PSMD10: Difference between revisions

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{{merge from|Gankyrin|discuss=Talk:PSMD10#Proposed merge with Gankyrin|date=January 2016}}
{{Infobox_gene}}
{{Infobox_gene}}
'''26S proteasome non-ATPase regulatory subunit 10''' is an [[enzyme]] that in humans is encoded by the ''PSMD10'' [[gene]].<ref name="pmid9714768">{{cite journal | vauthors = Hori T, Kato S, Saeki M, DeMartino GN, Slaughter CA, Takeuchi J, Toh-e A, Tanaka K | title = cDNA cloning and functional analysis of p28 (Nas6p) and p40.5 (Nas7p), two novel regulatory subunits of the 26S proteasome | journal = Gene | volume = 216 | issue = 1 | pages = 113–22 | date = Aug 1998 | pmid = 9714768 | pmc =  | doi = 10.1016/S0378-1119(98)00309-6 }}</ref>
'''26S proteasome non-ATPase regulatory subunit 10''' or '''gankyrin''' is an [[enzyme]] that in humans is encoded by the ''PSMD10'' [[gene]].<ref name="pmid9714768">{{cite journal | vauthors = Hori T, Kato S, Saeki M, DeMartino GN, Slaughter CA, Takeuchi J, Toh-e A, Tanaka K | title = cDNA cloning and functional analysis of p28 (Nas6p) and p40.5 (Nas7p), two novel regulatory subunits of the 26S proteasome | journal = Gene | volume = 216 | issue = 1 | pages = 113–22 | date = Aug 1998 | pmid = 9714768 | pmc =  | doi = 10.1016/S0378-1119(98)00309-6 }}</ref> '''Gankyrin''' is an [[oncogene|oncoprotein]] that is a component of the 19S regulatory cap of the [[proteasome]]. Structurally, it contains a 33-[[amino acid]] [[ankyrin repeat]] that forms a series of [[alpha helix|alpha helices]].<ref name="KrzywdaStructure">{{cite journal | vauthors = Krzywda S, Brzozowski AM, Higashitsuji H, Fujita J, Welchman R, Dawson S, Mayer RJ, Wilkinson AJ | title = The crystal structure of gankyrin, an oncoprotein found in complexes with cyclin-dependent kinase 4, a 19 S proteasomal ATPase regulator, and the tumor suppressors Rb and p53 | journal = The Journal of Biological Chemistry | volume = 279 | issue = 2 | pages = 1541–5 | year = 2004 | pmid = 14573599 | doi = 10.1074/jbc.M310265200 }}</ref> It plays a key role in regulating the [[cell cycle]] via [[protein-protein interaction]]s with the [[cyclin-dependent kinase]] CDK4. It also binds closely to the E3 [[ubiquitin ligase]] [[MDM2]], which is a regulator of the degradation of [[p53]] and [[retinoblastoma protein]], both [[transcription factor]]s involved in [[tumor suppressor|tumor suppression]] and found mutated in many [[cancer]]s.<ref name="Krzywda">{{cite journal | vauthors = Krzywda S, Brzozowski AM, Al-Safty R, Welchman R, Mee M, Dawson S, Fujita J, Higashitsuji H, Mayer RJ, Wilkinson AJ | title = Crystallization of gankyrin, an oncoprotein that interacts with CDK4 and the S6b (rpt3) ATPase of the 19S regulator of the 26S proteasome | journal = Acta Crystallographica Section D | volume = 59 | issue = Pt 7 | pages = 1294–5 | year = 2003 | pmid = 12832791 | doi = 10.1107/S0907444903009892 }}</ref> Gankyrin also has an anti-[[apoptosis|apoptotic]] effect and is overexpressed in certain types of [[tumor]] cells such as [[hepatocellular carcinoma]].<ref name="Higashitsuji">{{cite journal | vauthors = Higashitsuji H, Liu Y, Mayer RJ, Fujita J | title = The oncoprotein gankyrin negatively regulates both p53 and RB by enhancing proteasomal degradation | journal = Cell Cycle (Georgetown, Tex.) | volume = 4 | issue = 10 | pages = 1335–7 | year = 2005 | pmid = 16177571 | doi = 10.4161/cc.4.10.2107 }}</ref>


== Function ==
== Function ==
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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 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 [[proteasome|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 = Jun 2014 | pmid = 24457024 | pmc = 4037451 | doi = 10.1016/j.tcb.2013.12.003 }}</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 = Aug 1995 | pmid = 9383453 | doi=10.1016/1074-5521(95)90182-5}}</ref> Subsequently, a compromised proteasome complex assembly and function lead to reduced proteolytic activities and the accumulation of damaged or misfolded protein species. Such protein accumulation may contribute to the pathogenesis and phenotypic characteristics in neurodegenerative diseases,<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 = Jan 2015 | pmid = 25561438 | doi = 10.1007/s12035-014-9063-4 | volume=53 | pages=905–31}}</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 | pages = 77 | date = 2014 | pmid = 25324717 | pmc = 4179678 | doi = 10.3389/fnmol.2014.00077 }}</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 = Jun 2014 | pmid = 24380730 | pmc = 4011959 | doi = 10.1016/j.yjmcc.2013.12.015 }}</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 = Dec 2014 | pmid = 25133688 | pmc = 4241867 | doi = 10.1089/ars.2013.5823 }}</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 = Feb 2015 | pmid = 25651176 | pmc = 4317573 | doi = 10.1016/j.cmet.2015.01.016 }}</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 = Feb 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 | volume = 23 | issue = Pt A | pages = 3–11 | date = Sep 2015 | pmid = 25560147 | doi = 10.1016/j.arr.2014.12.009 | pmc=4886828}}</ref>
The proteasomes form a pivotal component for the [[proteasome|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 = Jun 2014 | pmid = 24457024 | pmc = 4037451 | doi = 10.1016/j.tcb.2013.12.003 }}</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 = Aug 1995 | pmid = 9383453 | doi=10.1016/1074-5521(95)90182-5}}</ref> Subsequently, a compromised proteasome complex assembly and function lead to reduced proteolytic activities and the accumulation of damaged or misfolded protein species. Such protein accumulation may contribute to the pathogenesis and phenotypic characteristics in neurodegenerative diseases,<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 = Jan 2015 | pmid = 25561438 | doi = 10.1007/s12035-014-9063-4 | volume=53 | issue = 2 | pages=905–31}}</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 | pages = 77 | date = 2014 | pmid = 25324717 | pmc = 4179678 | doi = 10.3389/fnmol.2014.00077 }}</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 = Jun 2014 | pmid = 24380730 | pmc = 4011959 | doi = 10.1016/j.yjmcc.2013.12.015 }}</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 = Dec 2014 | pmid = 25133688 | pmc = 4241867 | doi = 10.1089/ars.2013.5823 }}</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 = Feb 2015 | pmid = 25651176 | pmc = 4317573 | doi = 10.1016/j.cmet.2015.01.016 }}</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 = Feb 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 | volume = 23 | issue = Pt A | pages = 3–11 | date = Sep 2015 | pmid = 25560147 | doi = 10.1016/j.arr.2014.12.009 | pmc=4886828}}</ref>


Several experimental and clinical studies have indicated that aberrations and deregulations of the UPS contribute to the pathogenesis of several 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 | volume = 1502 | issue = 1 | pages = 133–8 | date = Jul 2000 | pmid = 10899438 | doi=10.1016/s0925-4439(00)00039-9}}</ref> [[Parkinson's disease]]<ref name="ReferenceC">{{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 = Nov 2001 | pmid = 11881748 | doi=10.1016/s0166-2236(00)01998-6}}</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 = Jul 2002 | pmid = 12070660 | doi = 10.1007/s00401-001-0513-5 }}</ref> [[Amyotrophic lateral sclerosis]] ([[ALS]]),<ref name="ReferenceB"/> [[Huntington's disease]],<ref name="ReferenceC"/> [[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}}</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 = Jan 2003 | pmid = 12507416 | doi=10.1007/s11910-003-0042-9}}</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 = Mar 2003 | pmid = 12792671 | doi=10.1358/dnp.2003.16.2.829327}}</ref> As part of the [[proteasome|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 = Feb 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 = Mar 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 = Jul 2006 | pmid = 16501026 | doi = 10.1152/ajpheart.00062.2006 }}</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 = Apr 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]] ([[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 selectine) 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 = Jan 2002 | pmid = 11753406 | doi = 10.1038/ni0102-20 }}</ref> Lastly, [[autoimmune disease]] patients with [[Systemic lupus erythematosus|SLE]], [[Sjogren's 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 = Oct 2002 | pmid = 12375310 }}</ref>
Several experimental and clinical studies have indicated that aberrations and deregulations of the UPS contribute to the pathogenesis of several 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 | volume = 1502 | issue = 1 | pages = 133–8 | date = Jul 2000 | pmid = 10899438 | doi=10.1016/s0925-4439(00)00039-9}}</ref> [[Parkinson's disease]]<ref name="ReferenceC">{{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 = Nov 2001 | pmid = 11881748 | doi=10.1016/s0166-2236(00)01998-6}}</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 = Jul 2002 | pmid = 12070660 | doi = 10.1007/s00401-001-0513-5 }}</ref> [[Amyotrophic lateral sclerosis]] ([[ALS]]),<ref name="ReferenceB"/> [[Huntington's disease]],<ref name="ReferenceC"/> [[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| bibcode = 2006NeuL..400..197D }}</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 = Jan 2003 | pmid = 12507416 | doi=10.1007/s11910-003-0042-9}}</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 = Mar 2003 | pmid = 12792671 | doi=10.1358/dnp.2003.16.2.829327}}</ref> As part of the [[proteasome|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 = Feb 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 = Mar 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 = Jul 2006 | pmid = 16501026 | doi = 10.1152/ajpheart.00062.2006 }}</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 = Apr 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]] ([[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 = Jan 2002 | pmid = 11753406 | doi = 10.1038/ni0102-20 }}</ref> Lastly, [[autoimmune disease]] patients with [[Systemic lupus erythematosus|SLE]], [[Sjogren's 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 = Oct 2002 | pmid = 12375310 }}</ref>


== Interactions ==
== Interactions ==
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* [[PAAF1]],<ref name = pmid17353931>{{cite journal | vauthors = Ewing RM, Chu P, Elisma F, Li H, Taylor P, Climie S, McBroom-Cerajewski L, Robinson MD, O'Connor L, Li M, Taylor R, Dharsee M, Ho Y, Heilbut A, Moore L, Zhang S, Ornatsky O, Bukhman YV, Ethier M, Sheng Y, Vasilescu J, Abu-Farha M, Lambert JP, Duewel HS, Stewart II, Kuehl B, Hogue K, Colwill K, Gladwish K, Muskat B, Kinach R, Adams SL, Moran MF, Morin GB, Topaloglou T, Figeys D | title = Large-scale mapping of human protein-protein interactions by mass spectrometry | journal = Mol. Syst. Biol. | volume = 3 | issue =  | pages = 89 | pmid = 17353931 | pmc = 1847948 | doi = 10.1038/msb4100134 | year = 2007 }}</ref>  and
* [[PAAF1]],<ref name = pmid17353931>{{cite journal | vauthors = Ewing RM, Chu P, Elisma F, Li H, Taylor P, Climie S, McBroom-Cerajewski L, Robinson MD, O'Connor L, Li M, Taylor R, Dharsee M, Ho Y, Heilbut A, Moore L, Zhang S, Ornatsky O, Bukhman YV, Ethier M, Sheng Y, Vasilescu J, Abu-Farha M, Lambert JP, Duewel HS, Stewart II, Kuehl B, Hogue K, Colwill K, Gladwish K, Muskat B, Kinach R, Adams SL, Moran MF, Morin GB, Topaloglou T, Figeys D | title = Large-scale mapping of human protein-protein interactions by mass spectrometry | journal = Mol. Syst. Biol. | volume = 3 | issue =  | pages = 89 | pmid = 17353931 | pmc = 1847948 | doi = 10.1038/msb4100134 | year = 2007 }}</ref>  and
* [[PSMC4]].<ref name = pmid17353931/><ref name = pmid16189514>{{cite journal | vauthors = Rual JF, Venkatesan K, Hao T, Hirozane-Kishikawa T, Dricot A, Li N, Berriz GF, Gibbons FD, Dreze M, Ayivi-Guedehoussou N, Klitgord N, Simon C, Boxem M, Milstein S, Rosenberg J, Goldberg DS, Zhang LV, Wong SL, Franklin G, Li S, Albala JS, Lim J, Fraughton C, Llamosas E, Cevik S, Bex C, Lamesch P, Sikorski RS, Vandenhaute J, Zoghbi HY, Smolyar A, Bosak S, Sequerra R, Doucette-Stamm L, Cusick ME, Hill DE, Roth FP, Vidal M | title = Towards a proteome-scale map of the human protein-protein interaction network | journal = Nature | volume = 437 | issue = 7062 | pages = 1173–8 | date = Oct 2005 | pmid = 16189514 | doi = 10.1038/nature04209 | bibcode = 2005Natur.437.1173R }}</ref><ref name = pmid11779854>{{cite journal | vauthors = Dawson S, Apcher S, Mee M, Higashitsuji H, Baker R, Uhle S, Dubiel W, Fujita J, Mayer RJ | title = Gankyrin is an ankyrin-repeat oncoprotein that interacts with CDK4 kinase and the S6 ATPase of the 26 S proteasome | journal = J. Biol. Chem. | volume = 277 | issue = 13 | pages = 10893–902 | date = Mar 2002 | pmid = 11779854 | doi = 10.1074/jbc.M107313200 }}</ref>
* [[PSMC4]].<ref name = pmid17353931/><ref name = pmid16189514>{{cite journal | vauthors = Rual JF, Venkatesan K, Hao T, Hirozane-Kishikawa T, Dricot A, Li N, Berriz GF, Gibbons FD, Dreze M, Ayivi-Guedehoussou N, Klitgord N, Simon C, Boxem M, Milstein S, Rosenberg J, Goldberg DS, Zhang LV, Wong SL, Franklin G, Li S, Albala JS, Lim J, Fraughton C, Llamosas E, Cevik S, Bex C, Lamesch P, Sikorski RS, Vandenhaute J, Zoghbi HY, Smolyar A, Bosak S, Sequerra R, Doucette-Stamm L, Cusick ME, Hill DE, Roth FP, Vidal M | title = Towards a proteome-scale map of the human protein-protein interaction network | journal = Nature | volume = 437 | issue = 7062 | pages = 1173–8 | date = Oct 2005 | pmid = 16189514 | doi = 10.1038/nature04209 | bibcode = 2005Natur.437.1173R }}</ref><ref name = pmid11779854>{{cite journal | vauthors = Dawson S, Apcher S, Mee M, Higashitsuji H, Baker R, Uhle S, Dubiel W, Fujita J, Mayer RJ | title = Gankyrin is an ankyrin-repeat oncoprotein that interacts with CDK4 kinase and the S6 ATPase of the 26 S proteasome | journal = J. Biol. Chem. | volume = 277 | issue = 13 | pages = 10893–902 | date = Mar 2002 | pmid = 11779854 | doi = 10.1074/jbc.M107313200 }}</ref>
{{clear}}


== References ==
== References ==
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== Further reading ==
== Further reading ==
{{refbegin|33em}}
{{refbegin|33em}}
* {{cite journal | vauthors = Coux O, Tanaka K, Goldberg AL | title = Structure and functions of the 20S and 26S proteasomes. | journal = Annu. Rev. Biochem. | volume = 65 | issue =  | pages = 801–47 | year = 1996 | pmid = 8811196 | doi = 10.1146/annurev.bi.65.070196.004101 }}
* {{cite journal | vauthors = Coux O, Tanaka K, Goldberg AL | title = Structure and functions of the 20S and 26S proteasomes | journal = Annu. Rev. Biochem. | volume = 65 | issue =  | pages = 801–47 | year = 1996 | pmid = 8811196 | doi = 10.1146/annurev.bi.65.070196.004101 }}
* {{cite journal | vauthors = Goff SP | title = Death by deamination: a novel host restriction system for HIV-1. | journal = Cell | volume = 114 | issue = 3 | pages = 281–3 | year = 2003 | pmid = 12914693 | doi = 10.1016/S0092-8674(03)00602-0 }}
* {{cite journal | vauthors = Goff SP | title = Death by deamination: a novel host restriction system for HIV-1 | journal = Cell | volume = 114 | issue = 3 | pages = 281–3 | year = 2003 | pmid = 12914693 | doi = 10.1016/S0092-8674(03)00602-0 }}
* {{cite journal | vauthors = Sastry L, Cao T, King CR | title = Multiple Grb2-protein complexes in human cancer cells. | journal = Int. J. Cancer | volume = 70 | issue = 2 | pages = 208–13 | year = 1997 | pmid = 9009162 | doi = 10.1002/(SICI)1097-0215(19970117)70:2<208::AID-IJC12>3.0.CO;2-E }}
* {{cite journal | vauthors = Sastry L, Cao T, King CR | title = Multiple Grb2-protein complexes in human cancer cells | journal = Int. J. Cancer | volume = 70 | issue = 2 | pages = 208–13 | year = 1997 | pmid = 9009162 | doi = 10.1002/(SICI)1097-0215(19970117)70:2<208::AID-IJC12>3.0.CO;2-E }}
* {{cite journal | vauthors = Seeger M, Ferrell K, Frank R, Dubiel W | title = HIV-1 tat inhibits the 20 S proteasome and its 11 S regulator-mediated activation. | journal = J. Biol. Chem. | volume = 272 | issue = 13 | pages = 8145–8 | year = 1997 | pmid = 9079628 | doi = 10.1074/jbc.272.13.8145 }}
* {{cite journal | vauthors = Seeger M, Ferrell K, Frank R, Dubiel W | title = HIV-1 tat inhibits the 20 S proteasome and its 11 S regulator-mediated activation | journal = J. Biol. Chem. | volume = 272 | issue = 13 | pages = 8145–8 | year = 1997 | pmid = 9079628 | doi = 10.1074/jbc.272.13.8145 }}
* {{cite journal | vauthors = Madani N, Kabat D | title = An endogenous inhibitor of human immunodeficiency virus in human lymphocytes is overcome by the viral Vif protein. | journal = J. Virol. | volume = 72 | issue = 12 | pages = 10251–5 | year = 1998 | pmid = 9811770 | pmc = 110608 | doi =  }}
* {{cite journal | vauthors = Madani N, Kabat D | title = An endogenous inhibitor of human immunodeficiency virus in human lymphocytes is overcome by the viral Vif protein | journal = J. Virol. | volume = 72 | issue = 12 | pages = 10251–5 | year = 1998 | pmid = 9811770 | pmc = 110608 | doi =  }}
* {{cite journal | vauthors = Simon JH, Gaddis NC, Fouchier RA, Malim MH | title = Evidence for a newly discovered cellular anti-HIV-1 phenotype. | journal = Nat. Med. | volume = 4 | issue = 12 | pages = 1397–400 | year = 1998 | pmid = 9846577 | doi = 10.1038/3987 }}
* {{cite journal | vauthors = Simon JH, Gaddis NC, Fouchier RA, Malim MH | title = Evidence for a newly discovered cellular anti-HIV-1 phenotype | journal = Nat. Med. | volume = 4 | issue = 12 | pages = 1397–400 | year = 1998 | pmid = 9846577 | doi = 10.1038/3987 }}
* {{cite journal | vauthors = Mulder LC, Muesing MA | title = Degradation of HIV-1 integrase by the N-end rule pathway. | journal = J. Biol. Chem. | volume = 275 | issue = 38 | pages = 29749–53 | year = 2000 | pmid = 10893419 | doi = 10.1074/jbc.M004670200 }}
* {{cite journal | vauthors = Mulder LC, Muesing MA | title = Degradation of HIV-1 integrase by the N-end rule pathway | journal = J. Biol. Chem. | volume = 275 | issue = 38 | pages = 29749–53 | year = 2000 | pmid = 10893419 | doi = 10.1074/jbc.M004670200 }}
* {{cite journal | vauthors = Dawson S, Apcher S, Mee M, Higashitsuji H, Baker R, Uhle S, Dubiel W, Fujita J, Mayer RJ | title = Gankyrin is an ankyrin-repeat oncoprotein that interacts with CDK4 kinase and the S6 ATPase of the 26 S proteasome. | journal = J. Biol. Chem. | volume = 277 | issue = 13 | pages = 10893–902 | year = 2002 | pmid = 11779854 | doi = 10.1074/jbc.M107313200 }}
* {{cite journal | vauthors = Dawson S, Apcher S, Mee M, Higashitsuji H, Baker R, Uhle S, Dubiel W, Fujita J, Mayer RJ | title = Gankyrin is an ankyrin-repeat oncoprotein that interacts with CDK4 kinase and the S6 ATPase of the 26 S proteasome | journal = J. Biol. Chem. | volume = 277 | issue = 13 | pages = 10893–902 | year = 2002 | pmid = 11779854 | doi = 10.1074/jbc.M107313200 }}
* {{cite journal | vauthors = Sheehy AM, Gaddis NC, Choi JD, Malim MH | title = Isolation of a human gene that inhibits HIV-1 infection and is suppressed by the viral Vif protein | journal = Nature | volume = 418 | issue = 6898 | pages = 646–50 | year = 2002 | pmid = 12167863 | doi = 10.1038/nature00939 | bibcode = 2002Natur.418..646S }}
* {{cite journal | vauthors = Sheehy AM, Gaddis NC, Choi JD, Malim MH | title = Isolation of a human gene that inhibits HIV-1 infection and is suppressed by the viral Vif protein | journal = Nature | volume = 418 | issue = 6898 | pages = 646–50 | year = 2002 | pmid = 12167863 | doi = 10.1038/nature00939 | bibcode = 2002Natur.418..646S }}
* {{cite journal | vauthors = Fu XY, Wang HY, Tan L, Liu SQ, Cao HF, Wu MC | title = Overexpression of p28/gankyrin in human hepatocellular carcinoma and its clinical significance. | journal = World J. Gastroenterol. | volume = 8 | issue = 4 | pages = 638–43 | year = 2002 | pmid = 12174370 | doi =  }}
* {{cite journal | vauthors = Fu XY, Wang HY, Tan L, Liu SQ, Cao HF, Wu MC | title = Overexpression of p28/gankyrin in human hepatocellular carcinoma and its clinical significance | journal = World J. Gastroenterol. | volume = 8 | issue = 4 | pages = 638–43 | year = 2002 | pmid = 12174370 | pmc = 4656312 | doi =  }}
* {{cite journal | vauthors = Huang X, Seifert U, Salzmann U, Henklein P, Preissner R, Henke W, Sijts AJ, Kloetzel PM, Dubiel W | title = The RTP site shared by the HIV-1 Tat protein and the 11S regulator subunit alpha is crucial for their effects on proteasome function including antigen processing. | journal = J. Mol. Biol. | volume = 323 | issue = 4 | pages = 771–82 | year = 2002 | pmid = 12419264 | doi = 10.1016/S0022-2836(02)00998-1 }}
* {{cite journal | vauthors = Huang X, Seifert U, Salzmann U, Henklein P, Preissner R, Henke W, Sijts AJ, Kloetzel PM, Dubiel W | title = The RTP site shared by the HIV-1 Tat protein and the 11S regulator subunit alpha is crucial for their effects on proteasome function including antigen processing | journal = J. Mol. Biol. | volume = 323 | issue = 4 | pages = 771–82 | year = 2002 | pmid = 12419264 | doi = 10.1016/S0022-2836(02)00998-1 }}
* {{cite journal | vauthors = Nagao T, Higashitsuji H, Nonoguchi K, Sakurai T, Dawson S, Mayer RJ, Itoh K, Fujita J | title = MAGE-A4 interacts with the liver oncoprotein gankyrin and suppresses its tumorigenic activity. | journal = J. Biol. Chem. | volume = 278 | issue = 12 | pages = 10668–74 | year = 2003 | pmid = 12525503 | doi = 10.1074/jbc.M206104200 }}
* {{cite journal | vauthors = Nagao T, Higashitsuji H, Nonoguchi K, Sakurai T, Dawson S, Mayer RJ, Itoh K, Fujita J | title = MAGE-A4 interacts with the liver oncoprotein gankyrin and suppresses its tumorigenic activity | journal = J. Biol. Chem. | volume = 278 | issue = 12 | pages = 10668–74 | year = 2003 | pmid = 12525503 | doi = 10.1074/jbc.M206104200 }}
* {{cite journal | vauthors = Gaddis NC, Chertova E, Sheehy AM, Henderson LE, Malim MH | title = Comprehensive investigation of the molecular defect in vif-deficient human immunodeficiency virus type 1 virions. | journal = J. Virol. | volume = 77 | issue = 10 | pages = 5810–20 | year = 2003 | pmid = 12719574 | pmc = 154025 | doi = 10.1128/JVI.77.10.5810-5820.2003 }}
* {{cite journal | vauthors = Gaddis NC, Chertova E, Sheehy AM, Henderson LE, Malim MH | title = Comprehensive investigation of the molecular defect in vif-deficient human immunodeficiency virus type 1 virions | journal = J. Virol. | volume = 77 | issue = 10 | pages = 5810–20 | year = 2003 | pmid = 12719574 | pmc = 154025 | doi = 10.1128/JVI.77.10.5810-5820.2003 }}
* {{cite journal | vauthors = Lecossier D, Bouchonnet F, Clavel F, Hance AJ | title = Hypermutation of HIV-1 DNA in the absence of the Vif protein. | journal = Science | volume = 300 | issue = 5622 | pages = 1112 | year = 2003 | pmid = 12750511 | doi = 10.1126/science.1083338 }}
* {{cite journal | vauthors = Lecossier D, Bouchonnet F, Clavel F, Hance AJ | title = Hypermutation of HIV-1 DNA in the absence of the Vif protein | journal = Science | volume = 300 | issue = 5622 | pages = 1112 | year = 2003 | pmid = 12750511 | doi = 10.1126/science.1083338 }}
* {{cite journal | vauthors = Zhang H, Yang B, Pomerantz RJ, Zhang C, Arunachalam SC, Gao L | title = The cytidine deaminase CEM15 induces hypermutation in newly synthesized HIV-1 DNA | journal = Nature | volume = 424 | issue = 6944 | pages = 94–8 | year = 2003 | pmid = 12808465 | pmc = 1350966 | doi = 10.1038/nature01707 | bibcode = 2003Natur.424...94Z }}
* {{cite journal | vauthors = Zhang H, Yang B, Pomerantz RJ, Zhang C, Arunachalam SC, Gao L | title = The cytidine deaminase CEM15 induces hypermutation in newly synthesized HIV-1 DNA | journal = Nature | volume = 424 | issue = 6944 | pages = 94–8 | year = 2003 | pmid = 12808465 | pmc = 1350966 | doi = 10.1038/nature01707 | bibcode = 2003Natur.424...94Z }}
* {{cite journal | vauthors = Mangeat B, Turelli P, Caron G, Friedli M, Perrin L, Trono D | title = Broad antiretroviral defence by human APOBEC3G through lethal editing of nascent reverse transcripts | journal = Nature | volume = 424 | issue = 6944 | pages = 99–103 | year = 2003 | pmid = 12808466 | doi = 10.1038/nature01709 | bibcode = 2003Natur.424...99M }}
* {{cite journal | vauthors = Mangeat B, Turelli P, Caron G, Friedli M, Perrin L, Trono D | title = Broad antiretroviral defence by human APOBEC3G through lethal editing of nascent reverse transcripts | journal = Nature | volume = 424 | issue = 6944 | pages = 99–103 | year = 2003 | pmid = 12808466 | doi = 10.1038/nature01709 | bibcode = 2003Natur.424...99M }}
* {{cite journal | vauthors = Harris RS, Bishop KN, Sheehy AM, Craig HM, Petersen-Mahrt SK, Watt IN, Neuberger MS, Malim MH | title = DNA deamination mediates innate immunity to retroviral infection. | journal = Cell | volume = 113 | issue = 6 | pages = 803–9 | year = 2003 | pmid = 12809610 | doi = 10.1016/S0092-8674(03)00423-9 }}
* {{cite journal | vauthors = Harris RS, Bishop KN, Sheehy AM, Craig HM, Petersen-Mahrt SK, Watt IN, Neuberger MS, Malim MH | title = DNA deamination mediates innate immunity to retroviral infection | journal = Cell | volume = 113 | issue = 6 | pages = 803–9 | year = 2003 | pmid = 12809610 | doi = 10.1016/S0092-8674(03)00423-9 }}
{{refend}}
{{refend}}
==External links==
* {{MeshName|gankyrin+protein,+human}}


{{PDB Gallery|geneid=5716}}
{{PDB Gallery|geneid=5716}}


{{Proteasome subunits}}
{{Proteasome subunits}}
[[Category:Proteins]]
[[Category:Oncogenes]]

Latest revision as of 12:12, 28 September 2018

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Identifiers
Aliases
External IDsGeneCards: [1]
Orthologs
SpeciesHumanMouse
Entrez

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Ensembl

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UniProt

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RefSeq (mRNA)

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RefSeq (protein)

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Location (UCSC)n/an/a
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View/Edit Human

26S proteasome non-ATPase regulatory subunit 10 or gankyrin is an enzyme that in humans is encoded by the PSMD10 gene.[1] Gankyrin is an oncoprotein that is a component of the 19S regulatory cap of the proteasome. Structurally, it contains a 33-amino acid ankyrin repeat that forms a series of alpha helices.[2] It plays a key role in regulating the cell cycle via protein-protein interactions with the cyclin-dependent kinase CDK4. It also binds closely to the E3 ubiquitin ligase MDM2, which is a regulator of the degradation of p53 and retinoblastoma protein, both transcription factors involved in tumor suppression and found mutated in many cancers.[3] Gankyrin also has an anti-apoptotic effect and is overexpressed in certain types of tumor cells such as hepatocellular carcinoma.[4]

Function

The 26S proteasome is a multicatalytic proteinase complex with a highly ordered structure composed of 2 complexes, a 20S core and a 19S regulator. The 20S core is composed of 4 rings of 28 non-identical subunits; 2 rings are composed of 7 alpha subunits and 2 rings are composed of 7 beta subunits. The 19S regulator is composed of a base, which contains 6 ATPase subunits and 2 non-ATPase subunits, and a lid, which contains up to 10 non-ATPase subunits. Proteasomes are distributed throughout eukaryotic cells at a high concentration and cleave peptides in an ATP/ubiquitin-dependent process in a non-lysosomal pathway. An essential function of a modified proteasome, the immunoproteasome, is the processing of class I MHC peptides. This gene encodes a non-ATPase subunit of the 19S regulator. Two transcripts encoding different isoforms have been described. Pseudogenes have been identified on chromosomes 3 and 20.[5]

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) [6] 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.[7] Subsequently, a compromised proteasome complex assembly and function lead to reduced proteolytic activities and the accumulation of damaged or misfolded protein species. Such protein accumulation may contribute to the pathogenesis and phenotypic characteristics in neurodegenerative diseases,[8][9] cardiovascular diseases,[10][11][12] inflammatory responses and autoimmune diseases,[13] and systemic DNA damage responses leading to malignancies.[14]

Several experimental and clinical studies have indicated that aberrations and deregulations of the UPS contribute to the pathogenesis of several neurodegenerative and myodegenerative disorders, including Alzheimer's disease,[15] Parkinson's disease[16] and Pick's disease,[17] Amyotrophic lateral sclerosis (ALS),[17] Huntington's disease,[16] Creutzfeldt–Jakob disease,[18] and motor neuron diseases, polyglutamine (PolyQ) diseases, Muscular dystrophies[19] and several rare forms of neurodegenerative diseases associated with dementia.[20] As part of the Ubiquitin-Proteasome System (UPS), the proteasome maintains cardiac protein homeostasis and thus plays a significant role in cardiac Ischemic injury,[21] ventricular hypertrophy[22] and Heart failure.[23] 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.[24] 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, Myc, Myb, Rel, Src, Mos, 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, IL-8, adhesion molecules (ICAM-1, VCAM-1, P-selectin) and prostaglandins and nitric oxide (NO).[13] Additionally, the UPS also plays a role in inflammatory responses as regulators of leukocyte proliferation, mainly through proteolysis of cyclines and the degradation of CDK inhibitors.[25] Lastly, autoimmune disease patients with SLE, Sjogren's syndrome and rheumatoid arthritis (RA) predominantly exhibit circulating proteasomes which can be applied as clinical biomarkers.[26]

Interactions

PSMD10 has been shown to interact with:

References

  1. ↑ Hori T, Kato S, Saeki M, DeMartino GN, Slaughter CA, Takeuchi J, Toh-e A, Tanaka K (Aug 1998). "cDNA cloning and functional analysis of p28 (Nas6p) and p40.5 (Nas7p), two novel regulatory subunits of the 26S proteasome". Gene. 216 (1): 113–22. doi:10.1016/S0378-1119(98)00309-6. PMID 9714768.
  2. ↑ Krzywda S, Brzozowski AM, Higashitsuji H, Fujita J, Welchman R, Dawson S, Mayer RJ, Wilkinson AJ (2004). "The crystal structure of gankyrin, an oncoprotein found in complexes with cyclin-dependent kinase 4, a 19 S proteasomal ATPase regulator, and the tumor suppressors Rb and p53". The Journal of Biological Chemistry. 279 (2): 1541–5. doi:10.1074/jbc.M310265200. PMID 14573599.
  3. ↑ Krzywda S, Brzozowski AM, Al-Safty R, Welchman R, Mee M, Dawson S, Fujita J, Higashitsuji H, Mayer RJ, Wilkinson AJ (2003). "Crystallization of gankyrin, an oncoprotein that interacts with CDK4 and the S6b (rpt3) ATPase of the 19S regulator of the 26S proteasome". Acta Crystallographica Section D. 59 (Pt 7): 1294–5. doi:10.1107/S0907444903009892. PMID 12832791.
  4. ↑ Higashitsuji H, Liu Y, Mayer RJ, Fujita J (2005). "The oncoprotein gankyrin negatively regulates both p53 and RB by enhancing proteasomal degradation". Cell Cycle (Georgetown, Tex.). 4 (10): 1335–7. doi:10.4161/cc.4.10.2107. PMID 16177571.
  5. ↑ "Entrez Gene: PSMD10 proteasome (prosome, macropain) 26S subunit, non-ATPase, 10".
  6. ↑ Kleiger G, Mayor T (Jun 2014). "Perilous journey: a tour of the ubiquitin-proteasome system". Trends in Cell Biology. 24 (6): 352–9. doi:10.1016/j.tcb.2013.12.003. PMC 4037451. PMID 24457024.
  7. ↑ Goldberg AL, Stein R, Adams J (Aug 1995). "New insights into proteasome function: from archaebacteria to drug development". Chemistry & Biology. 2 (8): 503–8. doi:10.1016/1074-5521(95)90182-5. PMID 9383453.
  8. ↑ Sulistio YA, Heese K (Jan 2015). "The Ubiquitin-Proteasome System and Molecular Chaperone Deregulation in Alzheimer's Disease". Molecular Neurobiology. 53 (2): 905–31. doi:10.1007/s12035-014-9063-4. PMID 25561438.
  9. ↑ Ortega Z, Lucas JJ (2014). "Ubiquitin-proteasome system involvement in Huntington's disease". Frontiers in Molecular Neuroscience. 7: 77. doi:10.3389/fnmol.2014.00077. PMC 4179678. PMID 25324717.
  10. ↑ Sandri M, Robbins J (Jun 2014). "Proteotoxicity: an underappreciated pathology in cardiac disease". Journal of Molecular and Cellular Cardiology. 71: 3–10. doi:10.1016/j.yjmcc.2013.12.015. PMC 4011959. PMID 24380730.
  11. ↑ Drews O, Taegtmeyer H (Dec 2014). "Targeting the ubiquitin-proteasome system in heart disease: the basis for new therapeutic strategies". Antioxidants & Redox Signaling. 21 (17): 2322–43. doi:10.1089/ars.2013.5823. PMC 4241867. PMID 25133688.
  12. ↑ Wang ZV, Hill JA (Feb 2015). "Protein quality control and metabolism: bidirectional control in the heart". Cell Metabolism. 21 (2): 215–26. doi:10.1016/j.cmet.2015.01.016. PMC 4317573. PMID 25651176.
  13. ↑ 13.0 13.1 Karin M, Delhase M (Feb 2000). "The I kappa B kinase (IKK) and NF-kappa B: key elements of proinflammatory signalling". Seminars in Immunology. 12 (1): 85–98. doi:10.1006/smim.2000.0210. PMID 10723801.
  14. ↑ Ermolaeva MA, Dakhovnik A, Schumacher B (Sep 2015). "Quality control mechanisms in cellular and systemic DNA damage responses". Ageing Research Reviews. 23 (Pt A): 3–11. doi:10.1016/j.arr.2014.12.009. PMC 4886828. PMID 25560147.
  15. ↑ Checler F, da Costa CA, Ancolio K, Chevallier N, Lopez-Perez E, Marambaud P (Jul 2000). "Role of the proteasome in Alzheimer's disease". Biochimica et Biophysica Acta. 1502 (1): 133–8. doi:10.1016/s0925-4439(00)00039-9. PMID 10899438.
  16. ↑ 16.0 16.1 Chung KK, Dawson VL, Dawson TM (Nov 2001). "The role of the ubiquitin-proteasomal pathway in Parkinson's disease and other neurodegenerative disorders". Trends in Neurosciences. 24 (11 Suppl): S7–14. doi:10.1016/s0166-2236(00)01998-6. PMID 11881748.
  17. ↑ 17.0 17.1 Ikeda K, Akiyama H, Arai T, Ueno H, Tsuchiya K, Kosaka K (Jul 2002). "Morphometrical reappraisal of motor neuron system of Pick's disease and amyotrophic lateral sclerosis with dementia". Acta Neuropathologica. 104 (1): 21–8. doi:10.1007/s00401-001-0513-5. PMID 12070660.
  18. ↑ Manaka H, Kato T, Kurita K, Katagiri T, Shikama Y, Kujirai K, Kawanami T, Suzuki Y, Nihei K, Sasaki H (May 1992). "Marked increase in cerebrospinal fluid ubiquitin in Creutzfeldt–Jakob disease". Neuroscience Letters. 139 (1): 47–9. Bibcode:2006NeuL..400..197D. doi:10.1016/0304-3940(92)90854-z. PMID 1328965.
  19. ↑ Mathews KD, Moore SA (Jan 2003). "Limb-girdle muscular dystrophy". Current Neurology and Neuroscience Reports. 3 (1): 78–85. doi:10.1007/s11910-003-0042-9. PMID 12507416.
  20. ↑ Mayer RJ (Mar 2003). "From neurodegeneration to neurohomeostasis: the role of ubiquitin". Drug News & Perspectives. 16 (2): 103–8. doi:10.1358/dnp.2003.16.2.829327. PMID 12792671.
  21. ↑ Calise J, Powell SR (Feb 2013). "The ubiquitin proteasome system and myocardial ischemia". American Journal of Physiology. Heart and Circulatory Physiology. 304 (3): H337–49. doi:10.1152/ajpheart.00604.2012. PMC 3774499. PMID 23220331.
  22. ↑ Predmore JM, Wang P, Davis F, Bartolone S, Westfall MV, Dyke DB, Pagani F, Powell SR, Day SM (Mar 2010). "Ubiquitin proteasome dysfunction in human hypertrophic and dilated cardiomyopathies". Circulation. 121 (8): 997–1004. doi:10.1161/CIRCULATIONAHA.109.904557. PMC 2857348. PMID 20159828.
  23. ↑ Powell SR (Jul 2006). "The ubiquitin-proteasome system in cardiac physiology and pathology". American Journal of Physiology. Heart and Circulatory Physiology. 291 (1): H1–H19. doi:10.1152/ajpheart.00062.2006. PMID 16501026.
  24. ↑ Adams J (Apr 2003). "Potential for proteasome inhibition in the treatment of cancer". Drug Discovery Today. 8 (7): 307–15. doi:10.1016/s1359-6446(03)02647-3. PMID 12654543.
  25. ↑ Ben-Neriah Y (Jan 2002). "Regulatory functions of ubiquitination in the immune system". Nature Immunology. 3 (1): 20–6. doi:10.1038/ni0102-20. PMID 11753406.
  26. ↑ Egerer K, Kuckelkorn U, Rudolph PE, Rückert JC, Dörner T, Burmester GR, Kloetzel PM, Feist E (Oct 2002). "Circulating proteasomes are markers of cell damage and immunologic activity in autoimmune diseases". The Journal of Rheumatology. 29 (10): 2045–52. PMID 12375310.
  27. ↑ Qiu W, Wu J, Walsh EM, Zhang Y, Chen CY, Fujita J, Xiao ZX (Jul 2008). "Retinoblastoma protein modulates gankyrin-MDM2 in regulation of p53 stability and chemosensitivity in cancer cells". Oncogene. 27 (29): 4034–43. doi:10.1038/onc.2008.43. PMID 18332869.
  28. ↑ 28.0 28.1 Ewing RM, Chu P, Elisma F, Li H, Taylor P, Climie S, McBroom-Cerajewski L, Robinson MD, O'Connor L, Li M, Taylor R, Dharsee M, Ho Y, Heilbut A, Moore L, Zhang S, Ornatsky O, Bukhman YV, Ethier M, Sheng Y, Vasilescu J, Abu-Farha M, Lambert JP, Duewel HS, Stewart II, Kuehl B, Hogue K, Colwill K, Gladwish K, Muskat B, Kinach R, Adams SL, Moran MF, Morin GB, Topaloglou T, Figeys D (2007). "Large-scale mapping of human protein-protein interactions by mass spectrometry". Mol. Syst. Biol. 3: 89. doi:10.1038/msb4100134. PMC 1847948. PMID 17353931.
  29. ↑ Rual JF, Venkatesan K, Hao T, Hirozane-Kishikawa T, Dricot A, Li N, Berriz GF, Gibbons FD, Dreze M, Ayivi-Guedehoussou N, Klitgord N, Simon C, Boxem M, Milstein S, Rosenberg J, Goldberg DS, Zhang LV, Wong SL, Franklin G, Li S, Albala JS, Lim J, Fraughton C, Llamosas E, Cevik S, Bex C, Lamesch P, Sikorski RS, Vandenhaute J, Zoghbi HY, Smolyar A, Bosak S, Sequerra R, Doucette-Stamm L, Cusick ME, Hill DE, Roth FP, Vidal M (Oct 2005). "Towards a proteome-scale map of the human protein-protein interaction network". Nature. 437 (7062): 1173–8. Bibcode:2005Natur.437.1173R. doi:10.1038/nature04209. PMID 16189514.
  30. ↑ Dawson S, Apcher S, Mee M, Higashitsuji H, Baker R, Uhle S, Dubiel W, Fujita J, Mayer RJ (Mar 2002). "Gankyrin is an ankyrin-repeat oncoprotein that interacts with CDK4 kinase and the S6 ATPase of the 26 S proteasome". J. Biol. Chem. 277 (13): 10893–902. doi:10.1074/jbc.M107313200. PMID 11779854.

Further reading

External links

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