AEG1
Metadherin, znan i kao protein LYRIC ili gen 1 ptoteina za podizanje astrocita (AEG-1) je protein, koji je kod ljudi kodiran genom MTDH.[5][6][7]
Aminokiselinska sekvenca
urediDužina polipeptidnog lanca je 582 aminokiseline, а molekulska težina 63.837 Da.[8]
| 10 | 20 | 30 | 40 | 50 | ||||
|---|---|---|---|---|---|---|---|---|
| MAARSWQDEL | AQQAEEGSAR | LREMLSVGLG | FLRTELGLDL | GLEPKRYPGW | ||||
| VILVGTGALG | LLLLFLLGYG | WAAACAGARK | KRRSPPRKRE | EAAAVPAAAP | ||||
| DDLALLKNLR | SEEQKKKNRK | KLSEKPKPNG | RTVEVAEGEA | VRTPQSVTAK | ||||
| QPPEIDKKNE | KSKKNKKKSK | SDAKAVQNSS | RHDGKEVDEG | AWETKISHRE | ||||
| KRQQRKRDKV | LTDSGSLDST | IPGIENTITV | TTEQLTTASF | PVGSKKNKGD | ||||
| SHLNVQVSNF | KSGKGDSTLQ | VSSGLNENLT | VNGGGWNEKS | VKLSSQISAG | ||||
| EEKWNSVSPA | SAGKRKTEPS | AWSQDTGDAN | TNGKDWGRSW | SDRSIFSGIG | ||||
| STAEPVSQST | TSDYQWDVSR | NQPYIDDEWS | GLNGLSSADP | NSDWNAPAEE | ||||
| WGNWVDEERA | SLLKSQEPIP | DDQKVSDDDK | EKGEGALPTG | KSKKKKKKKK | ||||
| KQGEDNSTAQ | DTEELEKEIR | EDLPVNTSKT | RPKQEKAFSL | KTISTSDPAE | ||||
| VLVKNSQPIK | TLPPATSTEP | SVILSKSDSD | KSSSQVPPIL | QETDKSKSNT | ||||
| KQNSVPPSQT | KSETSWESPK | QIKKKKKARR | ET |
Funkcija
urediMTDH (AEG-1) je uključen u angiogenezu , posredovanu preko HIF-1alfa posredovanu. Također stupa u interakciju s SND1 i uključen je u RNK-inducirani kompleks za utišavanje (RISC) i ima vrlo važnu ulogu u funkcijama RISC-a i miRNK.|[[9][10] Pokazalo se da MTDH stupa u interakciju sa proteinama splajsosoma u ćelijskom jedru i regulira proces alternativne prerade transkripta.[11]
MTDH inducira onkogen zvani kasni faktor SV40 (LSF/TFCP2) koji je uključen u indukciju timidilat-sintaze (TS) i biosintezu DNK.[12] Kasni faktor SV40 (LSF/TFCP2) pojačava angiogenezu transkripcijskom regulacijom matriksne metaloproteinaze-9 (MMP9).[13]
Klinički značaj
urediMTDH djeluje kao onkogen kod melanoma, malignog glioma, raka dojke i hepatoćelijskog karcinoma.[14] Vrlo je eksprimiran kod ovih karcinoma i pomaže u njihovoj progresiji i razvoju. Izaziva ga c-Myc onkogen i ima vrlo važnu ulogu u usidrenju neovisnog rasta ćelija raka.
Povišena ekspresija gena za metastaze metadherina (MTDH), koji je prekomjerno izražen u više od 40% slučajeva raka dojke, povezan je s lošim kliničkim ishodima. MTDH ima dvostruku ulogu u podsticanju metastatskih rasijaqvanja i poboljšanju hemorezistencije. MTDH je stoga potencijalna terapijska meta za poboljšanje hemoterapije i smanjenje metastaza.[15]
Pokazalo se da je MTDH prekomjerno eksprimiran u karcinomu prostate, gdje postoji pomak prema više citoplazmatskoj lokalizaciji, signalizirajući lošu prognozu.[16][17] Pokazalo se da u jezdrima ćelija raka prostate MTDH utiče na alternativnu preradu gena kao što je CD44 koji također može biti povezan s progresijom raka prostate.[11]
LSF/TFCP2 ima višestruku ulogu u hemorezistenciji, EMT, alergijskom odgovoru, upalama i Alzheimerovoj bolesti.[18]
MTDH kontrolira mnoga obilježja onkogena i raka. MTDH/AEG-1 inducira hepatosteatoze u jetri miša.[19] Nokdaun MTDH vještačkim interferencijama mikroRNK funkcionira kao potencijalni supresor tumora u raku dojke.[20] Povišena funkcija gena-1/MTDH izaziva povišenje u astrocitima i podvrgava se palmitoilaciji u normalnoj i abnormalnoj fiziologiji ćelije.[21] Biomaterijalne titanijske podloge s mikrožljebovima mogu promijeniti ekspresiju MTDH u primarnim ćelijama čovjeka.[22]
Reference
uredi- ^ a b c GRCh38: Ensembl release 89: ENSG00000147649 - Ensembl, maj 2017
- ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000022255 - Ensembl, maj 2017
- ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- ^ "Entrez Gene: MTDH metadherin".
- ^ Brown DM, Ruoslahti E (april 2004). "Metadherin, a cell surface protein in breast tumors that mediates lung metastasis". Cancer Cell. 5 (4): 365–74. doi:10.1016/S1535-6108(04)00079-0. PMID 15093543.
- ^ Sutherland HG, Lam YW, Briers S, Lamond AI, Bickmore WA (mart 2004). "3D3/lyric: a novel transmembrane protein of the endoplasmic reticulum and nuclear envelope, which is also present in the nucleolus". Experimental Cell Research. 294 (1): 94–105. doi:10.1016/j.yexcr.2003.11.020. PMID 14980505.
- ^ "UniProt, Q86UE4". Pristupljeno 13. 9. 2021.
- ^ Yoo BK, Santhekadur PK, Gredler R, Chen D, Emdad L, Bhutia S, et al. (maj 2011). "Increased RNA-induced silencing complex (RISC) activity contributes to hepatocellular carcinoma". Hepatology. 53 (5): 1538–48. doi:10.1002/hep.24216. PMC 3081619. PMID 21520169.
- ^ Yoo BK, Emdad L, Lee SG, Su ZZ, Santhekadur P, Chen D, et al. (april 2011). "Astrocyte elevated gene-1 (AEG-1): A multifunctional regulator of normal and abnormal physiology". Pharmacology & Therapeutics. 130 (1): 1–8. doi:10.1016/j.pharmthera.2011.01.008. PMC 3043119. PMID 21256156.
- ^ a b Luxton HJ, Simpson BS, Mills IG, Brindle NR, Ahmed Z, Stavrinides V, Heavey S, Stamm S, Whitaker HC (septembar 2019). "The Oncogene Metadherin Interacts with the Known Splicing Proteins YTHDC1, Sam68 and T-STAR and Plays a Novel Role in Alternative mRNA Splicing". Cancers. 11 (9): 1233. doi:10.3390/cancers11091233. PMC 6770463. PMID 31450747.
- ^ Yoo BK, Gredler R, Vozhilla N, Su ZZ, Chen D, Forcier T, et al. (august 2009). "Identification of genes conferring resistance to 5-fluorouracil". Proceedings of the National Academy of Sciences of the United States of America. 106 (31): 12938–43. Bibcode:2009PNAS..10612938Y. doi:10.1073/pnas.0901451106. PMC 2722317. PMID 19622726.
- ^ Santhekadur PK, Gredler R, Chen D, Siddiq A, Shen XN, Das SK, et al. (januar 2012). "Late SV40 factor (LSF) enhances angiogenesis by transcriptionally up-regulating matrix metalloproteinase-9 (MMP-9)". The Journal of Biological Chemistry. 287 (5): 3425–32. doi:10.1074/jbc.M111.298976. PMC 3270996. PMID 22167195.
- ^ Yoo BK, Emdad L, Su ZZ, Villanueva A, Chiang DY, Mukhopadhyay ND, et al. (mart 2009). "Astrocyte elevated gene-1 regulates hepatocellular carcinoma development and progression". The Journal of Clinical Investigation. 119 (3): 465–77. doi:10.1172/JCI36460. PMC 2648696. PMID 19221438.
- ^ Hu G, Chong RA, Yang Q, Wei Y, Blanco MA, Li F, et al. (januar 2009). "MTDH activation by 8q22 genomic gain promotes chemoresistance and metastasis of poor-prognosis breast cancer". Cancer Cell. 15 (1): 9–20. doi:10.1016/j.ccr.2008.11.013. PMC 2676231. PMID 19111877.
- ^ Kikuno N, Shiina H, Urakami S, Kawamoto K, Hirata H, Tanaka Y, et al. (decembar 2007). "Knockdown of astrocyte-elevated gene-1 inhibits prostate cancer progression through upregulation of FOXO3a activity". Oncogene. 26 (55): 7647–55. doi:10.1038/sj.onc.1210572. PMID 17563745.
- ^ Thirkettle HJ, Girling J, Warren AY, Mills IG, Sahadevan K, Leung H, et al. (maj 2009). "LYRIC/AEG-1 is targeted to different subcellular compartments by ubiquitinylation and intrinsic nuclear localization signals". Clinical Cancer Research. 15 (9): 3003–13. doi:10.1158/1078-0432.CCR-08-2046. PMID 19383828.
- ^ Santhekadur PK, Rajasekaran D, Siddiq A, Gredler R, Chen D, Schaus SC, Hansen U, Fisher PB, Sarkar D (2012). "The transcription factor LSF: a novel oncogene for hepatocellular carcinoma" (PDF). Am J Cancer Res. 2 (3): 269–285. PMC 3365805. PMID 22679558.
- ^ Srivastava J, Siddiq A, Emdad L, Santhekadur PK, Chen D, Gredler R, et al. (novembar 2012). "Astrocyte elevated gene-1 promotes hepatocarcinogenesis: novel insights from a mouse model". Hepatology. 56 (5): 1782–91. doi:10.1002/hep.25868. PMC 3449036. PMID 22689379.
- ^ Wang S, Shu JZ, Cai Y, Bao Z, Liang QM (2012). "Establishment and characterization of MTDH knockdown by artificial MicroRNA interference - functions as a potential tumor suppressor in breast cancer" (PDF). Asian Pacific Journal of Cancer Prevention. 13 (6): 2813–8. doi:10.7314/apjcp.2012.13.6.2813. PMID 22938464.
- ^ Martin BR, Wang C, Adibekian A, Tully SE, Cravatt BF (novembar 2011). "Global profiling of dynamic protein palmitoylation". Nature Methods. 9 (1): 84–9. doi:10.1038/nmeth.1769. PMC 3248616. PMID 22056678.
- ^ Lee MH, Kang JH, Lee SW (april 2012). "The significance of differential expression of genes and proteins in human primary cells caused by microgrooved biomaterial substrata". Biomaterials. 33 (11): 3216–34. doi:10.1016/j.biomaterials.2012.01.034. PMID 22285466.
Dopunska literatura
uredi- Emdad L, Sarkar D, Su ZZ, Lee SG, Kang DC, Bruce JN, et al. (maj 2007). "Astrocyte elevated gene-1: recent insights into a novel gene involved in tumor progression, metastasis and neurodegeneration". Pharmacology & Therapeutics. 114 (2): 155–70. doi:10.1016/j.pharmthera.2007.01.010. PMC 2039930. PMID 17397930.
- van 't Veer LJ, Dai H, van de Vijver MJ, He YD, Hart AA, Mao M, et al. (januar 2002). "Gene expression profiling predicts clinical outcome of breast cancer". Nature. 415 (6871): 530–6. doi:10.1038/415530a. hdl:1874/15552. PMID 11823860. S2CID 4369266.
- Sutherland HG, Lam YW, Briers S, Lamond AI, Bickmore WA (mart 2004). "3D3/lyric: a novel transmembrane protein of the endoplasmic reticulum and nuclear envelope, which is also present in the nucleolus". Experimental Cell Research. 294 (1): 94–105. doi:10.1016/j.yexcr.2003.11.020. PMID 14980505.
- Brown DM, Ruoslahti E (april 2004). "Metadherin, a cell surface protein in breast tumors that mediates lung metastasis". Cancer Cell. 5 (4): 365–74. doi:10.1016/S1535-6108(04)00079-0. PMID 15093543.
- Britt DE, Yang DF, Yang DQ, Flanagan D, Callanan H, Lim YP, et al. (oktobar 2004). "Identification of a novel protein, LYRIC, localized to tight junctions of polarized epithelial cells". Experimental Cell Research. 300 (1): 134–48. doi:10.1016/j.yexcr.2004.06.026. PMID 15383321.
- Kang DC, Su ZZ, Sarkar D, Emdad L, Volsky DJ, Fisher PB (juni 2005). "Cloning and characterization of HIV-1-inducible astrocyte elevated gene-1, AEG-1". Gene. 353 (1): 8–15. doi:10.1016/j.gene.2005.04.006. PMID 15927426.
- Olsen JV, Blagoev B, Gnad F, Macek B, Kumar C, Mortensen P, Mann M (novembar 2006). "Global, in vivo, and site-specific phosphorylation dynamics in signaling networks". Cell. 127 (3): 635–48. doi:10.1016/j.cell.2006.09.026. PMID 17081983. S2CID 7827573.
- Lee SG, Su ZZ, Emdad L, Sarkar D, Fisher PB (novembar 2006). "Astrocyte elevated gene-1 (AEG-1) is a target gene of oncogenic Ha-ras requiring phosphatidylinositol 3-kinase and c-Myc". Proceedings of the National Academy of Sciences of the United States of America. 103 (46): 17390–5. Bibcode:2006PNAS..10317390L. doi:10.1073/pnas.0608386103. PMC 1859939. PMID 17088530.