304-3940(92)90854-z| s2cid = 28190967 }}</ref> and motor neuron diseases, polyglutamine (PolyQ) diseases, [[muscular dystrophies]]<ref>{{cite journal | vauthors = Mathews KD, Moore SA | title = Limb-girdle muscular dystrophy | journal = Current Neurology and Neuroscience Reports | volume = 3 | issue = 1 | pages = 78–85 | date = January 2003 | pmid = 12507416 | doi=10.1007/s11910-003-0042-9| s2cid = 5780576 }}</ref> and several rare forms of neurodegenerative diseases associated with [[dementia]].<ref>{{cite journal | vauthors = Mayer RJ | title = From neurodegeneration to neurohomeostasis: the role of ubiquitin | journal = Drug News & Perspectives | volume = 16 | issue = 2 | pages = 103–8 | date = March 2003 | pmid = 12792671 | doi=10.1358/dnp.2003.16.2.829327}}</ref> As part of the ubiquitin–proteasome system (UPS), the proteasome maintains cardiac protein homeostasis and thus plays a significant role in cardiac [[ischemic]] injury,<ref>{{cite journal | vauthors = Calise J, Powell SR | title = The ubiquitin proteasome system and myocardial ischemia | journal = American Journal of Physiology. Heart and Circulatory Physiology | volume = 304 | issue = 3 | pages = H337–49 | date = February 2013 | pmid = 23220331 | pmc = 3774499 | doi = 10.1152/ajpheart.00604.2012 }}</ref> [[ventricular hypertrophy]]<ref>{{cite journal | vauthors = Predmore JM, Wang P, Davis F, Bartolone S, Westfall MV, Dyke DB, Pagani F, Powell SR, Day SM | title = Ubiquitin proteasome dysfunction in human hypertrophic and dilated cardiomyopathies | journal = Circulation | volume = 121 | issue = 8 | pages = 997–1004 | date = March 2010 | pmid = 20159828 | pmc = 2857348 | doi = 10.1161/CIRCULATIONAHA.109.904557 }}</ref> and [[heart failure]].<ref>{{cite journal | vauthors = Powell SR | title = The ubiquitin-proteasome system in cardiac physiology and pathology | journal = American Journal of Physiology. Heart and Circulatory Physiology | volume = 291 | issue = 1 | pages = H1–H19 | date = July 2006 | pmid = 16501026 | doi = 10.1152/ajpheart.00062.2006 | s2cid = 7073263 }}</ref> Additionally, evidence is accumulating that the UPS plays an essential role in malignant transformation. UPS proteolysis plays a major role in responses of cancer cells to stimulatory signals that are critical for the development of cancer. Accordingly, gene expression by degradation of [[transcription factors]], such as [[p53]], [[c-jun]], [[c-Fos]], [[NF-κB]], [[c-Myc]], HIF-1α, MATα2, [[STAT3]], sterol-regulated element-binding proteins and [[androgen receptors]] are all controlled by the UPS and thus involved in the development of various malignancies.<ref>{{cite journal | vauthors = Adams J | title = Potential for proteasome inhibition in the treatment of cancer | journal = Drug Discovery Today | volume = 8 | issue = 7 | pages = 307–15 | date = April 2003 | pmid = 12654543 | doi=10.1016/s1359-6446(03)02647-3}}</ref> Moreover, the UPS regulates the degradation of tumor suppressor gene products such as [[adenomatous polyposis coli]] (APC) in colorectal cancer, [[retinoblastoma]] (Rb). and [[von Hippel–Lindau tumor suppressor]] (VHL), as well as a number of [[proto-oncogenes]] ([[Raf kinase|Raf]], [[Myc]], [[MYB (gene)|Myb]], [[NF-κB|Rel]], [[Src (gene)|Src]], [[MOS (gene)|Mos]], [[ABL (gene)|ABL]]). The UPS is also involved in the regulation of inflammatory responses. This activity is usually attributed to the role of proteasomes in the activation of NF-κB which further regulates the expression of pro inflammatory [[cytokines]] such as [[TNF-α]], IL-β, [[Interleukin 8|IL-8]], [[adhesion molecules]] ([[ICAM-1]], [[VCAM-1]], [[P-selectin]]) and [[prostaglandins]] and [[nitric oxide]] (NO).<ref name="Karin M 2000"/> Additionally, the UPS also plays a role in inflammatory responses as regulators of leukocyte proliferation, mainly through proteolysis of cyclines and the degradation of [[cyclin-dependent kinase|CDK]] inhibitors.<ref>{{cite journal | vauthors = Ben-Neriah Y | title = Regulatory functions of ubiquitination in the immune system | journal = Nature Immunology | volume = 3 | issue = 1 | pages = 20–6 | date = January 2002 | pmid = 11753406 | doi = 10.1038/ni0102-20 | s2cid = 26973319 }}</ref> Lastly, [[autoimmune disease]] patients with [[systemic lupus erythematosus|SLE]], [[Sjögren syndrome]] and [[rheumatoid arthritis]] (RA) predominantly exhibit circulating proteasomes which can be applied as clinical biomarkers.<ref>{{cite journal | vauthors = Egerer K, Kuckelkorn U, Rudolph PE, Rückert JC, Dörner T, Burmester GR, Kloetzel PM, Feist E | title = Circulating proteasomes are markers of cell damage and immunologic activity in autoimmune diseases | journal = The Journal of Rheumatology | volume = 29 | issue = 10 | pages = 2045–52 | date = October 2002 | pmid = 12375310 }}</ref>