DKK1
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| Идентификаторы | |||||||||||||||||||||||||||||||||||||||||||||||||||
| Псевдонимы | DKK1 , DKK-1, SK, Dickkopf Wnt Ингибитор сигнального пути 1 | ||||||||||||||||||||||||||||||||||||||||||||||||||
| Внешние идентификаторы | Омим : 605189 ; MGI : 1329040 ; Гомологен : 7689 ; GeneCards : DKK1 ; OMA : DKK1 - ортологи | ||||||||||||||||||||||||||||||||||||||||||||||||||
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Связанный с диккопфом белок 1 является белком , который у людей кодируется DKK1 геном . [ 5 ]
Функция
[ редактировать ]Этот ген кодирует белок, который является членом семейства Диккопфа . Это секретируемый белок с двумя богатыми цистеинами и участвует в эмбриональном развитии посредством его ингибирования сигнального пути Wnt . Ингибитор сигнального пути Dickkopf Wnt 1 (DKK1) представляет собой ген, кодирующий белок, который действует из передней висцеральной эндодермы . [ 6 ] [ 7 ] Белок Dickkopf, кодируемый DKK1, является антагонистом сигнального пути Wnt/β-катенина, который действует путем выделения со-рецептора LRP6 , чтобы он не мог помочь в активации сигнального пути Wnt. [ 8 ] Это ингибирование играет ключевую роль в развитии сердца, головы и передней основе во время переднего морфогенеза эмбриона. [ 5 ] [ 9 ]
Interactions
[edit]DKK1 has been shown to interact with LRP6[10] and is a high affinity ligand of Kremen proteins.[11]
Clinical significance
[edit]Elevated levels of DKK1 in bone marrow, plasma and peripheral blood are associated with the presence of osteolytic bone lesions in patients with multiple myeloma.[5] Due to the role of DKK1 in inflammation induced bone loss DKK1 is under investigation as target for therapeutic strategies in medicine and dentistry.[12][13][14]
Animal studies
[edit]Scientists have created a DKK1 knockout model in mice that revealed the effects of this gene. All mice that were homozygous for the DKK1 knockout were dead at birth due to defects in the cranium and structures formed by the neural crest, such as failed development of eyes, olfactory placodes, frontonasal mass and mandibular processes, as well as incomplete development of the forebrain and midbrain and fusion of the digits of the forelimb.[7] This evidence supports the idea that inhibition of the Wnt signaling pathway by DKK1 is crucial to proper cranial development.
In vitro studies
[edit]DKK1 is one of the most upregulated genes in androgen-potentiated balding, with DKK-1 messenger RNA upregulated a few hours after DHT treatment of hair follicles at the dermal papilla in vitro. Neutralizing antibody against DKK-1 reversed DHT effects on outer root sheath keratinocytes.[15] DKK-1 expression is attenuated by L-threonate in vitro, with the latter a metabolite of ascorbate.[16]
DKK1 and Alzheimer's
[edit]Alzheimer's disease occurs due to the overproduction of amyloid beta that will cluster together to form amyloid plaques between neurons in the brain and disrupt cell function. In addition, there is an accumulation of neurofibrillary tangles of hyperphosphorylated tau inside the neuron.[17] The Wnt signaling pathway is crucial for brain development processes, which include neuron proliferation and differentiation as well as neuroblast migration and axon guidance.[18] Downregulation of this signaling has been shown in those with Alzheimer's as a result of high levels of DKK1.[18] Because of the hyperphosphorylation induced by DKK1, tau cannot interact with neuronal microtubules consequently compromising axonal transport resulting in synaptic loss and neuronal apoptosis.[17] Because of its antagonistic effects on the Wnt signaling pathway, it is believed that DKK1 is a common marker for neuronal death in neurodegenerative diseases like Alzheimer's.[18]
References
[edit]- ^ Jump up to: a b c GRCh38: Ensembl release 89: ENSG00000107984 – Ensembl, May 2017
- ^ Jump up to: a b c GRCm38: Ensembl release 89: ENSMUSG00000024868 – Ensembl, May 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.
- ^ Jump up to: a b c "Entrez Gene: DKK1 dickkopf homolog 1 (Xenopus laevis)".
- ^ Schneider VA, Mercola M (1999). "Spatially distinct head and heart inducers within the Xenopus organizer region". Current Biology. 9 (15): 800–9. Bibcode:1999CBio....9..800S. doi:10.1016/s0960-9822(99)80363-7. PMID 10469564. S2CID 16744197.
- ^ Jump up to: a b Mukhopadhyay M, Shtrom S, Rodriguez-Esteban C, Chen L, Tsukui T, Gomer L, et al. (September 2001). "Dickkopf1 is required for embryonic head induction and limb morphogenesis in the mouse". Developmental Cell. 1 (3): 423–34. doi:10.1016/s1534-5807(01)00041-7. PMID 11702953.
- ^ Lewis SL, Khoo PL, De Young RA, Steiner K, Wilcock C, Mukhopadhyay M, et al. (May 2008). "Dkk1 and Wnt3 interact to control head morphogenesis in the mouse". Development. 135 (10): 1791–801. doi:10.1242/dev.018853. PMID 18403408.
- ^ Schneider VA, Mercola M (February 2001). "Wnt antagonism initiates cardiogenesis in Xenopus laevis". Genes & Development. 15 (3): 304–15. doi:10.1101/gad.855601. PMC 312618. PMID 11159911.
- ^ Semënov MV, Tamai K, Brott BK, Kühl M, Sokol S, He X (June 2001). "Head inducer Dickkopf-1 is a ligand for Wnt coreceptor LRP6". Current Biology. 11 (12): 951–61. Bibcode:2001CBio...11..951S. doi:10.1016/S0960-9822(01)00290-1. PMID 11448771. S2CID 15702819.
- ^ Nakamura T, Nakamura T, Matsumoto K (April 2008). "The functions and possible significance of Kremen as the gatekeeper of Wnt signalling in development and pathology". Journal of Cellular and Molecular Medicine. 12 (2): 391–408. doi:10.1111/j.1582-4934.2007.00201.x. PMC 3822531. PMID 18088386.
- ^ Samiei M, Janjić K, Cvikl B, Moritz A, Agis H (2019-01-30). "The role of sclerostin and dickkopf-1 in oral tissues - A review from the perspective of the dental disciplines". F1000Research. 8: 128. doi:10.12688/f1000research.17801.1. PMC 6468704. PMID 31031968.
- ^ Ke HZ, Richards WG, Li X, Ominsky MS (October 2012). "Sclerostin and Dickkopf-1 as therapeutic targets in bone diseases". Endocrine Reviews. 33 (5): 747–83. doi:10.1210/er.2011-1060. PMID 22723594.
- ^ McCarthy HS, Marshall MJ (February 2010). "Dickkopf-1 as a potential therapeutic target in Paget's disease of bone". Expert Opinion on Therapeutic Targets. 14 (2): 221–30. doi:10.1517/14728220903525720. PMID 20055719. S2CID 23456886.
- ^ Kwack MH, Sung YK, Chung EJ, Im SU, Ahn JS, Kim MK, et al. (February 2008). "Dihydrotestosterone-inducible dickkopf 1 from balding dermal papilla cells causes apoptosis in follicular keratinocytes". The Journal of Investigative Dermatology. 128 (2): 262–9. doi:10.1038/sj.jid.5700999. PMID 17657240.
- ^ Kwack MH, Ahn JS, Kim MK, Kim JC, Sung YK (October 2010). "Preventable effect of L-threonate, an ascorbate metabolite, on androgen-driven balding via repression of dihydrotestosterone-induced dickkopf-1 expression in human hair dermal papilla cells". BMB Reports. 43 (10): 688–92. doi:10.5483/BMBRep.2010.43.10.688. PMID 21034532.
- ^ Jump up to: a b Boonen RA, van Tijn P, Zivkovic D (April 2009). "Wnt signaling in Alzheimer's disease: up or down, that is the question". Ageing Research Reviews. 8 (2): 71–82. doi:10.1016/j.arr.2008.11.003. PMID 19101658. S2CID 24424543.
- ^ Jump up to: a b c Huang Y, Liu L, Liu A (September 2018). "Dickkopf-1: Current knowledge and related diseases". Life Sciences. 209: 249–254. doi:10.1016/j.lfs.2018.08.019. PMID 30102902. S2CID 51974340.
Further reading
[edit]- Fedi P, Bafico A, Nieto Soria A, Burgess WH, Miki T, Bottaro DP, et al. (July 1999). "Isolation and biochemical characterization of the human Dkk-1 homologue, a novel inhibitor of mammalian Wnt signaling". The Journal of Biological Chemistry. 274 (27): 19465–72. doi:10.1074/jbc.274.27.19465. PMID 10383463. S2CID 39562013.
- Krupnik VE, Sharp JD, Jiang C, Robison K, Chickering TW, Amaravadi L, et al. (October 1999). "Functional and structural diversity of the human Dickkopf gene family". Gene. 238 (2): 301–13. doi:10.1016/S0378-1119(99)00365-0. PMID 10570958.
- Roessler E, Du Y, Glinka A, Dutra A, Niehrs C, Muenke M (2000). "The genomic structure, chromosome location, and analysis of the human DKK1 head inducer gene as a candidate for holoprosencephaly". Cytogenetics and Cell Genetics. 89 (3–4): 220–4. doi:10.1159/000015618. PMID 10965128. S2CID 22763213.
- Mao B, Wu W, Li Y, Hoppe D, Stannek P, Glinka A, et al. (May 2001). "LDL-receptor-related protein 6 is a receptor for Dickkopf proteins". Nature. 411 (6835): 321–5. Bibcode:2001Natur.411..321M. doi:10.1038/35077108. PMID 11357136. S2CID 4323027.
- Semënov MV, Tamai K, Brott BK, Kühl M, Sokol S, He X (June 2001). "Head inducer Dickkopf-1 is a ligand for Wnt coreceptor LRP6". Current Biology. 11 (12): 951–61. Bibcode:2001CBio...11..951S. doi:10.1016/S0960-9822(01)00290-1. PMID 11448771. S2CID 15702819.
- Zorn AM (August 2001). "Wnt signalling: antagonistic Dickkopfs". Current Biology. 11 (15): R592-5. Bibcode:2001CBio...11.R592Z. doi:10.1016/S0960-9822(01)00360-8. PMID 11516963. S2CID 14970864.
- Shou J, Ali-Osman F, Multani AS, Pathak S, Fedi P, Srivenugopal KS (January 2002). "Human Dkk-1, a gene encoding a Wnt antagonist, responds to DNA damage and its overexpression sensitizes brain tumor cells to apoptosis following alkylation damage of DNA". Oncogene. 21 (6): 878–89. doi:10.1038/sj.onc.1205138. PMID 11840333. S2CID 43987784.
- Mao B, Wu W, Davidson G, Marhold J, Li M, Mechler BM, et al. (June 2002). "Kremen proteins are Dickkopf receptors that regulate Wnt/beta-catenin signalling". Nature. 417 (6889): 664–7. Bibcode:2002Natur.417..664M. doi:10.1038/nature756. PMID 12050670. S2CID 4418943.
- Aguilera O, Fraga MF, Ballestar E, Paz MF, Herranz M, Espada J, et al. (July 2006). "Epigenetic inactivation of the Wnt antagonist DICKKOPF-1 (DKK-1) gene in human colorectal cancer". Oncogene. 25 (29): 4116–21. doi:10.1038/sj.onc.1209439. PMID 16491118.
- Brott BK, Sokol SY (September 2002). "Regulation of Wnt/LRP signaling by distinct domains of Dickkopf proteins". Molecular and Cellular Biology. 22 (17): 6100–10. doi:10.1128/MCB.22.17.6100-6110.2002. PMC 133995. PMID 12167704.
- Gregory CA, Singh H, Perry AS, Prockop DJ (July 2003). "The Wnt signaling inhibitor dickkopf-1 is required for reentry into the cell cycle of human adult stem cells from bone marrow". The Journal of Biological Chemistry. 278 (30): 28067–78. doi:10.1074/jbc.M300373200. PMID 12740383.
- Tian E, Zhan F, Walker R, Rasmussen E, Ma Y, Barlogie B, et al. (December 2003). "The role of the Wnt-signaling antagonist DKK1 in the development of osteolytic lesions in multiple myeloma". The New England Journal of Medicine. 349 (26): 2483–94. doi:10.1056/NEJMoa030847. PMID 14695408.
- Yamaguchi Y, Itami S, Watabe H, Yasumoto K, Abdel-Malek ZA, Kubo T, et al. (Апрель 2004 г.). «Мезенхимально-эпителиальные взаимодействия в коже: повышенная экспрессия dickkopf1 с помощью пальмоплантарных фибробластов ингибирует рост и дифференцировку меланоцитов» . Журнал клеточной биологии . 165 (2): 275–85. doi : 10.1083/jcb.200311122 . PMC 2172049 . PMID 15117970 .
- Caricasole A, Copani A, Caraci F, Aronica E, Rozemuller AJ, Caruso A, et al. (Июнь 2004 г.). «Индукция Dickkopf-1, негативного модулятора пути Wnt, связана с дегенерацией нейронов в мозге Альцгеймера» . Журнал нейробиологии . 24 (26): 6021–7. doi : 10.1523/jneurosci.1381-04.2004 . PMC 6729239 . PMID 15229249 .
- Colland F, Jacq X, Truplin V, Mougin C, Groizeleau C, Hamburger A, et al. (Июль 2004 г.). «Функциональная протеомика картирование сигнального пути человека» . Исследование генома . 14 (7): 1324–32. doi : 10.1101/gr.2334104 . PMC 442148 . PMID 15231748 .
- Zhang Z, Henzel WJ (октябрь 2004 г.). «Прогнозирование сигнальных пептидов на основе анализа экспериментально проверенных сайтов расщепления» . Белковая наука . 13 (10): 2819–24. doi : 10.1110/ps.04682504 . PMC 2286551 . PMID 15340161 .
- Ниида А., Хироко Т., Касаи М., Фурукава Ю., Накамура Ю., Сузуки Ю. и др. (Ноябрь 2004 г.). «DKK1, отрицательный регулятор передачи сигналов Wnt, является мишенью пути бета-катенина/TCF». Онкоген . 23 (52): 8520–6. doi : 10.1038/sj.onc.1207892 . PMID 15378020 . S2CID 9300321 .
- Ли Ай, он Б., ты Л, Сюй З, Мазьерес Дж., Регюарт Н. и др. (Октябрь 2004). «Dickkopf-1 противодействует передаче сигналов Wnt, независимо от бета-катенина при мезотелиоме человека». Биохимическая и биофизическая исследовательская коммуникация . 323 (4): 1246–50. doi : 10.1016/j.bbrc.2004.09.001 . PMID 15451431 .