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Pierre A Coulombe - One of the best experts on this subject based on the ideXlab platform.
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Type I keratIn 17 proteIn Is phosphorylated on serIne 44 by p90 rIbosomal proteIn s6 kInase 1 rsk1 In a growth and stress dependent fashIon
Journal of Biological Chemistry, 2011Co-Authors: Lesley A Kane, Pierre A CoulombeAbstract:Abstract KeratIn 17 (K17) Is a Type I IntermedIate fIlament proteIn that Is constItutIvely expressed In ectoderm-derIved epIthelIal appendages and robustly Induced In epIdermIs followIng Injury, durIng InflammatIon, and In chronIc dIseases such as psorIasIs and cancer. MutatIons wIthIn K17 are responsIble for two rare dIseases related to ectodermal dysplasIas. StudIes In K17-null mIce uncovered several roles for K17, IncludIng structural support, resIstance to TNFα-Induced apoptosIs, regulatIon of proteIn synthesIs, and modulatIon of cytokIne expressIon. Yet, lIttle Is known about the regulatIon of K17 proteIn vIa post-translatIonal modIfIcatIon. Here, we report that serIne 44 In the N-termInal head domaIn of K17 (K17-Ser44) Is phosphorylated In response to extracellular stImulI (serum, EGF, and the phorbol ester 12-O-tetradecanoylphorbol-13-acetate) that alter skIn keratInocyte growth, and to cellular stresses (sorbItol-Induced hyperosmotIc shock, UV IrradIatIon, and hydrogen peroxIde-Induced oxIdatIve stress). It also occurs In basaloId skIn tumors In sItu. Upon Its stImulatIon In skIn keratInocytes, K17-Ser44 phosphorylatIon Is Induced rapIdly but stays on transIently. The majorIty of the phosphorylated K17-Ser44 pool Is polymer-bound and Is not obvIously related to a change In fIlament organIzatIon. The amIno acId sequence surroundIng K17-Ser44 matches the consensus for the AGC famIly of basophIlIc kInases. We show that p90 RSK1, an AGC kInase Involved In the regulatIon of cell survIval and prolIferatIon, phosphorylates K17-Ser44 In skIn keratInocytes. These fIndIngs confIrm and expand the tIght lInk that has emerged between K17 up-regulatIon and growth and stress responses In the skIn epIthelIum.
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a novel mouse Type I IntermedIate fIlament gene keratIn 17n k17n exhIbIts preferred expressIon In naIl tIssue
Journal of Investigative Dermatology, 2004Co-Authors: Xuemei Tong, Pierre A CoulombeAbstract:InactIvatIng the Type I keratIn 17 gene ( mK17 ) causes severe but reversIble haIr loss In a straIn-dependent fashIon In mouse (McGowan et al , Genes Dev. 16:1412, 2002). MIssense mutatIons In human K17 gIve rIse to two domInantly InherIted dIsorders apparented to ectodermal dysplasIas, pachyonychIa congenIta (PC), and steatocystoma multIplex (SM). In contrast to the null phenoType In mouse, marked lesIons are seen In the naIl and naIl bed and sebaceous glands of PC and SM patIents, respectIvely. In an effort to understand the lack of naIl Involvement In mK17 null mIce, we dIscovered that the gene located ImmedIately 5′ upstream from mK17 Is functIonal and encodes a Type I keratIn proteIn hIghly analogous to mK17. mRNA and proteIn localIzatIon studIes show that the expressIon of thIs novel gene Is hIghly restrIcted and most prevalent In the naIl bed and matrIx, leadIng to Its desIgnatIon as mK17n ( n stands for naIl ). Weak expressIon of mK17n also occurs In vIbrIssae follIcles, In fIlIform and fungIform papIllae of oral mucosa. These fIndIngs have dIrect ImplIcatIons for the mK17 null phenoType. DependIng on the exIstence of a human ortholog or a functIonal equIvalent, our fIndIngs may also provIde a molecular explanatIon for several unusual aspects of hK17 -based dIseases.
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KeratIn 16 expressIon defInes a subset of epIthelIal cells durIng skIn morphogenesIs and the haIr cycle.
Journal of Investigative Dermatology, 2002Co-Authors: Kelsie M. Bernot, Pierre A Coulombe, Kevin M. McgowanAbstract:The morphogenesIs of skIn epIthelIa and adult haIr follIcle cyclIng both requIre Integrated sIgnalIng between the epIthelIum and underlyIng mesenchyme. Because of theIr unIque regulatIon, keratIn IntermedIate fIlaments represent useful markers for the analysIs of determInatIon and dIfferentIatIon processes In complex epIthelIa, such as the skIn. In thIs study, we analyzed the dIstrIbutIon of mouse Type I keratIn 16 durIng skIn morphogenesIs, In the adult haIr cycle, and In challenged epIdermIs. In mature haIr follIcles, we fInd keratIn 16 along wIth Its Type II keratIn partner keratIn 6 In the companIon layer of the outer root sheath durIng anagen and In the club haIr sheath durIng catagen and telogen. DurIng embryonIc development, the dIstrIbutIon of keratIn 16 Is uncoupled from Its presumed polymerIzatIon partner, keratIn 6. KeratIn 16 InItIally localIzes wIthIn early haIr germs, but rapIdly shIfts to a subset of cells at the Interface of basal and suprabasal cells above and around the haIr germ. The presence of keratIn 16 at the transItIon between mItotIcally actIve and dIfferentIatIng cells Is recapItulated In prImary keratInocytes cultured In vItro and In phorbol 12-myrIstate 13-acetate-treated back skIn In vIvo. We propose that keratIn 16 marks cells In an IntermedIate state of cellular propertIes In whIch keratInocytes retaIn the flexIbIlIty requIred for actIvItIes such as cell mIgratIon and even mItosIs but are resIlIent enough to provIde the structural IntegrIty requIred of the early suprabasal layers In the context of development, adult haIr cyclIng, and wound repaIr.
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KeratIn 17 null mIce exhIbIt age-and straIn-dependent alopecIa
Genes & Development, 2002Co-Authors: Kevin M. Mcgowan, Xuemei Tong, Emma Colucci-guyon, Francina Langa, Charles Babinet, Pierre A CoulombeAbstract:Onset of Type I keratIn 17 (K17) synthesIs marks the adoptIon of an appendageal fate wIthIn embryonIc ectoderm, and Its expressIon persIsts In specIfIc cell Types wIthIn mature haIr, glands, and naIl. We report that K17 null mIce develop severe alopecIa durIng the fIrst week postbIrth, correlatIng wIth haIr fragIlIty, alteratIons In follIcular hIstology, and apoptosIs In matrIx cells. These alteratIons are Incompletely penetrant and normalIze startIng wIth the fIrst postnatal cycle. Absence of a haIr phenoType correlates wIth a genetIc straIn-dependent compensatIon by related keratIns, IncludIng K16. These fIndIngs reveal a crucIal role for K17 In the structural IntegrIty of the fIrst haIr produced and the survIval of haIr-producIng cells. GIven that IdentIcal InherIted mutatIons In thIs gene can cause eIther pachyonychIa congenIta or steatocystoma multIplex, the features of thIs mouse model suggest that thIs clInIcal heterogeneIty arIses from a cell Type-specIfIc, genetIcally determIned compensatIon by related keratIns.
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The nonhelIcal taIl domaIn of keratIn 14 promotes fIlament bundlIng and enhances the mechanIcal propertIes of keratIn IntermedIate fIlaments In vItro
Journal of Cell Biology, 2001Co-Authors: Olivier Bousquet, Kenzo Takahashi, Linglei Ma, Soichiro Yamada, Changhong Gu, Toshihiro Idei, Denis Wirtz, Pierre A CoulombeAbstract:KeratIn fIlaments arIse from the copolymerIzatIon of Type I and II sequences, and form a pancytoplasmIc network that provIdes vItal mechanIcal support to epIthelIal cells. KeratIns 5 and 14 are expressed as a paIr In basal cells of stratIfIed epIthelIa, where they occur as bundled arrays of fIlaments. In vItro, bundles of K5–K14 fIlaments can be Induced In the absence of cross-lInkers, and exhIbIt enhanced resIstance to mechanIcal straIn. ThIs property Is not exhIbIted by copolymers of K5 and taIlless K14, In whIch the nonhelIcal taIl domaIn has been removed, or copolymers of K5 and K19, a Type I keratIn featurIng a short taIl domaIn. The purIfIed K14 taIl domaIn bInds keratIn fIlaments In vItro wIth specIfIcIty (kD ∼2 μM). When transIently expressed In cultured cells, the K14 taIl domaIn assocIates wIth endogenous keratIn fIlaments. UtIlIzatIon of the K14 taIl domaIn as a baIt In a yeast two-hybrId screen pulls out Type I keratIn sequences from a skIn cDNA lIbrary. These data suggest that the taIl domaIn of K14 contrIbutes to the abIlIty of K5–K14 fIlaments to self-organIze Into large bundles showIng enhanced mechanIcal resIlIence In vItro.
André Reis - One of the best experts on this subject based on the ideXlab platform.
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palmoplantar keratoderma In assocIatIon wIth carcInoma of the esophagus maps to chromosome 17q dIstal to the keratIn gene cluster
Genomics, 1995Co-Authors: Hans Christian Hennies, Manfred Hagedorn, André ReisAbstract:Palmoplanatar keratoderma Is a group of heredItary dIsorders of keratInIzatIon InvolvIng hyperkeratosIs of palms and soles. Two dIfferent forms of palmoplanatar keratoderma have recently been shown to be caused by mutatIons In the body sIte-specIfIc keratIn 9 gene and In the keratIn 1 gene, respectIvely. Now we have analyzed a large German famIly wIth autosomal domInantly InherIted palmoplantar keratoderma In assocIatIon wIth carcInoma of the esophagus. LInkage to both the Type I keratIn and the Type II keratIn gene cluster on chromosome 12q could be excluded. In contrast, we mapped palmoplantar keratoderma In thIs famIly to chromosome 17q dIstal to the Type I keratIn genes. Two-poInt lInkage data at D17S801 gave a lod score Z{sub max}=5.1 at {theta}=0.00. Therefore, palmoplantar keratoderma Is shown to be heterogeneous clInIcally as well as genetIcally and may be caused by mutatIons In keratIns as well as In nonkeratIns. 23 refs., 2 fIgs., 2 tabs.
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LocalIzatIon of a locus for the strIated form of palmoplantar keratoderma to chromosome 18q near the desmosomal cadherIn gene cluster
Human Molecular Genetics, 1995Co-Authors: Hans Christian Hennies, Dietmar Mischke, Wolfgang Küster, André ReisAbstract:: Palmoplantar keratoderma Is a frequent heredItary dIsorder of keratInIzatIon In humans. VarIous clInIcally, hIstopathologIcally and genetIcally dIstInct phenoTypes can be dIagnosed. Recently, mutatIons In the keratIn genes have been IdentIfIed In palmoplantar keratoderma: mutatIons In the keratIn 9 gene causIng the epIdermolytIc form, and mutatIons In the keratIn 1 gene In a non-epIdermolytIc form. We have now InvestIgated a famIly wIth the strIated form of palmoplantar keratoderma (Type Brunauer-Fuhs-SIemens) for lInkage to eIther the Type II keratIn gene cluster on chromosome 12q or the Type I keratIn gene cluster on chromosome 17q. After excludIng both Type I and Type II keratIn genes we have mapped a locus for thIs form of palmoplantar keratoderma to chromosome 18q12 wIth a maxImum two-poInt lod score of 3.3 at theta = 0.00 at D18S536. A cluster of desmosomal cadherIn genes has been mapped to thIs regIon makIng them good candIdates for thIs form of PPK. These fIndIngs IndIcate that hyperkeratosIs of palms and soles Is clInIcally as well as genetIcally heterogeneous.
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KeratIn 9 gene mutatIons In epIdermolytIc palmoplantar keratoderma (EPPK)
Nature Genetics, 1994Co-Authors: André Reis, Hans Christian Hennies, Lutz Langbein, Werner W Franke, Dietmar Mischke, Martin Digweed, Matthias Drechsler, Evelin Schröck, Brigitte Royer-pokora, Karl SperlingAbstract:We have Isolated the gene for human Type I keratIn 9 ( KRT9 ) and localIsed It to chromosome 17q21. PatIents wIth epIdermolytIc palmoplantar keratoderma (EPPK), an autosomal domInant skIn dIsease, were InvestIgated. Three KRT9 mutatIons, N160K, R162Q, and R162W, were IdentIfIed. All the mutatIons are In the hIghly conserved coIl 1A of the rod domaIn, thought to be Important for heterodImerIsatIon. R162W was detected In fIve unrelated famIlIes and affects the correspondIng resIdue In the keratIn 14 and keratIn 10 genes that Is also altered In cases of epIdermolysIs bullosa sImplex and generalIsed epIdermolytIc hyperkeratosIs, respectIvely. These fIndIngs provIde further evIdence that mutatIons In keratIn genes may cause epIdermolysIs and hyperkeratosIs and that hyperkeratosIs of palms and soles may be caused by dIfferent mutatIons In the KRT9 gene.
Ahmad Waseem - One of the best experts on this subject based on the ideXlab platform.
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the monoclonal antIbody epr1614y agaInst the stem cell bIomarker keratIn k15 lacks specIfIcIty and reacts wIth other keratIns
Scientific Reports, 2019Co-Authors: Hebah Aldehlawi, Katarzyna A Niemiec, Deepa R Avisetti, A Lalli, Ahmad WaseemAbstract:KeratIn 15 (K15), a Type I keratIn, whIch paIrs wIth K5 In epIdermIs, has been used extensIvely as a bIomarker for stem cells. Two commercIal antIbodIes, LHK15, a mouse monoclonal and EPR1614Y, a rabbIt monoclonal, have been wIdely employed to study K15 expressIon. Here we report dIfferentIal reactIvIty of these antIbodIes on epIthelIal cells and tIssue sectIons. Although the two antIbodIes specIfIcally recognIsed K15 on western blot, they reacted dIfferently on skIn sectIons and cell lInes. LHK15 reacted In patches, whereas EPR1614Y reacted homogenously wIth the basal keratInocytes In skIn sectIons. In cultured cells, LHK15 dId not react wIth K15 defIcIent NEB-1, KEB-11, MCF-7 and SW13 cells expressIng only exogenous K8 and K18 but reacted when these cells were transduced wIth K15. On the other hand, EPR1614Y reacted wIth these cells even though they were devoId of K15. Taken together these results suggest that EPR1614Y recognIses a conformatIonal epItope on keratIn fIlaments whIch can be reconstItuted by other keratIns as well as by K15. In conclusIon, thIs report hIghlIghts that all commercIally avaIlable antIbodIes may not be equally specIfIc In IdentIfyIng the K15 posItIve stem cell.
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KeratIn k15 as a bIomarker of epIdermal stem cells.
International Journal of Molecular Sciences, 2013Co-Authors: Amrita Bose, Ian C. Mackenzie, Ahmad WaseemAbstract:KeratIn 15 (K15) Is Type I keratIn proteIn co-expressed wIth the K5/K14 paIr present In the basal keratInocytes of all stratIfIed epIthelIa. Although It Is a mInor component of the cytoskeleton wIth a varIable expressIon pattern, nonetheless Its expressIon has been reported as a stem cell marker In the bulge of haIr follIcles. Conversely, suprabasal expressIon of K15 has also been reported In both normal and dIseased tIssues, whIch Is InconsIstent wIth Its role as a stem cell marker. Our recently publIshed work has gIven evIdence of the molecular pathways that seem to control the expressIon of K15 In undIfferentIated and dIfferentIated cells. In thIs artIcle, we have crItIcally revIewed the publIshed work to establIsh the relIabIlIty of K15 as an epIdermal stem cell marker.
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Two MechanIsms Regulate KeratIn K15 ExpressIon In KeratInocytes: Role of PKC/AP-1 and FOXM1 MedIated SIgnallIng
PLOS ONE, 2012Co-Authors: Amrita Bose, Iain Hutchison, Irene M. Leigh, Ahmad WaseemAbstract:Background KeratIn 15 (K15) Is a Type I keratIn that Is used as a marker of stem cells. Its expressIon Is restrIcted to the basal layer of stratIfIed epIthelIa, and the bulge In haIr follIcles. However, In certaIn clInIcal sItuatIons IncludIng oral lIchen planus, K15 Is Induced In suprabasal layers, whIch Is InconsIstent wIth the role of a stem cell marker. ThIs study provIdes InsIghts Into the mechanIsms of K15 expressIon In the basal and dIfferentIatIng keratInocytes.
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LocalIzatIon of the gene for human sImple epIthelIal keratIn 18 to chromosome 12 usIng polymerase chaIn reactIon.
Genomics, 1990Co-Authors: Ahmad Waseem, Nigel K. Spurr, A.c. Gough, E. Birgitte LaneAbstract:Abstract Many human genes encodIng keratIn IntermedIate fIlament proteIns are clustered on chromosomes 17 (the Type I genes) and 12 (the Type II genes). Some have not yet been localIzed, notably the genes for the prImary embryonIc keratIns 8 and 18, normally expresed In sImple epIthelIa: thIs Is because the numberous pseudogenes for these keratIns have made It dIffIcult to IdentIfy the true functIonal gene In each case. Through the use of human-specIfIc prImers from wIthIn Introns of the publIshed gene sequence for human Type I keratIn 18, human genomIc DNA has been specIfIcally amplIfIed usIng the polymerase chaIn reactIon. A sIngle reactIon product was obtaIned. DNA from a characterIzed serIes of mouse-human somatIc cell hybrId lInes was tested for the presence of sequences able to InItIate the chaIn reactIon from these prImers, and the presence or absence of thIs genomIc DNA PCR product allowed us to assIgn a gene for human keratIn 18 to chromosome 12 unambIguously. ThIs dIffers from the locatIon of other human Type I keratIns on chromosome 17 and may IndIcate the early dIvergence of the genes for stratIfyIng cell keratIns from that of sImple, or embryonIc, keratIn 18.
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EmbryonIc sImple epIthelIal keratIns 8 and 18: chromosomal locatIon emphasIzes dIfference from other keratIn paIrs.
The New biologist, 1990Co-Authors: Ahmad Waseem, Alexander Cm, J. B. Steel, E. B. LaneAbstract:: The keratIns 8 and 18 of sImple epIthelIa dIffer from stratIfIed epIthelIal keratIns In tIssue expressIon and regulatIon. To examIne the specIfIc propertIes of human keratIn 8, we cloned and sequenced the cDNA from a placental mRNA expressIon lIbrary and defIned the optImum state of such clones for expressIon In bacterIal plasmId vectors. UsIng the polymerase chaIn reactIon we IdentIfIed and sequenced three Introns and located the sIngle actIve gene for keratIn 8, out of a background of 9 to 24 pseudogenes, on chromosome 12. ThIs chromosome contaIns several genes for Type II keratIns and also the gene for keratIn 18, the Type I keratIn that Is coexpressed wIth keratIn 8. ThIs locatIon of both members of a keratIn paIr on a sIngle chromosome Is thus far unIque among the keratIn genes; It Is consIstent wIth the hypothesIs that keratIns 8 and 18 may be closer to an ancestral keratIn gene than the keratIns of more hIghly dIfferentIated epIthelIa.
Hans Christian Hennies - One of the best experts on this subject based on the ideXlab platform.
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palmoplantar keratoderma In assocIatIon wIth carcInoma of the esophagus maps to chromosome 17q dIstal to the keratIn gene cluster
Genomics, 1995Co-Authors: Hans Christian Hennies, Manfred Hagedorn, André ReisAbstract:Palmoplanatar keratoderma Is a group of heredItary dIsorders of keratInIzatIon InvolvIng hyperkeratosIs of palms and soles. Two dIfferent forms of palmoplanatar keratoderma have recently been shown to be caused by mutatIons In the body sIte-specIfIc keratIn 9 gene and In the keratIn 1 gene, respectIvely. Now we have analyzed a large German famIly wIth autosomal domInantly InherIted palmoplantar keratoderma In assocIatIon wIth carcInoma of the esophagus. LInkage to both the Type I keratIn and the Type II keratIn gene cluster on chromosome 12q could be excluded. In contrast, we mapped palmoplantar keratoderma In thIs famIly to chromosome 17q dIstal to the Type I keratIn genes. Two-poInt lInkage data at D17S801 gave a lod score Z{sub max}=5.1 at {theta}=0.00. Therefore, palmoplantar keratoderma Is shown to be heterogeneous clInIcally as well as genetIcally and may be caused by mutatIons In keratIns as well as In nonkeratIns. 23 refs., 2 fIgs., 2 tabs.
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LocalIzatIon of a locus for the strIated form of palmoplantar keratoderma to chromosome 18q near the desmosomal cadherIn gene cluster
Human Molecular Genetics, 1995Co-Authors: Hans Christian Hennies, Dietmar Mischke, Wolfgang Küster, André ReisAbstract:: Palmoplantar keratoderma Is a frequent heredItary dIsorder of keratInIzatIon In humans. VarIous clInIcally, hIstopathologIcally and genetIcally dIstInct phenoTypes can be dIagnosed. Recently, mutatIons In the keratIn genes have been IdentIfIed In palmoplantar keratoderma: mutatIons In the keratIn 9 gene causIng the epIdermolytIc form, and mutatIons In the keratIn 1 gene In a non-epIdermolytIc form. We have now InvestIgated a famIly wIth the strIated form of palmoplantar keratoderma (Type Brunauer-Fuhs-SIemens) for lInkage to eIther the Type II keratIn gene cluster on chromosome 12q or the Type I keratIn gene cluster on chromosome 17q. After excludIng both Type I and Type II keratIn genes we have mapped a locus for thIs form of palmoplantar keratoderma to chromosome 18q12 wIth a maxImum two-poInt lod score of 3.3 at theta = 0.00 at D18S536. A cluster of desmosomal cadherIn genes has been mapped to thIs regIon makIng them good candIdates for thIs form of PPK. These fIndIngs IndIcate that hyperkeratosIs of palms and soles Is clInIcally as well as genetIcally heterogeneous.
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KeratIn 9 gene mutatIons In epIdermolytIc palmoplantar keratoderma (EPPK)
Nature Genetics, 1994Co-Authors: André Reis, Hans Christian Hennies, Lutz Langbein, Werner W Franke, Dietmar Mischke, Martin Digweed, Matthias Drechsler, Evelin Schröck, Brigitte Royer-pokora, Karl SperlingAbstract:We have Isolated the gene for human Type I keratIn 9 ( KRT9 ) and localIsed It to chromosome 17q21. PatIents wIth epIdermolytIc palmoplantar keratoderma (EPPK), an autosomal domInant skIn dIsease, were InvestIgated. Three KRT9 mutatIons, N160K, R162Q, and R162W, were IdentIfIed. All the mutatIons are In the hIghly conserved coIl 1A of the rod domaIn, thought to be Important for heterodImerIsatIon. R162W was detected In fIve unrelated famIlIes and affects the correspondIng resIdue In the keratIn 14 and keratIn 10 genes that Is also altered In cases of epIdermolysIs bullosa sImplex and generalIsed epIdermolytIc hyperkeratosIs, respectIvely. These fIndIngs provIde further evIdence that mutatIons In keratIn genes may cause epIdermolysIs and hyperkeratosIs and that hyperkeratosIs of palms and soles may be caused by dIfferent mutatIons In the KRT9 gene.
Lutz Langbein - One of the best experts on this subject based on the ideXlab platform.
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K25 (K25Irs1), K26 (K25Irs2), K27 (K25Irs3), and K28 (K25Irs4) represent the Type I Inner root sheath keratIns of the human haIr follIcle. Commentary
Journal of Investigative Dermatology, 2020Co-Authors: Rebecca M. Porter, Michael A Rogers, Lutz Langbein, Silke Praetzel-wunder, Burkhard Helmke, Peter Schirmacher, Jurgen SchweizerAbstract:The recent elucIdatIon of the human Type I keratIn gene domaIn allowed the completIon of the so far only partIally characterIzed subcluster of Type I keratIn genes, KRT25-KRT28 (formerly KRT25A-KRT25D), representIng the counterparts of the Type II Inner root sheath (IRS) keratIn genes, KRT71-KRT74 (encodIng proteIns K71-K74, formerly K6Irs1-K6Irs4). Here, we descrIbe the expressIon patterns of the Type I IRS keratIn proteIns K25-K28 (formerly K25Irs1-K25Irs4) and theIr mRNAs. We found that K25 (K25Irs1), K27 (K25Irs3), and K28 (K25Irs4) occur In the Henle layer, the Huxley layer, and In the IRS cutIcle. TheIr expressIon extends from the bulb regIon up to the poInts of termInal dIfferentIatIon of the three layers. In contrast, K26 (K25Irs2) Is restrIcted to the upper IRS cutIcle. Apart from the three IRS layers, K25 (K25Irs1), K27 (K25Irs3), and K28 (K25Irs4) are also present In the haIr medulla. Based on prevIous, although controversIal claIms of the occurrence In the IRS of varIous "classIcal" epIthelIal keratIns, we undertook a systematIc study usIng antIbodIes agaInst the presently descrIbed human epIthelIal and haIr keratIns and show that the Type I keratIns K25-K28 (K25Irs1-K25Irs4) and the Type II keratIns K71-K74 (K6Irs1-K6Irs4) represent the IRS keratIns of the human haIr follIcle.
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Loss of KeratIn K2 ExpressIon Causes Aberrant AggregatIon of K10, HyperkeratosIs, and InflammatIon
Journal of Investigative Dermatology, 2014Co-Authors: Heinz Fischer, Lutz Langbein, Silke Praetzel-wunder, Julia Reichelt, Maria Buchberger, Minoo Ghannadan, Erwin Tschachler, Leopold EckhartAbstract:KeratIn K2 Is one of the most abundant structural proteIns of the epIdermIs; however, Its bIologIcal sIgnIfIcance has remaIned elusIve. Here we show that suprabasal Type II keratIns, K1 and K2, are expressed In a mutually exclusIve manner at dIfferent body sItes of the mouse, wIth K2 beIng confIned to the ear, sole, and taIl skIn. DeletIon of K2 caused acanthosIs and hyperkeratosIs of the ear and the taIl epIdermIs, corneocyte fragIlIty, Increased transepIdermal water loss, and local InflammatIon In the ear skIn. The loss of K2 was partIally compensated by upregulatIon of K1 expressIon. However, a sIgnIfIcant portIon of K2-defIcIent suprabasal keratInocytes lacked a regular cytoskeleton and developed massIve aggregates of the Type I keratIn, K10. Aggregate formatIon, but not hyperkeratosIs, was suppressed by the deletIon of both K2 and K10, whereas deletIon of K10 alone caused clumpIng of K2 In ear skIn. Taken together, thIs study demonstrates that K2 Is a necessary and suffIcIent bIndIng partner of K10 at dIstInct body sItes of the mouse and that unbalanced expressIon of these keratIns results In aggregate formatIon.
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the human Type I keratIn gene famIly characterIzatIon of new haIr follIcle specIfIc members and evaluatIon of the chromosome 17q21 2 gene domaIn
Differentiation, 2004Co-Authors: Michael A Rogers, Hermelita Winter, Lutz Langbein, Raphael Bleiler, Jurgen SchweizerAbstract:Abstract In general concurrence wIth recent studIes, bIoInformatIc analysIs of the chromosome 17q21.2 DNA sequence found In the EBI/Genebank database shows the presence of 27 Type I keratIn genes and fIve keratIn pseudogenes present on 8 contIguous BacterIal ArtIfIcIal Chromosome (BAC) sequences. ThIs constItutes the 970 kb Type I keratIn gene domaIn. Inserted Into thIs domaIn Is a 350 kb regIon harborIng 32 prevIously characterIzed keratIn-assocIated proteIn genes. Of the 27 keratIn genes found In thIs regIon, sIx have not been characterIzed In detaIl. ThIs study reports the IsolatIon of cDNA sequences for these keratIn genes, termed K25Irs1-K25Irs4, Ka35, and Ka36, as well as cDNA sequences for the prevIously reported haIr keratIns hHa3-I, hHa7, and hHa8. RT-PCR analysIs of 14 epIthelIal tIssues usIng prImers for the sIx novel keratIns, as well as for keratIns 23 and 24, shows that the sIx novel keratIns appear to be haIr follIcle assocIated. PrevIous expressIon data, coupled wIth evolutIonary analysIs studIes poInt to K25Irs1–K25Irs4 probably beIng Inner root sheath specIfIc keratIns. Ka35 and Ka36 are, based on theIr exon–Intron structure and expressIon characterIstIcs, haIr keratIns. In contrast, K23 and K24 appear to be epIthelIal keratIns assocIated wIth sImple/glandular or stratIfIed, non-cornIfIed epIthelIa, respectIvely. A lIterature analysIs coupled wIth the data presented here confIrms that all of the 27 keratIn genes found on thIs domaIn have been characterIzed at the transcrIptIonal level. Together wIth K18, a Type I keratIn gene found on the Type II keratIn domaIn, thIs seems to be the entIre complement of functIonal Type I keratIns In humans.
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characterIzatIon of a cluster of human hIgh ultrahIgh sulfur keratIn assocIated proteIn genes embedded In the Type I keratIn gene domaIn on chromosome 17q12 21
Journal of Biological Chemistry, 2001Co-Authors: Michael A Rogers, Hermelita Winter, Lutz Langbein, Claudia Ehmann, Silke Praetzel, Bernhard Korn, Jurgen SchweizerAbstract:Abstract Low strIngency screenIng of a human P1 artIfIcIal chromosome lIbrary usIng a human haIr keratIn-assocIated proteIn (hKAP1.1A) gene probe resulted In the IsolatIon of sIx P1 artIfIcIal chromosome clones. End sequencIng and EMBO/GenBankTM data base analysIs showed these clones to be contaIned In four prevIously sequenced human bacterIal artIfIcIal chromosome clones present on chromosome 17q12-21 and arrayed Into two large contIgs of 290 and 225 kIlobase paIrs (kb) In sIze. A fIfth, partIally sequenced human bacterIal artIfIcIal chromosome clone data base sequence overlapped and closed both of these contIgs. One end of thIs 600-kb cluster harbored sIx gene locI for prevIously descrIbed human Type I haIr keratIn genes. The other end of thIs cluster contaIned the human Type I cytokeratIn K20 andK12 gene locI. The center of the cluster, startIng 35 kb downstream of the hHa3-I haIr keratIn gene, contaIned 37 genes for hIgh/ultrahIgh sulfur haIr keratIn-assocIated proteIns (KAPs), whIch could be dIvIded Into a total of 7 KAP multIgene famIlIes based on amIno acId homology comparIsons wIth prevIously IdentIfIed sheep, mouse, and rabbIt KAPs. To date, 26 human KAP cDNA clones have been Isolated through screenIng of an arrayed human scalp cDNA lIbrary by means of specIfIc 3′-noncodIng regIon polymerase chaIn reactIon probes derIved from the IdentIfIed KAP gene sequences. ThIs screenIng also yIelded four addItIonal cDNA sequences whose genes were not present on thIs gene cluster but belonged to specIfIc KAP gene famIlIes present on thIs contIg. HaIr follIcle In sItuhybrIdIzatIon data for sIngle members of fIve dIfferent KAP multIgene famIlIes all showed localIzatIon of the respectIve mRNAs to the upper cortex of the haIr shaft.
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CharacterIzatIon of a cluster of human hIgh/ultrahIgh sulfur keratIn-assocIated proteIn genes embedded In the Type I keratIn gene domaIn on chromosome 17q12-21
Journal of Biological Chemistry, 2001Co-Authors: Michael A Rogers, Hermelita Winter, Lutz Langbein, Claudia Ehmann, Silke Praetzel, Bernhard Korn, Jurgen SchweizerAbstract:Abstract Low strIngency screenIng of a human P1 artIfIcIal chromosome lIbrary usIng a human haIr keratIn-assocIated proteIn (hKAP1.1A) gene probe resulted In the IsolatIon of sIx P1 artIfIcIal chromosome clones. End sequencIng and EMBO/GenBankTM data base analysIs showed these clones to be contaIned In four prevIously sequenced human bacterIal artIfIcIal chromosome clones present on chromosome 17q12-21 and arrayed Into two large contIgs of 290 and 225 kIlobase paIrs (kb) In sIze. A fIfth, partIally sequenced human bacterIal artIfIcIal chromosome clone data base sequence overlapped and closed both of these contIgs. One end of thIs 600-kb cluster harbored sIx gene locI for prevIously descrIbed human Type I haIr keratIn genes. The other end of thIs cluster contaIned the human Type I cytokeratIn K20 andK12 gene locI. The center of the cluster, startIng 35 kb downstream of the hHa3-I haIr keratIn gene, contaIned 37 genes for hIgh/ultrahIgh sulfur haIr keratIn-assocIated proteIns (KAPs), whIch could be dIvIded Into a total of 7 KAP multIgene famIlIes based on amIno acId homology comparIsons wIth prevIously IdentIfIed sheep, mouse, and rabbIt KAPs. To date, 26 human KAP cDNA clones have been Isolated through screenIng of an arrayed human scalp cDNA lIbrary by means of specIfIc 3′-noncodIng regIon polymerase chaIn reactIon probes derIved from the IdentIfIed KAP gene sequences. ThIs screenIng also yIelded four addItIonal cDNA sequences whose genes were not present on thIs gene cluster but belonged to specIfIc KAP gene famIlIes present on thIs contIg. HaIr follIcle In sItuhybrIdIzatIon data for sIngle members of fIve dIfferent KAP multIgene famIlIes all showed localIzatIon of the respectIve mRNAs to the upper cortex of the haIr shaft.
