Disease relevance of Krt14

• Absence of K14 gives rise to epidermolysis bullosa simplex, a human blistering skin disorder involving cytolysis in the basal layer of epidermis [1].
• These results suggest that papilloma cells fail to respond to or generate signals to regulate K14 expression in the differentiating suprabasal cell layers and may not fully express their suprabasal cell keratins [2].
• K14 protein and transcripts are highly expressed in all strata in carcinomas while protein and transcripts for K1 and K10 are essentially absent [2].
• The replacement of PTHrP expression in the enamel epithelium with a keratin 14-driven transgene corrects the defect in bone resorption and restores the normal program of tooth eruption [3].
• K14-MEK mice exhibit moderate hyperplasia, with spontaneous skin tumor development within 5 weeks of birth [4].

Psychiatry related information on Krt14

• We observed that a decrease in both LAT enhancer histone H3 (K9, K14) acetylation and LAT RNA abundance occurs prior to an increase in acetylation, or transcriptional permissiveness, at the ICP0 promoter [5].

High impact information on Krt14

• The expression of beta1 integrin, which is preferentially expressed in epidermal stem cells is unusually low in the epidermis of K14.MYC2 mice [6].
• Adult K14.MYC2 mice gradually lose their hair and develop spontaneous ulcerated lesions due to a severe impairment in wound healing; their keratinocytes show impaired migration in response to wounding [6].
• Label-retaining analysis to identify epidermal stem cells reveals a 75% reduction in the number of stem cells in 3-month-old K14.MYC2 mice, compared with wildtype mice [6].
• To determine the role of c-Myc in epidermal stem cells in vivo, we have targeted expression of human MYC2 to the hair follicles and the basal layer of mouse epidermis using a keratin 14 vector (K14.MYC2) [6].
• We now demonstrate that two patients with spontaneous cases of Dowling-Meara EBS have point mutations in a critical region in one (K14) of two basal keratin genes [7].

Chemical compound and disease context of Krt14

• This lymphoproliferative skin disease is substantially more severe in mice homozygous for the K14/IL-7 transgene [8].
• Interestingly, similar features of carcinogenesis, including multiple, large (up to 0.5 cm) exophytic papillary squamous tumors and invasive squamous cell carcinomas, increased bromodeoxyuridine staining, and increased K14 expression, were also observed in the esophagi of 4-NQO-treated mice [9].
• To create targeted somatic mutations in the epidermis, we established transgenic mice expressing the bacteriophage P1 Cre recombinase or the tamoxifen-dependent Cre-ER(T2) recombinase under the control of the human keratin 14 (K14) promoter [10].

Biological context of Krt14

• The functional diversity of epidermal keratins revealed by the partial rescue of the keratin 14 null phenotype by keratin 16 [11].
• When combinations of active recombinant gene constructs for keratins 1, 5, 10, and 14 were tested in transient NIH 3T3 transfections, the most intact cytokeratin network observed by immunofluorescence was formed by the K5/K14 pair [12].
• To model human papillomavirus-induced neoplastic progression, expression of the early region of human papillomavirus type 16 (HPV16) was targeted to the basal cells of the squamous epithelium in transgenic mice, using a human keratin 14 (K14) enhancer/promoter [13].
• K14 null animals die several days after birth, making the detailed study of the consequences of K14 deletion in epidermal cell physiology in vivo particularly difficult [14].
• Keratin 14 (K14) is believed to play a pivotal role in the maintenance of epidermal cell shape and contributing to their resistance to mechanical trauma, thereby protecting the cells from lysing [14].

Anatomical context of Krt14

• While a structural function has been clearly defined for K14, we have proposed that a function of K16 may be to play a role in the process of keratinocyte activation that occurs after acute injury to stratified epithelia [11].
• Several keratinocyte cell lines were generated from 6-day-old mice homozygous for a targeted disruption of the K14 gene (lines designated MKC-5, MKC-23, and MKC-33) and from their wild-type littermates (lines designated MKC-1 and MKC-6) [14].
• Keratin 14 protein in cultured nonparenchymal rat hepatic epithelial cells: characterization of keratin 14 and keratin 19 as antigens for the commonly used mouse monoclonal antibody OV-6 [15].
• In the study presented here, we confirmed by protein sequence analysis that K14 was a major component of the intermediate filaments in a nonparenchymal cell line of hepatic origin [15].
• Immunocytochemical analysis of the cells in monolayer demonstrated that K8 as well as K14 were incorporated in the cellular cytoskeleton [15].

Associations of Krt14 with chemical compounds

• The subcolumnar reserve cells induced by vitamin A deficiency displayed positive staining for K5 and K14 [16].
• However, low level of phenylalanine clearance was observed in mice expressing PAH and GTP-CH from the K14 promoter, suggesting that the skin can be genetically engineered to function as a 'metabolic sink' [17].
• Keratin 14 was consistently expressed by mammary basal cells, and was detected in scattered luminal cells from 13.5 days after conception through puberty [18].
• In cell culture, the INV and K14 promoter constructs demonstrated significant beta-galactosidase expression in human keratinocytes, but minimal expression in 293 and NIH 3T3 cell types [19].
• However, the epithelial cell lines expressed cytokeratin 14 and cytokeratin 10 when exposed to medium containing different concentrations of Ca(2+) [20].

Regulatory relationships of Krt14

• We have demonstrated that keratin 14 (K14) is expressed together with vimentin in undifferentiated RLE cells [21].
• The number of K14-positive cells that coexpressed K12 increased with age and reached a plateau after P180 [22].
• Surprisingly, Bcl-2 overexpression under the control of the keratin-14 promoter leads to accelerated catagen progression and increased chemotherapy-induced apoptosis, HF dystrophy and alopecia [23].
• To test this possibility, we generated transgenic mice that overexpress the activin betaA chain in the epidermis under the control of a keratin 14 promoter [24].
• To explore the role of CaSR in the epidermis, we utilised the keratin 14 promoter to express CaSR cDNA constitutively in the basal cells of the stratified squamous epithelium of transgenic mice [25].

Other interactions of Krt14

• The K1/K14 pair was capable of forming a cytoskeletal network, but the network was poorly developed, and usually perinuclear [12].
• A distinct mTEC subset binds UEA-1 and expresses K8, but not K5 or K14 [26].
• The distribution of K5, the natural partner of K14, at the immunofluorescence level was also normal looking in the K14-/- MKC-5 cells, but with fewer filaments detectable, consistent with the approximately 20% reduction in K5 detectable on immunoblots [14].
• K17 expression was increased approximately 40% in the K14-/- cells [14].
• Nipple connective tissue and its development: insights from the K14-PTHrP mouse [27].

Analytical, diagnostic and therapeutic context of Krt14

• Further analysis by immunoprecipitation showed that filament complexes were formed between K8 and K14 as atypical partners [15].
• Transcripts for K14 were confined largely to the basal cell layer by in situ hybridization [2].
• The epithelia of these ducts also demonstrated precocious and aberrant differentiation, when examined by immunohistochemistry for p63 and cytokeratin 14 [28].
• Secondly, after electroporation of a construct containing the K14 promoter driving nuclear GFP into the epithelium of E15.5 oesophagus, some cells expressed both K8 and GFP [29].
• Here we report the generation of a mouse model that allows focal activation of a mutant keratin 14 allele in epidermal stem cells upon topical administration of an inducer, resulting in EBS phenotypes in treated areas [30].

References