View source for Krüppel

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{{Infobox nonhuman protein |UniProt=P07247|Organism=Drosophila melanogaster |Name=Krüppel|Symbol=kr}}
{{Infobox nonhuman protein |UniProt=P08155|Organism=Drosophila melanogaster |Name=Krüppel homolog 1|Symbol=kr-h1}}
{{Infobox nonhuman protein |UniProt=Q9V447|Organism=Drosophila melanogaster |Name=Krüppel homolog 2|Symbol=kr-h2}}
{{Infobox nonhuman protein |UniProt=Q8MR37|Organism=Drosophila melanogaster |Name=Krüppel-like factor luna|Symbol=luna}}
[[File:Drosophila gap gene in situ brakeless mutant.png|thumb|358x358px|In situ hybridization against mRNA of the gap genes ''knirps, Krüppel'' and ''giant'' in the ''Drosophila melanogaster'' early embryo. Panels also show how these genes are affected by the mutation ''brakeless (bks).'']]
'''Krüppel''' is a [[gap gene]] in ''[[Drosophila melanogaster]]'', located on the 2R chromosome, which encodes a [[Zinc finger transcription factor|zinc finger C2H2 transcription factor]].<ref name=":0">{{cite journal | vauthors = Kinzler KW, Ruppert JM, Bigner SH, Vogelstein B | title = The GLI gene is a member of the Kruppel family of zinc finger proteins | journal = Nature | volume = 332 | issue = 6162 | pages = 371–4 | date = March 1988 | pmid = 2832761 | doi = 10.1038/332371a0 | bibcode = 1988Natur.332..371K | s2cid = 4279828 }}</ref><ref>{{Cite web|url=http://flybase.org/reports/FBgn0001325|title=FlyBase Gene Report: Dmel\Kr|website=flybase.org|access-date=2019-10-08}}</ref> Gap genes work together to establish the anterior-posterior segment patterning of the insect through regulation of the transcription factor encoding [[Pair-rule gene|pair rule genes]]. These genes in turn regulate [[segment polarity gene]]s.<ref>{{cite book |last=Hoy |first=Marjorie A. |title=Insect Molecular Genetics | name-list-style = vanc |chapter=Genetic Systems, Genome Evolution, and Genetic Control of Embryonic Development in Insects |date= January 2019 |work=Insect Molecular Genetics (Fourth Edition)|pages=103–175|editor-last=Hoy|editor-first=Marjorie A. |publisher=Academic Press |isbn=9780128152300 |doi=10.1016/B978-0-12-815230-0.00004-2}}</ref> ''Krüppel'' means "cripple" in German, named for the crippled appearance of mutant larvae, who have failed to develop proper thoracic and anterior segments in the abdominal region.<ref>{{cite journal | vauthors = Nüsslein-Volhard C, Wieschaus E | title = Mutations affecting segment number and polarity in Drosophila | journal = Nature | volume = 287 | issue = 5785 | pages = 795–801 | date = October 1980 | pmid = 6776413 | doi = 10.1038/287795a0 | bibcode = 1980Natur.287..795N | s2cid = 4337658 }}</ref><ref>{{cite journal | vauthors = Nüsslein-Volhard C, Wieschaus E, Kluding H | title = Mutations affecting the pattern of the larval cuticle inDrosophila melanogaster : I. Zygotic loci on the second chromosome | journal = Wilhelm Roux's Archives of Developmental Biology | volume = 193 | issue = 5 | pages = 267–282 | date = September 1984 | pmid = 28305337 | doi = 10.1007/BF00848156 | s2cid = 2195415 }}</ref><ref>{{cite journal | vauthors = Wieschaus E, Nusslein-Volhard C, Kluding H | title = Krüppel, a gene whose activity is required early in the zygotic genome for normal embryonic segmentation | journal = Developmental Biology | volume = 104 | issue = 1 | pages = 172–86 | date = July 1984 | pmid = 6428949 | doi = 10.1016/0012-1606(84)90046-0 }}</ref> Mutants can also have abdominal mirror duplications.
Human [[Homology (biology)|homologs]] of Krüppel are collectively named [[Kruppel-like factors|''Krüppel''-like factors]], a set of proteins well characterized for their role in carcinogenesis.<ref>{{cite journal | vauthors = Schuh R, Aicher W, Gaul U, Côté S, Preiss A, Maier D, Seifert E, Nauber U, Schröder C, Kemler R | display-authors = 6 | title = A conserved family of nuclear proteins containing structural elements of the finger protein encoded by Krüppel, a Drosophila segmentation gene | journal = Cell | volume = 47 | issue = 6 | pages = 1025–32 | date = December 1986 | pmid = 3096579 | doi = 10.1016/0092-8674(86)90817-2 | doi-access = free }}</ref><ref>{{cite journal | vauthors = Yori JL, Seachrist DD, Johnson E, Lozada KL, Abdul-Karim FW, Chodosh LA, Schiemann WP, Keri RA | display-authors = 6 | title = Krüppel-like factor 4 inhibits tumorigenic progression and metastasis in a mouse model of breast cancer | journal = Neoplasia | volume = 13 | issue = 7 | pages = 601–10 | date = July 2011 | pmid = 21750654 | pmc = 3132846 | doi = 10.1593/neo.11260 }}</ref><ref>{{cite journal | vauthors = Lin ZS, Chu HC, Yen YC, Lewis BC, Chen YW | title = Krüppel-like factor 4, a tumor suppressor in hepatocellular carcinoma cells reverts epithelial mesenchymal transition by suppressing slug expression | journal = PLOS ONE | volume = 7 | issue = 8 | pages = e43593 | date = 2012 | pmid = 22937066 | pmc = 3427336 | doi = 10.1371/journal.pone.0043593 | bibcode = 2012PLoSO...743593L | doi-access = free }}</ref><ref>{{cite journal | vauthors = Wei D, Gong W, Kanai M, Schlunk C, Wang L, Yao JC, Wu TT, Huang S, Xie K | display-authors = 6 | title = Drastic down-regulation of Krüppel-like factor 4 expression is critical in human gastric cancer development and progression | journal = Cancer Research | volume = 65 | issue = 7 | pages = 2746–54 | date = April 2005 | pmid = 15805274 | doi = 10.1158/0008-5472.CAN-04-3619 | doi-access =  }}</ref><ref>{{cite journal | vauthors = Lee UE, Ghiassi-Nejad Z, Paris AJ, Yea S, Narla G, Walsh M, Friedman SL | title = Tumor suppressor activity of KLF6 mediated by downregulation of the PTTG1 oncogene | journal = FEBS Letters | volume = 584 | issue = 5 | pages = 1006–10 | date = March 2010 | pmid = 20116377 | pmc = 2827621 | doi = 10.1016/j.febslet.2010.01.049 }}</ref>
==''Krüppel'' expression pathway  ==
''Krüppel'' is expressed in the center of the embryo during the cellular blastoderm stage of development.<ref>{{cite journal | vauthors = Licht JD, Grossel MJ, Figge J, Hansen UM | title = Drosophila Krüppel protein is a transcriptional repressor | journal = Nature | volume = 346 | issue = 6279 | pages = 76–9 | date = July 1990 | pmid = 2114551 | doi = 10.1038/346076a0 | bibcode = 1990Natur.346...76L | s2cid = 10301966 }}</ref> Its expression pattern is restricted to this domain largely through interactions with the maternal effect genes ''Bicoid'' and ''Nanos'', and fellow gap gene ''Hunchback'' and ''Knirps.''<ref>{{cite journal | vauthors = Knipple DC, Seifert E, Rosenberg UB, Preiss A, Jäckle H | title = Spatial and temporal patterns of Krüppel gene expression in early Drosophila embryos | journal = Nature | volume = 317 | issue = 6032 | pages = 40–4 | date = 1985 | pmid = 2412131 | doi = 10.1038/317040a0 | bibcode = 1985Natur.317...40K | s2cid = 4340589 }}</ref>
''Bicoid'' maternal transcripts are deposited at the anterior end of the embryo, while ''Nanos'' maternal transcripts are located at the posterior. ''Hunchback'' mRNA transcripts are present throughout the embryo. ''Bicoid'' and ''Nanos'' both encode [[morphogen]]s that have the opposite effect on ''Hunchback'' mRNA translation – ''Bicoid'' activates translation, whereas ''Nanos'' represses it.<ref>{{cite journal | vauthors = Porcher A, Dostatni N | title = The bicoid morphogen system | journal = Current Biology | volume = 20 | issue = 5 | pages = R249-54 | date = March 2010 | pmid = 20219179 | doi = 10.1016/j.cub.2010.01.026 | doi-access = free }}</ref> As such, ''Hunchback'' mRNA is translated so that ''Hunchback'' protein is present in the concentration gradient which decreases along the anterior – posterior axis. This ''Hunchback'' gradient indirectly results in an anterior boundary for ''Knirps'' expression. Other factors induce a posterior boundary, so that ''Knirps'' is expressed in a stripe in the posterior region of the embryo.
''Hunchback'' and ''Knirps'' are both transcription factors that regulate ''Krüppel'' expression. High levels of ''Hunchback'' inhibit expression, whereas low levels of ''Hunchback'' activate expression. ''Knirps'' acts as a repressor to inhibit expression. This results in ''Krüppel'' being expressed in a stripe in the center of the embryo's A-P axis, where Hunchback concentration has dropped to a low enough level so that it can act as an activator, but ''Knirps'' is not yet present to inhibit.
In this way the initial gradients of morphogens can lead to the establishment of a specific region within the blastoderm.
It can be compared to a narrow bandwidth filter in engineering.
== Effects of ''Krüppel'' expression ==
The ''Krüppel'' protein is a [[transcription factor]], and has been shown to act as a [[repressor]]. It functions in collaboration with other gap genes and their localized protein products to regulate the expression of the primary pair rule genes – ''even skipped'' (''eve''), ''hairy'' (''h''), and ''runt.''<ref>{{cite journal | vauthors = Pankratz MJ, Seifert E, Gerwin N, Billi B, Nauber U, Jäckle H | title = Gradients of Krüppel and knirps gene products direct pair-rule gene stripe patterning in the posterior region of the Drosophila embryo | journal = Cell | volume = 61 | issue = 2 | pages = 309–17 | date = April 1990 | pmid = 2331752 | doi = 10.1016/0092-8674(90)90811-R | s2cid = 44716994 }}</ref> It has been postulated that ''Krüppel'' inhibits ''eve'' expression to create the posterior boundary of ''eve'' stripe two, and evidence has also been found for ''Krüppel'' being a player specifically in the formation of ''hairy'' stripe 7.<ref>{{cite journal | vauthors = Small S, Kraut R, Hoey T, Warrior R, Levine M | title = Transcriptional regulation of a pair-rule stripe in Drosophila | journal = Genes & Development | volume = 5 | issue = 5 | pages = 827–39 | date = May 1991 | pmid = 2026328 | doi = 10.1101/gad.5.5.827 | doi-access = free }}</ref><ref>{{cite journal | vauthors = La Rosée-Borggreve A, Häder T, Wainwright D, Sauer F, Jäckle H | title = hairy stripe 7 element mediates activation and repression in response to different domains and levels of Krüppel in the Drosophila embryo | journal = Mechanisms of Development | volume = 89 | issue = 1–2 | pages = 133–40 | date = December 1999 | pmid = 10559488 | doi = 10.1016/s0925-4773(99)00219-1 | hdl = 11858/00-001M-0000-002A-18E2-F | s2cid = 17728959 | hdl-access = free }}</ref> The expression patterns of pair rule gene will in turn regulate the segment polarity genes, making ''Krüppel'' essential for proper development along the anterior posterior axis and segment identity.
== Clinical significance ==
''Krüppel'' has shown homology to the mammalian [[Kruppel-like factors|''Krüppel''-like factors]], which play key biological roles in the pathogenesis of many human diseases: cancer,<ref>{{cite journal | vauthors = Ghaleb AM, Katz JP, Kaestner KH, Du JX, Yang VW | title = Krüppel-like factor 4 exhibits antiapoptotic activity following gamma-radiation-induced DNA damage | journal = Oncogene | volume = 26 | issue = 16 | pages = 2365–73 | date = April 2007 | pmid = 17016435 | pmc = 2230633 | doi = 10.1038/sj.onc.1210022 }}</ref> obesity,<ref>{{cite journal | vauthors = Brey CW, Nelder MP, Hailemariam T, Gaugler R, Hashmi S | title = Krüppel-like family of transcription factors: an emerging new frontier in fat biology | journal = International Journal of Biological Sciences | volume = 5 | issue = 6 | pages = 622–36 | date = October 2009 | pmid = 19841733 | pmc = 2757581 | doi = 10.7150/ijbs.5.622 }}</ref> inflammatory disorders<ref>{{cite journal | vauthors = Hamik A, Lin Z, Kumar A, Balcells M, Sinha S, Katz J, Feinberg MW, Gerzsten RE, Edelman ER, Jain MK | display-authors = 6 | title = Kruppel-like factor 4 regulates endothelial inflammation | journal = The Journal of Biological Chemistry | volume = 282 | issue = 18 | pages = 13769–79 | date = May 2007 | pmid = 17339326 | doi = 10.1074/jbc.M700078200 | doi-access = free }}</ref> and cardiovascular complications.<ref>{{cite journal | vauthors = Rajamannan NM, Subramaniam M, Abraham TP, Vasile VC, Ackerman MJ, Monroe DG, Chew TL, Spelsberg TC | display-authors = 6 | title = TGFbeta inducible early gene-1 (TIEG1) and cardiac hypertrophy: Discovery and characterization of a novel signaling pathway | journal = Journal of Cellular Biochemistry | volume = 100 | issue = 2 | pages = 315–25 | date = February 2007 | pmid = 16888812 | pmc = 3927779 | doi = 10.1002/jcb.21049 }}</ref> Moreover, KLFs are known to be involved in [[Induced pluripotent stem cell|inducible pluripotent stem cells]] generation, and preservation of the [[pluripotent]] state of [[embryonic stem cell]]s.<ref>{{cite journal | vauthors = Jiang J, Chan YS, Loh YH, Cai J, Tong GQ, Lim CA, Robson P, Zhong S, Ng HH | display-authors = 6 | title = A core Klf circuitry regulates self-renewal of embryonic stem cells | journal = Nature Cell Biology | volume = 10 | issue = 3 | pages = 353–60 | date = March 2008 | pmid = 18264089 | doi = 10.1038/ncb1698 | s2cid = 22150633 }}</ref><ref>{{cite journal | vauthors = Nandan MO, Yang VW | title = The role of Krüppel-like factors in the reprogramming of somatic cells to induced pluripotent stem cells | journal = Histology and Histopathology | volume = 24 | issue = 10 | pages = 1343–55 | date = October 2009 | pmid = 19688699 | pmc = 2753264 | doi = 10.14670/HH-24.1343 }}</ref><ref>{{cite journal | vauthors = Takahashi K, Tanabe K, Ohnuki M, Narita M, Ichisaka T, Tomoda K, Yamanaka S | title = Induction of pluripotent stem cells from adult human fibroblasts by defined factors | journal = Cell | volume = 131 | issue = 5 | pages = 861–72 | date = November 2007 | pmid = 18035408 | doi = 10.1016/j.cell.2007.11.019 | hdl = 2433/49782 | s2cid = 8531539 | hdl-access = free }}</ref>
== See also ==
* ''[[Drosophila melanogaster]]''
* [[Drosophila embryogenesis|''Drosophila'' embryogenesis]]
* [[Maternal effect]]
== References ==
{{Reflist}}
== External links ==
* [http://www.bio.davidson.edu/courses/MolBio/fly/embryred.jpeg Diagram] at [[Davidson College]] - a Drosophila embryo at the cellular blastoderm stage triple-labeled for three segmentation proteins including Krüppel (in blue) Hairy (green) and Giant (red).
* {{MeshName|Kruppel+protein,+Drosophila}}
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{{DEFAULTSORT:Kruppel}}
[[Category:Drosophila melanogaster genes]]