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Dennis R Roop - One of the best experts on this subject based on the ideXlab platform.
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Loricrin past present and future
International Journal of Molecular Sciences, 2020Co-Authors: Yosuke Ishitsuka, Dennis R RoopAbstract:The terminal differentiation of the epidermis is a complex physiological process. During the past few decades, medical genetics has shown that defects in the stratum corneum (SC) permeability barrier cause a myriad of pathological conditions, ranging from common dry skin to lethal ichthyoses. Contrarily, molecular phylogenetics has revealed that amniotes have acquired a specialized form of cytoprotection cornification that provides mechanical resilience to the SC. This superior biochemical property, along with desiccation tolerance, is attributable to the proper formation of the macromolecular protein-lipid complex termed cornified cell envelopes (CE). Cornification largely depends on the peculiar biochemical and biophysical properties of Loricrin, which is a major CE component. Despite its quantitative significance, Loricrin knockout (LKO) mice have revealed it to be dispensable for the SC permeability barrier. Nevertheless, LKO mice have brought us valuable lessons. It is also becoming evident that absent Loricrin affects skin homeostasis more profoundly in many more aspects than previously expected. Through an extensive review of aggregate evidence, we discuss herein the functional significance of the thiol-rich protein Loricrin from a biochemical, genetic, pathological, metabolic, or immunological aspect with some theoretical and speculative perspectives.
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lce1 family members are nrf2 target genes that are induced to compensate for the loss of Loricrin
Journal of Investigative Dermatology, 2016Co-Authors: Yosuke Ishitsuka, Alasdair C Steven, Peter J Koch, Aaron J Huebner, Robert H Rice, Vladislav V Speransky, Dennis R RoopAbstract:Loricrin is a major component of the cornified cell envelope, a highly insoluble structure composed of covalently cross-linked proteins. Although Loricrin knockout mice only exhibit a mild transient phenotype at birth, they show a marked delay in the formation of an epidermal barrier in utero. We recently discovered that induction of a compensatory response to repair the defective barrier is initiated by amniotic fluid via activation of NF-E2-related factor 2 and identified Sprr2d and Sprr2h as direct transcriptional targets. Proteomic analysis suggested that other proteins were also incorporated into the Loricrin knockout cell envelope, in addition to the small proline rich proteins. Here we present evidence suggesting that the late cornified envelope 1 proteins are also compensatory components as determined by their localization within the Loricrin knockout cell envelope via immunoelectron microscopy. We also demonstrate that late cornified envelope 1 genes are upregulated at the transcriptional level in Loricrin knockout mouse skin and confirm that late cornified envelope 1 genes are transcriptional targets of NRF2. Our present study further highlights the complexity and importance of a compensatory mechanism that evolved in terrestrial animals to ensure the formation of a functional epidermal barrier.
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proteomic analysis of Loricrin knockout mouse epidermis
Journal of Proteome Research, 2016Co-Authors: Robert H Rice, Yosuke Ishitsuka, Blythe Durbinjohnson, Michelle Salemi, Brett S Phinney, David M Rocke, Dennis R RoopAbstract:The crosslinked envelope of the mammalian epidermal corneocyte serves as a scaffold for assembly of the lipid barrier of the epidermis. Thus, deficient envelope crosslinking by keratinocyte transglutaminase (TGM1) is a major cause of the human autosomal recessive congenital ichthyoses characterized by barrier defects. Expectations that loss of some envelope protein components would also confer an ichthyosis phenotype have been difficult to demonstrate. To help rationalize this observation, the protein profile of epidermis from Loricrin knockout mice has been compared to that of wild type. Despite the mild phenotype of the knockout, some 40 proteins were incorporated into envelope material to significantly different extents compared to those of wild type. Nearly half were also incorporated to similarly altered extents into the disulfide bonded keratin network of the corneocyte. The results suggest that loss of Loricrin alters their incorporation into envelopes as a consequence of protein–protein interactio...
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amniotic fluid activates the nrf2 keap1 pathway to repair an epidermal barrier defect in utero
Developmental Cell, 2012Co-Authors: Aaron J Huebner, Daisy Dai, Maria Morasso, Edward E Schmidt, Matthias Schafer, Sabine Werner, Dennis R RoopAbstract:Summary The loss of Loricrin, a major component of the cornified envelope, results in a delay of epidermal barrier formation. Therefore, the living layers of the epidermis are aberrantly exposed to late-stage amniotic fluid, which may serve as the signal to upregulate genes that functionally compensate for the loss of Loricrin. Consistent with this hypothesis, metabolomic studies revealed marked changes in amniotic fluid between E14.5 and E16.5 days postcoitum. In addition, we discovered that the Nrf2/Keap1 pathway detects these compositional changes and directly upregulates the expression of genes involved in the compensatory response, thus ensuring postnatal survival. In support of this finding, we demonstrate that genetically blocking the Nrf2 pathway abolishes the compensatory response and that preemptively activating Nrf2 pharmacologically rescues the delay in barrier formation in utero. Our findings reveal that the functions of Nrf2 and the composition of amniotic fluid have coevolved to ensure the formation of a functional barrier.
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yin yang 1 negatively regulates the differentiation specific transcription of mouse Loricrin gene in undifferentiated keratinocytes
Journal of Investigative Dermatology, 2004Co-Authors: Yasuhiro Kawachi, Dennis R Roop, Yasuhiro Nakamura, Hideko Sakurai, Ayako Hirota, Tomohiro Banno, Takenori Takahashi, Fujio OtsukaAbstract:Loricrin is a major component of the epidermal cornified cell envelope, and is expressed only in terminally differentiated keratinocytes. This cell differentiation-specific expression pattern suggests specific suppression of Loricrin gene expression in undifferentiated keratinocytes as well as its activation in differentiated keratinocytes. We identified a negative regulatory sequence element in the first intron of the mouse Loricrin gene involved in suppression of Loricrin gene expression in undifferentiated keratinocytes. A database search indicated that this sequence contained the putative inverted Yin-Yang 1 (YY1)-binding motif. Constructs with point mutations in the putative YY1-binding motif showed increased reporter activity, indicating that YY1 negatively regulates Loricrin gene transcription. Co-transfection experiments using a YY1 expression vector revealed that YY1 represses Loricrin promoter activity. Western blotting and immunohistochemical analyses indicated that YY1 is more abundant in undifferentiated than in differentiated keratinocytes. These findings suggest that YY1 contributes to specific Loricrin gene expression in differentiated keratinocytes by suppression of its transcription in undifferentiated keratinocytes. Furthermore, we demonstrated that forced expression of YY1 in differentiated keratinocytes results in specific downregulation of expression of other early and late differentiation markers.
Hajime Iizuka - One of the best experts on this subject based on the ideXlab platform.
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Up-regulation of Loricrin Expression by Cell Adhesion Molecule Nectin-1 through Rap1-ERK Signaling in Keratinocytes
The Journal of biological chemistry, 2007Co-Authors: Kotaro Wakamatsu, Akemi Ishida-yamamoto, Hajime Iizuka, Kenji Irie, Miki Tanaka-okamoto, Hisakazu Ogita, Noriko Okabe, H Ishizaki, Jun MiyoshiAbstract:Abstract Nectin is an immunoglobulin-like cell-cell adhesion molecule, which plays essential roles in the initial step of formation of adherens junctions and tight junctions. We demonstrate here the role of nectin-1 in the epidermis using nectin-1–/– mice. Newborn nectin-1–/– pups showed shiny and slightly reddish skin; the amount of Loricrin, one of the differentiation markers and also a major component of cornified cell envelopes, was markedly reduced in the epidermis of nectin-1–/– mice. The amounts of repetin and SPRRP, other components of cornified cell envelopes, were markedly elevated probably due to a compensatory mechanism to overcome the impaired expression of Loricrin. However, cornified cells from nectin-1–/– mice were sensitive to mechanical stress. Moreover, Ca2+-induced activation of ERK through Rap1 and expression of Loricrin were reduced in primary cultured nectin-1–/– keratinocytes; in turn, the inhibition of ERK activation reduced the amount of Loricrin in wild-type keratinocytes. These results indicate that nectin-1 plays a key role in the expression of Loricrin in the epidermis.
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unique keratinization process in psoriasis late differentiation markers are abolished because of the premature cell death
Journal of Dermatology, 2004Co-Authors: Hajime Iizuka, Hidetoshi Takahashi, Masaru Honma, Akemi IshidayamamotoAbstract:The keratinization process in psoriasis is a unique phenomenon. We have proposed an organized system for keratinization in psoriasis based on the recognition of early and late differentiation markers combined with premature cell death. The early differentiation markers, such as involucrin, small proline-rich proteins (SPRR), cystatin A and transglutaminase l, are more conspicuously expressed in psoriasis, while the late differentiation markers, such as profilaggrin and Loricrin, are abolished. Keratinization markers that are not observed in the normal epidermis are also detected; these include SKALP/elafin as well as K6 and K16. With a markedly diminished turnover time, the psoriatic epidermis rapidly synthesizes differentiation markers that are mostly under the control of the protein kinase C-AP1 transcriptional control system. Because of the premature cell death, however, the late differentiation markers are not expressed. During the improvement of the lesion and the therefore longer turnover time, the late differentiation markers rapidly catch up to reveal their expression. This explains the rapid appearance of keratohyalin granules (profilaggrin) in the healing lesion of psoriasis. Thus the keratinization process in psoriasis can be explained by the accelerated keratinization combined with premature cell death. The keratinization process in psoriasis is unique, because both accelerated keratinization and premature cell death co-exist, resulting in the disappearance of late differentiation markers such as profilaggrin and Loricrin. It is interesting to note that the premature cell death is also under the control of protein kinase C signaling.
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olmsted syndrome with squamous cell carcinoma of extremities and adenocarcinoma of the lung failure to detect Loricrin gene mutation
European Journal of Dermatology, 2003Co-Authors: Fumihide Ogawa, Hidetoshi Takahashi, Hajime Iizuka, Akemi Ishidayamamoto, Masako Udono, Hiroyuki Murota, Kazuhiro Shimizu, Ichiro KatayamaAbstract:Olmsted syndrome is an uncommon disorder of keratinization that presents mutilating palmoplantar keratoderma, periorificial hyperkeratosis, leukokeratosis and alopecia. We report a new case of this rare syndrome diagnosed in 48-year-old woman who developed several squamous cell carcinomas of limbs and adenocarcinoma of the lung. She has been followed up for about 40 years and osteolytic changes of the fingers and toes accompanied the keratinizing disorder and squamous cell carcinoma. Loricrin gene mutation that is occasionally observed in Loricrin keratoderma such as Vohwinkel's syndrome was not detected in the present case.
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Loricrin keratoderma: a cause of congenital ichthyosiform erythroderma and collodion baby
British Journal of Dermatology, 2001Co-Authors: Kazuhiko Matsumoto, Akemi Ishida-yamamoto, M. Muto, S. Seki, Toshiaki Saida, Nobuyuki Horiuchi, Hidetoshi Takahashi, Hajime IizukaAbstract:A group of hereditary palmoplantar keratodermas due to heterozygous mutation in the Loricrin gene has recently been identified. Of five reported pedigrees, four presented as mutilating keratoderma with ichthyosis (variant Vohwinkel syndrome), and one as progressive symmetric erythrokeratoderma. We report a new Japanese pedigree of Loricrin keratoderma. A 14-year-old male and his 11-year-old female sibling had both been born as collodion babies and were initially diagnosed as having non-bullous congenital ichthyosiform erythroderma, but later developed palmoplantar keratoderma with pseudoainhum. Their father was similarly affected. Direct sequencing of genomic DNA revealed a G residue insertion at codon 230-231 of the Loricrin gene. Antibody studies confirmed the presence of mutant Loricrin in the retained nuclei. We conclude that Loricrin gene mutation may present as congenital ichthyosiform erythroderma, and should be included in the differential diagnosis of collodion baby.
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mutant Loricrin is not crosslinked into the cornified cell envelope but is translocated into the nucleus in Loricrin keratoderma
Journal of Investigative Dermatology, 2000Co-Authors: Akemi Ishidayamamoto, Hidetoshi Takahashi, Hajime Iizuka, Satoshi Nakamura, Motoshi Kinouchi, Hidemasa Kato, Hiroshi Kiyama, Keith D B Armstrong, Colin S Munro, R A J EadyAbstract:Loricrin is a major constituent of the epidermal cornified cell envelope. We have recently identified heterozygous Loricrin gene mutations in two dominantly inherited skin diseases, the ichthyotic variant of Vohwinkel syndrome and progressive symmetric erythrokeratoderma, collectively termed Loricrin keratoderma. In order to see whether the mutant Loricrin molecules predicted by DNA sequencing are expressed in vivo and to define their pathologic effects, we raised antibodies against synthetic peptides corresponding to the mutated sequences of Loricrin. Immunoblotting of horny cell extracts from Loricrin keratoderma patients showed specific bands for mutant Loricrin. Immunohisto- chemistry of Loricrin keratoderma skin biopsies showed positive immunoreactivity to the mutant Loricrin antibodies in the nuclei of differentiated epidermal keratinocytes. The immunostaining was localized to the nucleoli of the lower granular cell layer. As keratinocyte differentiation progressed the immunoreactivity moved gradually into the nucleoplasm leaving nucleoli mostly nonimmunoreactive. No substantial staining was observed along the cornified cell envelope. This study confirmed that mutant Loricrin was expressed in the Loricrin keratoderma skin. Mutant Loricrin, as a dominant negative disrupter, is not likely to affect cornified cell envelope crosslinking directly, but seems to interfere with nuclear/nucleolar functions of differentiating keratinocytes. In addition, detection of the mutant Loricrin in scraped horny layer could provide a simple noninvasive screening test for Loricrin keratoderma.
Peter M Steinert - One of the best experts on this subject based on the ideXlab platform.
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Loricrin expression in cultured human keratinocytes is controlled by a complex interplay between transcription factors of the sp1 creb ap1 and ap2 families
Journal of Biological Chemistry, 2002Co-Authors: Shyhing Jang, Peter M SteinertAbstract:The major protein component of the cornified cell envelope barrier structure of the epidermis is Loricrin, and it is expressed late during terminal differentiation in epidermal keratinocytes. We have previously shown that an AP1 site located in the proximal promoter region (position −55) is essential for human Loricrin promoter activity (Rossi, A., Jang, S-I., Ceci, R., Steinert, P. M., and Markova, N. G. (1998) J. Invest. Dermatol. 110, 34–40). In this study we show that its regulation requires complex cooperative and competitive interactions between multiple transcription factors in keratinocytes located in different compartments of the epidermis. We show that as few as 154 base pairs of 5′-upstream sequences from the cap site can direct the keratinocyte-specific expression in cultured keratinocytes. Mutation and DNA-protein analyses show that Sp1, c-Jun, an unidentified regulator, and the co-activator p300/CREB-binding protein up-regulate whereas Sp3, CREB-1/CREMα/ATF-1, Jun B, and an AP2-like protein (termed the keratinocyte-specific repressor-1 (KSR-1)) suppress Loricrin promoter activity. We show that CREB protein can compete with c-Jun for the AP1 site and repress Loricrin promoter activity. We show here that the protein kinase A pathway can activate Loricrin expression by manipulation of the Sp1, Sp3, and KSR-1 levels in the nucleus. Thus, in undifferentiated cells, Loricrin expression is suppressed by Jun B, Sp3, and KSR-1 proteins. But in advanced differentiated cells, levels of Sp3, KSR-1, and CREB proteins are lower; the unidentified regulator protein can bind; Sp1 and c-Jun are increased; and then p300/CBP is recruited. Together, these events allow Loricrin transcription to proceed. Indeed, the synergistic effects of the Sp1, c-Jun, and p300 factors indicate that p300/CBP might act as bridge to form an active transcription complex.
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transglutaminase cross linking properties of the small proline rich 1 family of cornified cell envelope proteins integration with Loricrin
Journal of Biological Chemistry, 1999Co-Authors: Eleonora Candi, Tonja Kartasova, Lyuben N Marekov, Edit Tarcsa, William W Idler, Peter M SteinertAbstract:Small proline-rich 1 (SPR1) proteins are important for barrier function in stratified squamous epithelia. To explore their properties, we expressed in bacteria a recombinant human SPR1 protein and isolated native SPR1 proteins from cultured mouse keratinocytes. By circular dichroism, they possess no α or β structure but have some organized structure associated with their central peptide repeat domain. The transglutaminase (TGase) 1 and 3 enzymes use the SPR1 proteins as complete substrates in vitro but in different ways: head domain A sequences at the amino terminus were used preferentially for cross-linking by TGase 3, whereas those in head domain B sequences were used for cross-linking by TGase 1. The TGase 2 enzyme cross-linked SPR1 proteins poorly. Together with our data base of 141 examples of in vivo cross-links between SPRs and Loricrin, this means that both TGase 1 and 3 are required for cross-linking SPR1 proteins in epithelia in vivo. Double in vitro cross-linking experiments suggest that oligomerization of SPR1 into large polymers can occur only by further TGase 1 cross-linking of an initial TGase 3 reaction. Accordingly, we propose that TGase 3 first cross-links Loricrin and SPRs together to form small interchain oligomers, which are then permanently affixed to the developing CE by further cross-linking by the TGase 1 enzyme. This is consistent with the known consequences of diminished barrier function in TGase 1 deficiency models.
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biochemical evidence that small proline rich proteins and trichohyalin function in epithelia by modulation of the biomechanical properties of their cornified cell envelopes
Journal of Biological Chemistry, 1998Co-Authors: Peter M Steinert, Tonja Kartasova, Lyuben N MarekovAbstract:The cornified cell envelope (CE) is a specialized structure involved in barrier function in stratified squamous epithelia, and is assembled by transglutaminase cross-linking of several proteins. Murine forestomach epithelium undergoes particularly rigorous mechanical trauma, and these CEs contain the highest known content of small proline-rich proteins (SPRs). Sequencing analyses of these CEs revealed that SPRs function as cross-bridgers by joining other proteins by use of multiple adjacent glutamines and lysines on only the amino and carboxyl termini and in functionally non-polar ways. Forestomach CEs also use trichohyalin as a novel cross-bridging protein. We performed mathematical modeling of amino acid compositions of the CEs of mouse and human epidermis of different body sites. Although the sum of Loricrin + SPRs was conserved, the amount of SPRs varied in relation to the presumed physical requirements of the tissues. Our data suggest that SPRs could serve as modifiers of a composite CE material composed of mostly Loricrin; we propose that increasing amounts of cross-bridging SPRs modify the structure of the CE, just as cross-linking proteins strengthen other types of tissues. In this way, different epithelia may use varying amounts of the cross-bridging SPRs to alter the biomechanical properties of the tissue in accordance with specific physical requirements and functions.
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biochemical structural and transglutaminase substrate properties of human Loricrin the major epidermal cornified cell envelope protein
Journal of Biological Chemistry, 1995Co-Authors: Eleonora Candi, Lyuben N Marekov, Gerry Melino, Giampiero Mei, Edit Tarcsa, Sooil Chung, Peter M SteinertAbstract:Loricrin is the major protein of the cornified cell envelope of terminally differentiated epidermal keratinocytes which functions as a physical barrier. In order to understand its properties and role in cornified cell envelope, we have expressed human Loricrin from a full-length cDNA clone in bacteria and purified it to homogeneity. We have also isolated Loricrin from newborn mouse epidermis. By circular dichroism and fluorescence spectroscopy, the in vivo mouse and bacterially expressed human Loricrins possess no α or β structure but have some organized structure in solution associated with their multiple tyrosines and can be reversibly denatured by either guanidine hydrochloride or temperature. The transglutaminase (TGase) 1, 2, and 3 enzymes expressed during epidermal differentiation utilized Loricrin in vitro as a complete substrate, but the types of cross-linking were different. The TGase 3 reaction favored certain lysines and glutamines by forming mostly intrachain cross-links, whereas TGase 1 formed mostly large oligomeric complexes by interchain cross-links involving different lysines and glutamines. Together, the glutamines and lysines used in vitro are almost identical to those seen in vivo. The data support a hypothesis for the essential and complementary roles of both TGase 1 and TGase 3 in cross-linking of Loricrin in vivo. Failure to cross-link Loricrin by TGase 1 may explain the phenotype of lamellar ichthyosis, a disease caused by mutations in the TGase 1 gene.
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the proteins elafin filaggrin keratin intermediate filaments Loricrin and small proline rich proteins 1 and 2 are isodipeptide cross linked components of the human epidermal cornified cell envelope
Journal of Biological Chemistry, 1995Co-Authors: Peter M Steinert, Lyuben N MarekovAbstract:Abstract The cornified cell envelope (CE) is a 15-nm thick layer of insoluble protein deposited on the intracellular side of the cell membrane of terminally differentiated stratified squamous epithelia. The CE is thought to consist of a complex amalgam of proteins cross-linked by isodipeptide bonds formed by the action of transglutaminases, but little is known about how or in which order the several putative proteins are cross-linked together. In this paper, CEs purified from human foreskin epidermis were digested in two steps by proteinase K, which released as soluble peptides about 30% and then another 35% of CE protein mass, corresponding to approximately the outer third (cytoplasmic surface) and middle third, respectively. Following fractionation, 145 unique peptides containing two or more sequences cross-linked by isodipeptide bond(s) were sequenced. Based on these data, most (94% molar mass) of the outer third of CE structure consists of intra- and interchain cross-linked Loricrin, admixed with SPR1 and SPR2 proteins as bridging cross-links between Loricrin. Likewise, the middle third of CE structure consists largely of cross-linked Loricrin and SPR proteins, but is mixed with the novel protein elafin which also forms cross-bridges between Loricrin. In addition, cross-links involving Loricrin and keratins 1, 2e, and 10 or filaggrin were recovered in both levels. The data establish for the first time that these several proteins are indeed cross-linked protein components of the CE structure. In addition, the data support a model for the intermediate to final stages of CE assembly: the proteins elafin, SPR1 and SPR2, and Loricrin begin to be deposited on a preformed scaffold; later, elafin deposition decreases as Loricrin and SPR accumulation continues to effect final assembly. The recovery of cross-links involving keratins further suggests that the subjacent cytoplasmic keratin intermediate filament-filaggrin network is anchored to the developing CE during these events.
Hidetoshi Takahashi - One of the best experts on this subject based on the ideXlab platform.
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expression of wild type but not mutant Loricrin causes programmed cell death in hacat keratinocytes
Journal of Dermatology, 2010Co-Authors: Kozo Yoneda, Hidetoshi Takahashi, Toshio Demitsu, Junsuke Igarashi, Hiroaki Kosaka, Motomu Manabe, Nobuya Inagaki, Atsushi Kon, Maki Kakurai, Yasuo KubotaAbstract:The epidermal cornified cell envelope is a complex protein-lipid composite that replaces the plasma membrane of corneocytes and is crucial for epidermal barrier function. Loricrin is a major constituent of the epidermal cornified cell envelope, contributing approximately 70% by mass. In order to explore novel function of wild-type (WT) Loricrin other than the major component of the epidermal cornified cell envelope, we transiently expressed construct encoding human WT and mutant Loricrin (730insG) in HaCaT keratinocytes. HaCaT cells transfected with WT or mutant Loricrin were at differentiation level. WT Loricrin in the transfected cells was seen diffusely in the cytoplasm and nuclei. Positive transferase deoxytidyl uridine end labeling staining was observed in the nuclei of WT Loricrin-transfected HaCaT keratinocytes. Data from the DNA fragmentation assay showed that only WT Loricrin induced DNA ladders compared with that of mutant Loricrin. WT Loricrin-transfected HaCaT keratinocytes were susceptible to programmed cell death (PCD). Activation of caspase-14 was also seen. In contrast, PCD or activation of caspase-14 did not occur in mutant Loricrin-transfected HaCaT cells. These results suggest that the expression of WT Loricrin facilitates induction of PCD in HaCaT keratinocytes.
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unique keratinization process in psoriasis late differentiation markers are abolished because of the premature cell death
Journal of Dermatology, 2004Co-Authors: Hajime Iizuka, Hidetoshi Takahashi, Masaru Honma, Akemi IshidayamamotoAbstract:The keratinization process in psoriasis is a unique phenomenon. We have proposed an organized system for keratinization in psoriasis based on the recognition of early and late differentiation markers combined with premature cell death. The early differentiation markers, such as involucrin, small proline-rich proteins (SPRR), cystatin A and transglutaminase l, are more conspicuously expressed in psoriasis, while the late differentiation markers, such as profilaggrin and Loricrin, are abolished. Keratinization markers that are not observed in the normal epidermis are also detected; these include SKALP/elafin as well as K6 and K16. With a markedly diminished turnover time, the psoriatic epidermis rapidly synthesizes differentiation markers that are mostly under the control of the protein kinase C-AP1 transcriptional control system. Because of the premature cell death, however, the late differentiation markers are not expressed. During the improvement of the lesion and the therefore longer turnover time, the late differentiation markers rapidly catch up to reveal their expression. This explains the rapid appearance of keratohyalin granules (profilaggrin) in the healing lesion of psoriasis. Thus the keratinization process in psoriasis can be explained by the accelerated keratinization combined with premature cell death. The keratinization process in psoriasis is unique, because both accelerated keratinization and premature cell death co-exist, resulting in the disappearance of late differentiation markers such as profilaggrin and Loricrin. It is interesting to note that the premature cell death is also under the control of protein kinase C signaling.
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olmsted syndrome with squamous cell carcinoma of extremities and adenocarcinoma of the lung failure to detect Loricrin gene mutation
European Journal of Dermatology, 2003Co-Authors: Fumihide Ogawa, Hidetoshi Takahashi, Hajime Iizuka, Akemi Ishidayamamoto, Masako Udono, Hiroyuki Murota, Kazuhiro Shimizu, Ichiro KatayamaAbstract:Olmsted syndrome is an uncommon disorder of keratinization that presents mutilating palmoplantar keratoderma, periorificial hyperkeratosis, leukokeratosis and alopecia. We report a new case of this rare syndrome diagnosed in 48-year-old woman who developed several squamous cell carcinomas of limbs and adenocarcinoma of the lung. She has been followed up for about 40 years and osteolytic changes of the fingers and toes accompanied the keratinizing disorder and squamous cell carcinoma. Loricrin gene mutation that is occasionally observed in Loricrin keratoderma such as Vohwinkel's syndrome was not detected in the present case.
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Loricrin keratoderma: a cause of congenital ichthyosiform erythroderma and collodion baby
British Journal of Dermatology, 2001Co-Authors: Kazuhiko Matsumoto, Akemi Ishida-yamamoto, M. Muto, S. Seki, Toshiaki Saida, Nobuyuki Horiuchi, Hidetoshi Takahashi, Hajime IizukaAbstract:A group of hereditary palmoplantar keratodermas due to heterozygous mutation in the Loricrin gene has recently been identified. Of five reported pedigrees, four presented as mutilating keratoderma with ichthyosis (variant Vohwinkel syndrome), and one as progressive symmetric erythrokeratoderma. We report a new Japanese pedigree of Loricrin keratoderma. A 14-year-old male and his 11-year-old female sibling had both been born as collodion babies and were initially diagnosed as having non-bullous congenital ichthyosiform erythroderma, but later developed palmoplantar keratoderma with pseudoainhum. Their father was similarly affected. Direct sequencing of genomic DNA revealed a G residue insertion at codon 230-231 of the Loricrin gene. Antibody studies confirmed the presence of mutant Loricrin in the retained nuclei. We conclude that Loricrin gene mutation may present as congenital ichthyosiform erythroderma, and should be included in the differential diagnosis of collodion baby.
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mutant Loricrin is not crosslinked into the cornified cell envelope but is translocated into the nucleus in Loricrin keratoderma
Journal of Investigative Dermatology, 2000Co-Authors: Akemi Ishidayamamoto, Hidetoshi Takahashi, Hajime Iizuka, Satoshi Nakamura, Motoshi Kinouchi, Hidemasa Kato, Hiroshi Kiyama, Keith D B Armstrong, Colin S Munro, R A J EadyAbstract:Loricrin is a major constituent of the epidermal cornified cell envelope. We have recently identified heterozygous Loricrin gene mutations in two dominantly inherited skin diseases, the ichthyotic variant of Vohwinkel syndrome and progressive symmetric erythrokeratoderma, collectively termed Loricrin keratoderma. In order to see whether the mutant Loricrin molecules predicted by DNA sequencing are expressed in vivo and to define their pathologic effects, we raised antibodies against synthetic peptides corresponding to the mutated sequences of Loricrin. Immunoblotting of horny cell extracts from Loricrin keratoderma patients showed specific bands for mutant Loricrin. Immunohisto- chemistry of Loricrin keratoderma skin biopsies showed positive immunoreactivity to the mutant Loricrin antibodies in the nuclei of differentiated epidermal keratinocytes. The immunostaining was localized to the nucleoli of the lower granular cell layer. As keratinocyte differentiation progressed the immunoreactivity moved gradually into the nucleoplasm leaving nucleoli mostly nonimmunoreactive. No substantial staining was observed along the cornified cell envelope. This study confirmed that mutant Loricrin was expressed in the Loricrin keratoderma skin. Mutant Loricrin, as a dominant negative disrupter, is not likely to affect cornified cell envelope crosslinking directly, but seems to interfere with nuclear/nucleolar functions of differentiating keratinocytes. In addition, detection of the mutant Loricrin in scraped horny layer could provide a simple noninvasive screening test for Loricrin keratoderma.
Akemi Ishidayamamoto - One of the best experts on this subject based on the ideXlab platform.
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somatic recombination underlies frequent revertant mosaicism in Loricrin keratoderma
Life science alliance, 2019Co-Authors: Shotaro Suzuki, Masashi Akiyama, Akemi Ishidayamamoto, Toshifumi Nomura, Toshinari Miyauchi, Masae Takeda, Yasuyuki Fujita, Wataru Nishie, Hiroshi ShimizuAbstract:Revertant mosaicism is a phenomenon in which pathogenic mutations are rescued by somatic events, representing a form of natural gene therapy. Here, we report on the first evidence for revertant mosaicism in Loricrin keratoderma (LK), an autosomal dominant form of ichthyosis caused by mutations in LOR on 1q21.3. We identified two unrelated LK families exhibiting dozens of previously unreported white spots, which increased in both number and size with age. Biopsies of these spots revealed that they had normal histology and that causal LOR mutations were lost. Notably, dense single nucleotide polymorphism mapping identified independent copy-neutral loss-of-heterozygosity events on chromosome 1q extending from regions centromeric to LOR to the telomere in all investigated spots, suggesting that somatic recombination represents a common reversion mechanism in LK. Furthermore, we demonstrated that reversion of LOR mutations confers a growth advantage to cells in vitro, but the clinically limited size of revertant spots suggests the existence of mechanisms constraining revertant clone expansion. Nevertheless, the identification of revertant mosaicism in LK might pave the way for revertant therapy for this intractable disease.
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unique keratinization process in psoriasis late differentiation markers are abolished because of the premature cell death
Journal of Dermatology, 2004Co-Authors: Hajime Iizuka, Hidetoshi Takahashi, Masaru Honma, Akemi IshidayamamotoAbstract:The keratinization process in psoriasis is a unique phenomenon. We have proposed an organized system for keratinization in psoriasis based on the recognition of early and late differentiation markers combined with premature cell death. The early differentiation markers, such as involucrin, small proline-rich proteins (SPRR), cystatin A and transglutaminase l, are more conspicuously expressed in psoriasis, while the late differentiation markers, such as profilaggrin and Loricrin, are abolished. Keratinization markers that are not observed in the normal epidermis are also detected; these include SKALP/elafin as well as K6 and K16. With a markedly diminished turnover time, the psoriatic epidermis rapidly synthesizes differentiation markers that are mostly under the control of the protein kinase C-AP1 transcriptional control system. Because of the premature cell death, however, the late differentiation markers are not expressed. During the improvement of the lesion and the therefore longer turnover time, the late differentiation markers rapidly catch up to reveal their expression. This explains the rapid appearance of keratohyalin granules (profilaggrin) in the healing lesion of psoriasis. Thus the keratinization process in psoriasis can be explained by the accelerated keratinization combined with premature cell death. The keratinization process in psoriasis is unique, because both accelerated keratinization and premature cell death co-exist, resulting in the disappearance of late differentiation markers such as profilaggrin and Loricrin. It is interesting to note that the premature cell death is also under the control of protein kinase C signaling.
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olmsted syndrome with squamous cell carcinoma of extremities and adenocarcinoma of the lung failure to detect Loricrin gene mutation
European Journal of Dermatology, 2003Co-Authors: Fumihide Ogawa, Hidetoshi Takahashi, Hajime Iizuka, Akemi Ishidayamamoto, Masako Udono, Hiroyuki Murota, Kazuhiro Shimizu, Ichiro KatayamaAbstract:Olmsted syndrome is an uncommon disorder of keratinization that presents mutilating palmoplantar keratoderma, periorificial hyperkeratosis, leukokeratosis and alopecia. We report a new case of this rare syndrome diagnosed in 48-year-old woman who developed several squamous cell carcinomas of limbs and adenocarcinoma of the lung. She has been followed up for about 40 years and osteolytic changes of the fingers and toes accompanied the keratinizing disorder and squamous cell carcinoma. Loricrin gene mutation that is occasionally observed in Loricrin keratoderma such as Vohwinkel's syndrome was not detected in the present case.
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mutant Loricrin is not crosslinked into the cornified cell envelope but is translocated into the nucleus in Loricrin keratoderma
Journal of Investigative Dermatology, 2000Co-Authors: Akemi Ishidayamamoto, Hidetoshi Takahashi, Hajime Iizuka, Satoshi Nakamura, Motoshi Kinouchi, Hidemasa Kato, Hiroshi Kiyama, Keith D B Armstrong, Colin S Munro, R A J EadyAbstract:Loricrin is a major constituent of the epidermal cornified cell envelope. We have recently identified heterozygous Loricrin gene mutations in two dominantly inherited skin diseases, the ichthyotic variant of Vohwinkel syndrome and progressive symmetric erythrokeratoderma, collectively termed Loricrin keratoderma. In order to see whether the mutant Loricrin molecules predicted by DNA sequencing are expressed in vivo and to define their pathologic effects, we raised antibodies against synthetic peptides corresponding to the mutated sequences of Loricrin. Immunoblotting of horny cell extracts from Loricrin keratoderma patients showed specific bands for mutant Loricrin. Immunohisto- chemistry of Loricrin keratoderma skin biopsies showed positive immunoreactivity to the mutant Loricrin antibodies in the nuclei of differentiated epidermal keratinocytes. The immunostaining was localized to the nucleoli of the lower granular cell layer. As keratinocyte differentiation progressed the immunoreactivity moved gradually into the nucleoplasm leaving nucleoli mostly nonimmunoreactive. No substantial staining was observed along the cornified cell envelope. This study confirmed that mutant Loricrin was expressed in the Loricrin keratoderma skin. Mutant Loricrin, as a dominant negative disrupter, is not likely to affect cornified cell envelope crosslinking directly, but seems to interfere with nuclear/nucleolar functions of differentiating keratinocytes. In addition, detection of the mutant Loricrin in scraped horny layer could provide a simple noninvasive screening test for Loricrin keratoderma.
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antigen retrieval of Loricrin epitopes at desmosomal areas of cornified cell envelopes an immunoelectron microscopic analysis
Experimental Dermatology, 1999Co-Authors: Akemi Ishidayamamoto, Hidetoshi Takahashi, Hikaru Tanaka, Hiroshi Nakane, Hajime IizukaAbstract:Cell envelopes (CEs) are insoluble, chemically and mechanically tough structures formed during terminal differentiation of keratinocytes, providing skin with a protective barrier against the environment. They are 15 to 20 nm thick structures beneath the plasma membrane and continuous with desmosomal attachment plaques. Sequential deposition of several proteins including involucrin and Loricrin leads to a gradual increase in envelope thickness and rigidity. Cross-linking of desmosomal components to other CE-proteins has been demonstrated and desmosomes in the cornified cells have been regarded as a part of CEs. Our previous immunoelectron microscopy studies showed that desmosomal areas of granular cells were Loricrin-positive, but those in cornified cells were negative. We asked whether this is due to epitope masking and applied trypsin digestion of the electron microscopy sections to retrieve the possibly masked epitopes. Since this treatment made desmosomal structures obscure, one side of the sections was stained with anti-desmoglein antibody as an indicator of desmosomes. Trypsin was applied on the other side followed by immunolabeling with anti-Loricrin antibody. Trypsin digestion indeed unmasked the Loricrin epitopes in the desmoglein-positive desmosomal areas of CEs. It seems therefore that Loricrin is first accumulated at the desmosomes before the CE-assembly and cross-linking of Loricrin occurs at the desmosomal areas of CEs as well as at the non-desmosomal areas.
