This gene encodes a protein that is a member of the dickkopf family. It is a secreted protein with two cysteine rich regions and is involved in embryonic development through its inhibition of the Wnt signaling pathway. Dickkopf WNT signaling pathway inhibitor 1 (Dkk1) is a protein-coding gene that acts from the anterior visceral endoderm.[2][3] The dickkopf protein encoded by DKK1 is an antagonist of the Wnt/β-catenin signalling pathway that acts by isolating the LRP6 co-receptor so that it cannot aid in activating the WNT signaling pathway.[4] DKK1 was also demonstrated to antagonize the Wnt/β-catenin pathway via a reduction in β-catenin and an increase in OCT4 expression.[5]
This inhibition plays a key role in heart, head and forelimb development during anterior morphogenesis of the embryo.[1][6]
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.[3] This evidence supports the idea that inhibition of the Wnt signaling pathway by DKK1 is crucial to proper cranial development.
In vitro studies
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 papillain vitro. Neutralizing antibody against DKK-1 reversed DHT effects on outer root sheath keratinocytes.[9] DKK-1 expression is attenuated by L-threonatein vitro, with the latter a metabolite of ascorbate.[10]
↑Schneider VA, Mercola M (1999). "Spatially distinct head and heart inducers within the Xenopus organizer region". Curr Biol. 9: 800–809. doi:10.1016/s0960-9822(99)80363-7.
↑ 3.03.1Mukhopadhyay M, Shtrom S, Rodriguez-Esteban C, Chen L, Tsukui T, Gomer L, Dorward DW, Glinka A, Grinberg A, Huang SP, Niehrs C, Izpisúa Belmonte JC, Westphal H (Sep 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. PMID11702953.
↑Lewis SL, Khoo PL, De Young RA, Steiner K, Wilcock C, Mukhopadhyay M, Westphal H, Jamieson RV, Robb L, Tam PP (May 2008). "Dkk1 and Wnt3 interact to control head morphogenesis in the mouse". Development. 135 (10): 1791–801. doi:10.1242/dev.018853. PMID18403408.
↑Semënov MV, Tamai K, Brott BK, Kühl M, Sokol S, He X (Jun 2001). "Head inducer Dickkopf-1 is a ligand for Wnt coreceptor LRP6". Current Biology. 11 (12): 951–61. doi:10.1016/S0960-9822(01)00290-1. PMID11448771.
↑Kwack MH, Sung YK, Chung EJ, Im SU, Ahn JS, Kim MK, Kim JC (Feb 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. PMID17657240.
↑Kwack MH, Ahn JS, Kim MK, Kim JC, Sung YK (Oct 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. PMID21034532.
Further reading
Fedi P, Bafico A, Nieto Soria A, Burgess WH, Miki T, Bottaro DP, Kraus MH, Aaronson SA (Jul 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. PMID10383463.
Krupnik VE, Sharp JD, Jiang C, Robison K, Chickering TW, Amaravadi L, Brown DE, Guyot D, Mays G, Leiby K, Chang B, Duong T, Goodearl AD, Gearing DP, Sokol SY, McCarthy SA (Oct 1999). "Functional and structural diversity of the human Dickkopf gene family". Gene. 238 (2): 301–13. doi:10.1016/S0378-1119(99)00365-0. PMID10570958.
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. PMID10965128.
Mao B, Wu W, Li Y, Hoppe D, Stannek P, Glinka A, Niehrs C (May 2001). "LDL-receptor-related protein 6 is a receptor for Dickkopf proteins". Nature. 411 (6835): 321–5. doi:10.1038/35077108. PMID11357136.
Semënov MV, Tamai K, Brott BK, Kühl M, Sokol S, He X (Jun 2001). "Head inducer Dickkopf-1 is a ligand for Wnt coreceptor LRP6". Current Biology. 11 (12): 951–61. doi:10.1016/S0960-9822(01)00290-1. PMID11448771.
Shou J, Ali-Osman F, Multani AS, Pathak S, Fedi P, Srivenugopal KS (Jan 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. PMID11840333.
Mao B, Wu W, Davidson G, Marhold J, Li M, Mechler BM, Delius H, Hoppe D, Stannek P, Walter C, Glinka A, Niehrs C (Jun 2002). "Kremen proteins are Dickkopf receptors that regulate Wnt/beta-catenin signalling". Nature. 417 (6889): 664–7. doi:10.1038/nature756. PMID12050670.
Aguilera O, Fraga MF, Ballestar E, Paz MF, Herranz M, Espada J, García JM, Muñoz A, Esteller M, González-Sancho JM (Jul 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. PMID16491118.
Gregory CA, Singh H, Perry AS, Prockop DJ (Jul 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. PMID12740383.
Tian E, Zhan F, Walker R, Rasmussen E, Ma Y, Barlogie B, Shaughnessy JD (Dec 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. PMID14695408.
Caricasole A, Copani A, Caraci F, Aronica E, Rozemuller AJ, Caruso A, Storto M, Gaviraghi G, Terstappen GC, Nicoletti F (Jun 2004). "Induction of Dickkopf-1, a negative modulator of the Wnt pathway, is associated with neuronal degeneration in Alzheimer's brain". The Journal of Neuroscience. 24 (26): 6021–7. doi:10.1523/JNEUROSCI.1381-04.2004. PMID15229249.
Niida A, Hiroko T, Kasai M, Furukawa Y, Nakamura Y, Suzuki Y, Sugano S, Akiyama T (Nov 2004). "DKK1, a negative regulator of Wnt signaling, is a target of the beta-catenin/TCF pathway". Oncogene. 23 (52): 8520–6. doi:10.1038/sj.onc.1207892. PMID15378020.
Lee AY, He B, You L, Xu Z, Mazieres J, Reguart N, Mikami I, Batra S, Jablons DM (Oct 2004). "Dickkopf-1 antagonizes Wnt signaling independent of beta-catenin in human mesothelioma". Biochemical and Biophysical Research Communications. 323 (4): 1246–50. doi:10.1016/j.bbrc.2004.09.001. PMID15451431.