DKK1
Dickkopf-related protein 1 is a protein that in humans is encoded by the DKK1 gene.[1]
Function
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] The dickkopf protein encoded by DKK1 is an antagonistic inhibitor of the WNT signaling pathway that acts by isolating the LRP6 co-receptor so that it cannot aid in activating the WNT signaling pathway.[3] This inhibition plays a key role in head and forelimb development during anterior morphogenesis of the embryo.[1]
Interactions
DKK1 has been shown to interact with LRP6.[4]
Clinical significance
Elevated levels of DKK1 in bone marrow, plasma and peripheral blood is associated with the presence of osteolytic bone lesions in patients with multiple myeloma.[1]
Animal studies
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.[2] This evidence supports the idea that inhibition of the Wnt signaling pathway by DKK1 is crucial to proper cranial development.
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 body against DKK-1 reversed DHT effects on outer root sheath keratinocytes.[5] DKK-1 expression is attenuated by L-threonate in vitro, with the latter a metabolite of ascorbate.[6]
References
- ↑ 1.0 1.1 1.2 "Entrez Gene: DKK1 dickkopf homolog 1 (Xenopus laevis)".
- ↑ 2.0 2.1 Mukhopadhyay M, Shtrom S, Rodriguez-Esteban C, Chen L, Tsukui T, Gomer L et al. (Sep 2001). "Dickkopf1 is required for embryonic head induction and limb morphogenesis in the mouse". Developmental Cell 1 (3). 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). doi:10.1242/dev.018853. PMID 18403408.
- ↑ 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. PMID 11448771. Vancouver style error (help)
- ↑ Kwack MH, Sung YK, Chung EJ, Im SU, Ahn JS, Kim MK et al. (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. PMID 17657240.
- ↑ 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. PMID 21034532.
Further reading
- Fedi P, Bafico A, Nieto Soria A, Burgess WH, Miki T, Bottaro DP et al. (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. PMID 10383463.
- Krupnik VE, Sharp JD, Jiang C, Robison K, Chickering TW, Amaravadi L et al. (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. 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.
- 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. doi:10.1038/35077108. PMID 11357136.
- 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. PMID 11448771. Vancouver style error (help)
- Zorn AM (Aug 2001). "Wnt signalling: antagonistic Dickkopfs". Current Biology 11 (15): R592–5. doi:10.1016/S0960-9822(01)00360-8. PMID 11516963.
- 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. PMID 11840333.
- Mao B, Wu W, Davidson G, Marhold J, Li M, Mechler BM et al. (Jun 2002). "Kremen proteins are Dickkopf receptors that regulate Wnt/beta-catenin signalling". Nature 417 (6889): 664–7. doi:10.1038/nature756. PMID 12050670.
- Aguilera O, Fraga MF, Ballestar E, Paz MF, Herranz M, Espada J et al. (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. PMID 16491118.
- Brott BK, Sokol SY (Sep 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 (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. PMID 12740383.
- Tian E, Zhan F, Walker R, Rasmussen E, Ma Y, Barlogie B et al. (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. PMID 14695408.
- Yamaguchi Y, Itami S, Watabe H, Yasumoto K, Abdel-Malek ZA, Kubo T et al. (Apr 2004). "Mesenchymal-epithelial interactions in the skin: increased expression of dickkopf1 by palmoplantar fibroblasts inhibits melanocyte growth and differentiation". The Journal of Cell Biology 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. (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. PMID 15229249.
- Colland F, Jacq X, Trouplin V, Mougin C, Groizeleau C, Hamburger A et al. (Jul 2004). "Functional proteomics mapping of a human signaling pathway". Genome Research 14 (7): 1324–32. doi:10.1101/gr.2334104. PMC 442148. PMID 15231748.
- Zhang Z, Henzel WJ (Oct 2004). "Signal peptide prediction based on analysis of experimentally verified cleavage sites". Protein Science 13 (10): 2819–24. doi:10.1110/ps.04682504. PMC 2286551. PMID 15340161.
- Niida A, Hiroko T, Kasai M, Furukawa Y, Nakamura Y, Suzuki Y et al. (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. PMID 15378020.
- Lee AY, He B, You L, Xu Z, Mazieres J, Reguart N et al. (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. PMID 15451431.