Disease relevance of KRT14

• A novel recessive missense mutation in KRT14 reveals striking phenotypic heterogeneity in epidermolysis bullosa simplex [1].
• No effect on the keratin cytoskeleton was observed upon transfection of NHK with the various K14 constructs neither with nor without a subsequently induced heat-stress [2].
• Our results demonstrate that p63, CK 5/6 and CK 14 may be used together in immunohistochemical panels to characterize squamous differentiation in poorly differentiated carcinomas or carcinomas of unknown origin [3].
• Positive reaction was obtained for CK4, CK34betaE12, CK10, CK14 in skin and cholesteatoma epithelium [4].
• Naegeli-Franceschetti-Jadassohn Syndrome and Dermatopathia Pigmentosa Reticularis: Two Allelic Ectodermal Dysplasias Caused by Dominant Mutations in KRT14 [5].

High impact information on KRT14

• 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 [6].
• Epidermolysis bullosa simplex (EBS) is a group of epidermal blistering diseases almost invariably transmitted as a dominant trait, which has recently been shown to arise from mutations in keratins 14 and 5 (K14 and K5) [7].
• A missense mutation in the rod domain of keratin 14 associated with recessive epidermolysis bullosa simplex [7].
• We describe a family with recessive EBS in which the disease is tightly linked to the substitution of the highly conserved glutamic acid-144 to alanine in the first helical segment of the rod domain of keratin 14 [7].
• Remarkably, this same residue is mutated in the basal epidermal K14 in three incidences of another skin disease, epidermolysis bullosa simplex (EBS) [8].

Chemical compound and disease context of KRT14

• Epidermolysis bullosa simplex Dowling-Meara due to an arginine to cysteine substitution in exon 1 of keratin 14 [9].
• In order to distinguish between basal and intermediate cells, and to assess the effects of androgen deprivation on prostate cancer, 56 human prostate cancer metastases and three cancer cell lines were characterized using antibodies to K5, K14, K18, and the neuroendocrine marker chromogranin A (ChA) [10].
• CK14 and CK16 were also expressed, suggestive of squamous metaplasia in culture, which could be inhibited with 13-cis-retinoic acid [11].
• In normal breast tissue and in noninvasive breast carcinomas, various keratin-14 antibodies were reactive predominantly with the basal/myoepithelial cell layer, although mainly in terminal and larger ducts luminal cells sometimes also were stained [12].
• The lysine residue K14 of cytochrome c-550 of Thiobacillus versutus has been mutated to a glutamine (Q) and a glutamate (E) residue [13].

Biological context of KRT14

• Epidermolysis bullosa simplex: recurrent and de novo mutations in the KRT5 and KRT14 genes, phenotype/genotype correlations, and implications for genetic counseling and prenatal diagnosis [14].
• Mutation detection of KRT14 on a DNA level is, however, hampered by the presence of a highly homologous but nontranscribed KRT14 pseudogene [15].
• After cutting the KRT14 pseudogene genomic sequences with restriction enzymes while leaving the homologous genomic sequences of the functional gene intact, only the mutation hotspot-containing exons of the functional KRT14 gene are amplified [15].
• These novel amino acid substitutions provide further information for genotype-phenotype correlation in KRT14 mutations, and demonstrate the first molecular genetic data in EBS patients from Hungary [16].
• KRT14 expression vectors were constructed by fusing the nucleotide sequence encoding the FLAG reporter peptide to the 3' end of the KRT14 cDNA sequences [2].

Anatomical context of KRT14

• Epidermolysis bullosa simplex (EBS) is caused by defective assembly of keratin intermediate filaments in basal keratinocytes and recent studies indicated causal mutations in the keratin KRT5 and KRT14 genes [17].
• The KRT5 and KRT14 genes encode the proteins keratin 5 and 14, respectively, which are the primary structural components of the 10-nm intermediate filaments of the mitotic epidermal basal cells [18].
• De novo K5/K14 (mutant and wild-type) filament assembly in cultured cells was studied to determine the effect of this mutation on filament polymerization and stability [19].
• The expression vectors were transiently transfected into normal human primary keratinocytes (NHK), HaCaT or HeLa cells in order to analyze the ability of the mutant K14 proteins to integrate into the existing endogenous keratin filament network (KFN) [2].
• Medium from both CAFs and NMFs induced novel expression of alpha-smooth muscle actin and cytokeratin-14 in PMC42-LA organoids [20].

Associations of KRT14 with chemical compounds

• We report a patient manifesting the Dowling-Meara variant of EBS in whom we characterized a cytosine to thymine transition at codon 125 (R125C) in K14 [9].
• In one family studied, inheritance of EBS is linked to the gene encoding keratin 14, and a thymine to cytosine mutation in exon 6 of keratin 14 has introduced a proline in the middle of an alpha-helical region [21].
• One patient carries a point mutation in keratin 14 (converting arginine at position 125 to histidine) and the other has a novel point mutation in keratin 5 (converting serine at position 181 to proline) [22].
• In young keratinocytes, two days of calcium treatment reduced the K14 level by 78%, and increased the levels of K10 and involucrin by 40% and 29%, respectively [23].
• In comparison, 40 microM kinetin had no effect on the K14 level, but increased the K10 level by 28% and that of involucrin by four-fold [23].

Physical interactions of KRT14

• The purified K14 tail domain binds keratin filaments in vitro with specificity (kD approximately 2 microM) [24].

Regulatory relationships of KRT14

• K5 was expressed in all organotypic epithelia but K14 was absent in SVpgC2a [25].
• The nonhelical tail domain of keratin 14 promotes filament bundling and enhances the mechanical properties of keratin intermediate filaments in vitro [24].
• Co-staining for cytokeratins and Ki-67 indicated that 44% of proliferative cells expressed K14 and 36% K19, although the difference was not statistically significant [26].
• CD44 v3-v10 was also expressed in other keratin 14-negative prostate tissues, the ejaculatory ducts and prostatic urethra [27].
• Thus, we generated a transgenic mouse line expressing cathepsin V under the control of the human keratin 14 promoter, which mimics the genuine cathepsin V expression pattern in human skin, by directing it to basal epidermal keratinocytes and the outer root sheath of hair follicles [28].

Other interactions of KRT14

• In the cyst wall of DC, CK1 and 10 were expressed in suprabasal layer, and CK14 was limited to the basal layer [29].
• Basal layers expressed Ks 4, 13, 14 and 17 and variably K16, while suprabasal layers expressed Ks 4 and 13, 14 and 17 and variably K16, while suprabasal layers expressed Ks 4 and 13 and variably K14, 16 and 17 [30].
• A reduced expression of K18+ cells, without modification in K14 expression, was evident in high grade PCa in which we observed also an increment in K5 expression representing an intermediate basal/differentiating epithelial cell marker [31].
• In BCCs without STA, CK1-8, CK14 and CK17 antibodies were expressed by tumour tissue in all biopsy specimens [32].
• For the amplification of the KRT14 genes, we make use of restriction sites to exempt the keratin 14 pseudogene sequence from polymerase chain reaction amplification [33].

Analytical, diagnostic and therapeutic context of KRT14

• The mutation was identified by direct sequencing of polymerase chain reaction (PCR)-amplified genomic DNA encoding the exons of the KRT5 and KRT14 genes, and confirmed by mismatch allele-specific PCR, followed by restriction enzyme digestion with Tsp509 I [34].
• Using sequence analysis of genomic DNA, a novel K14 nonsense mutation was identified [35].
• Histological examination revealed the presence of mucin-producing cells, and immunohistochemistry using antibodies against p63 and keratin 14 showed the presence of basal cells [36].
• In situ double immunolocalization analyses by laser scanning confocal microscopy showed that CK14 was not present in hepatocytes (HES6+ cells) and was expressed in some biliary epithelial (BDS7+ cells) [37].
• The expression of cytokeratin 14, involucrin and filaggrin (marker proteins of keratinocyte differentiation) was investigated by immunohistochemical staining, and the DNA-binding activity of CCAAT/enhancer binding protein alpha (C/EBPalpha), a transcription factor, was examined by electrophoretic mobility shift assay [38].

References