A functional "knockout" of human keratin 14.

Rugg, Elizabeth L.; McLean, William; Lane, E. Birgitte; Pitera, Rosabella T.; McMillan, James R.; Dopping-Hepenstal, P J C; Navsaria, Harshad; Leigh, Irene M.; Eady, R.A.J.

doi:10.1101/gad.8.21.2563

Cited by 166 publications

(136 citation statements)

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“…3 a). The degree of skin blistering in newborn animals was significantly more severe than that of the two human EBS patients with K14 premature stop codon mutations (Chan et al, 1994;Rugg et al, 1994). These mice were generally sacrificed within 48 h after birth; however, some survived, and when their first hair coat became plush (~2--4 wk), their body trunk blisters healed, without scarring.…”

Section: Mk14 Mice Exhibit Gross Blistering Over Their Body Surfacementioning

confidence: 99%

“…These patients still had appreciable levels of K5, which was surprising, since studies in fibroblasts had shown that in the absence of its partner, a keratin is unstable and rapidly turns over (Kulesh and Oshima, 1988;Lersch et al, 1989). Rugg et al (1994) proposed that the K5 protein might be stabilized by association with the plasma membrane. Chan et al (1994) suggested that K5 might be stabilized by a second, as yet unidentified type I keratin which then forms a lesser, but bona fide, keratin filament network in basal cells.…”

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confidence: 99%

“…A clue that there might be additional explanations underlying the relatively mild effects of K14 mutations and/ or ablation on other stratified squamous epithelia came from biochemical and electron microscopy studies on the two recessive EBS patients that seemingly lacked K14 (Rugg et al, 1994;Chan et al, 1994). These patients still had appreciable levels of K5, which was surprising, since studies in fibroblasts had shown that in the absence of its partner, a keratin is unstable and rapidly turns over (Kulesh and Oshima, 1988;Lersch et al, 1989).…”

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confidence: 99%

“…Although autosomal dominant, i.e., dominant negative, mutations do not allow unequivocal assignment of function, it was recently shown that patients homozygous for a premature termination codon in their K14 gene do not have detectable K14-K5 keratin networks and yet have severe EBS (Chan et al, 1994;Rugg et al, 1994). While demonstration of function still awaits the creation of true K14 null mutations, these data provide further support for the notion that cell fragility is a consequence of the absence of a major keratin filament network, rather than the presence of insoluble aggregates of improperly polymerized keratin.…”

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The basal keratin network of stratified squamous epithelia: defining K15 function in the absence of K14.

Lloyd

Cheng

et al. 1995

The Journal of Cell Biology

250

254

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Abstract. Keratin 5 and keratin 14 have been touted as the hallmarks of the basal keratin networks of all stratified squamous epithelia. Absence of K14 gives rise to epidermolysis bullosa simplex, a human blistering skin disorder involving cytolysis in the basal layer of epidermis. To address the puzzling question of why this disease is primarily manifested in skin rather than other stratified squamous epithelia, we ablated the K14 gene in mice and examined various tissues expressing this gene. We show that a key factor is the presence of another keratin, K15, which was hitherto unappreciated as a basal cell component. We show that the levels of K15 relative to K14 vary dramatically among stratified squamous epithelial tissues, and with neonatal development. In the absence of K14, K15 makes a bona fide, but ultrastructurally distinct, keratin filament network with K5. In the epidermis of neonatal mutant mice, K15 levels are low and do not compensate for the loss of K14. In contrast, the esophagus is unaffected in the neonatal mutant mice, but does appear to be fragile in the adult. Parallel to this phenomenon is that esophageal K14 is expressed at extremely low levels in the neonate, but rises in postnatal development. Finally, despite previous conclusions that the formation of suprabasal keratin filaments might depend upon K5/K14, we find that a wide variety of suprabasal networks composed of different keratins can form in the absence of K14 in the basal layer.

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Section: Mk14 Mice Exhibit Gross Blistering Over Their Body Surfacementioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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The basal keratin network of stratified squamous epithelia: defining K15 function in the absence of K14.

Lloyd

Cheng

et al. 1995

The Journal of Cell Biology

250

254

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“…The H1 region has been implicated in filament assembly and contains major phosphorylation sites that are essential for the regulation of KIF dynamics [12], while the linker and stutter regions provide critical flexibility to the otherwise rigid alpha-helical rod [13]. In addition, a few rare autosomal recessive mutations leading to the 'knock-out' of keratin 14 in the basal epidermis have also been described in EBS [14][15][16].…”

Section: Pathology Of Epidermal Keratins Epidermolysis Bullosa Simplementioning

confidence: 99%

Diseases of epidermal keratins and their linker proteins

Uitto

Richard

McGrath³

2007

Experimental Cell Research

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Epidermal keratins, a diverse group of structural proteins, form intermediate filament networks responsible for the structural integrity of keratinocytes. The networks extend from the nucleus of the epidermal cells to the plasma membrane where the keratins attach to linker proteins which are part of desmosomal and hemidesmosomal attachment complexes. The expression of specific keratin genes is regulated by differentiation of the epidermal cells within the stratifying squamous epithelium. Progress in molecular characterization of the epidermal keratins and their linker proteins has formed the basis to identify mutations which are associated with distinct cutaneous manifestations in patients with genodermatoses. The precise phenotype of each disease apparently reflects the spatial level of expression of the mutated genes, as well as the types and positions of the mutations and their consequences at mRNA and protein levels. Identification of specific mutations in keratinization disorders has provided the basis for improved diagnosis and subclassification with prognostic implications and has formed the platform for prenatal testing and preimplantation genetic diagnosis. Finally, precise knowledge of the mutations is a prerequisite for development of gene therapy approaches to counteract, and potentially cure, these often devastating and currently intractable diseases. KeywordsEpidermal keratins; intermediate filaments; epidermal differentiation; hemidesmosomes; desmosomes; genodermatoses; skin fragility; epidermolysis bullosa; epidermolytic hyperkeratosis; ichthyosis Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. BIOLOGY OF EPIDERMAL KERATINSKeratins NIH Public Access Author ManuscriptExp Cell Res. Author manuscript; available in PMC 2008 November 4. Published in final edited form as:Exp Cell Res. 2007 June 10; 313(10): 1995-2009. doi:10.1016/j.yexcr.2007.03.029. NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript dimensional and highly dynamic cytoskeleton spanning between the nucleus and the cell membrane, where they are anchored by interactions with desmosomal and hemidesmosomal linker proteins (Fig. 1). This organization provides both structural stability and flexibility, and ensures the mechanical integrity of different epithelial tissues. Keratins are expressed as obligate heterodimers of acidic (type I) and basic (type II) proteins, which assemble, through a multi-step process, into intermediate filaments (Fig. 2). The genes encoding type I and type II keratins cluster on chromosomal regions 17q12-q21 and 12q11-q13, respectively. Keratin ...

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