Disease relevance of KRT5

• Primers for exon-specific amplification of the KRT5 gene: identification of novel and recurrent mutations in epidermolysis bullosa simplex patients [1].
• Factor IX in plasma of mice grafted with vectors containing the HPV-16 and hK5 elements was two- to three-fold higher than with vectors containing the CMV promoter alone [2].
• In complex hyperplasia, p63 expression was also increased, whereas CK5/6 was positive in areas with squamous differentiation only [3].
• Loss of p63 and cytokeratin 5/6 expression is associated with more aggressive tumors in endometrial carcinoma patients [3].
• A specific increase in the proportion of K5 among the keratin subunits was suggestive of the nature of melanoma cells [4].

Psychiatry related information on KRT5

• Although changes in PWA during physical activities are known to occur in DDD/R pacing, there is little information on the P wave stability in single pass lead VDD/R pacemakers using floating P wave sensing [5].
• RESULTS: A fracture risk reduction was seen in women aged>or=50 years using >or=0.3 DDD/day [6].
• A questionnaire with regard to cardiovascular symptoms, sleep disturbances, cognitive functioning, physical ability, social interaction, emotional functioning, and self-perceived health was completed after 2 months of atrial synchronous (DDD) and rate modulated ventricular pacing (VVI,R), respectively [7].
• Pacing in the DDD mode temporarily assists the critical period preceding the onset of cerebral autoregulation that plays a key role in preventing the deleterious effects of vasodepression [8].
• Significant improvement in the mean total quality-of-life score (20.5 +/- 14.9 vs 34.8 +/- 17.4) as well as in dyspnea on effort, dizzy spells, palpitation, sweating, fatigue, lethargy, emotional functioning, and self-perceived health was observed during DDD compared to VVIR pacing [9].

High impact information on KRT5

• 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) [10].
• DDT is reductively dechlorinated to DDD and dehydrochlorinated to DDE; it has been thought that DDE is not degraded further in the environment [11].
• The relative risk reduction in time to syncope with DDD pacing was 30% (95% CI, -33% to 63%; 1-sided P =.14) [12].
• Two DDT derivatives, Ethylan and DDD, were additionally associated with pancreatic cancer (RR = 5.0 and 4.3, respectively); exposures to these two chemicals were correlated, and it was not possible to determine whether each acted independently of the other [13].
• Smoking was identified as an independent risk factor, but controlling for smoking (and other potential confounders) in the analyses did not appreciably alter the risks seen for DDT, DDD, or Ethylan [13].

Chemical compound and disease context of KRT5

• We describe a family with an autosomal dominant skin-blistering disorder, epidermolysis bullosa simplex, Koebner subtype (EBS-K), that has a novel point mutation, occurring in the keratin 5 gene (KRT5), that predicts the substitution of an evolutionarily conserved lysine by an asparagine residue (K173N) [14].
• In formalin-fixed sections of 13 cases of macular amyloidosis and lichen amyloidosus, amyloid deposits were labelled with LP34 in three sections, MNF 116 in four sections, LL020 (labelling keratins K5 and K6) in one section, and LP2K in two sections [15].
• K5 expression was displayed in 28.9% of the tumours without treatment, in 75% after androgen deprivation, and in 57.1% of hormone-escaped prostate carcinomas [16].
• Epidermolysis bullosa simplex (Weber-Cockayne) associated with a novel missense mutation of Asp328 to Val in Linker 12 domain of keratin 5 [17].
• K5/K6 LLTPL phosphorylation occurs in vivo during mitosis and apoptosis induced by UV light or anisomycin, and in human psoriatic skin and squamous cell carcinoma [18].

Biological context of KRT5

• 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 [19].
• Direct sequencing of KRT5-amplified exons identified three novel missense mutations [1].
• Affected members of two seemingly unrelated families with EBS-MP had a C to T point mutation in the second base position of codon 24 of one of two K5 alleles, leading to a Pro: Leu mutation [20].
• These results are consistent with the expected up-regulation in differentiated suprabasal cells by the HPV-16 and hK5 elements [2].
• An unusual mutation has been identified in K5 which is responsible for EBS with mottled pigmentation and genetic linkage analysis suggests that the hair disorder monilethrix is likely to be due to a mutation in a hair keratin [21].

Anatomical context of KRT5

• We have established a mutation detection system that facilitates KRT5 gene analysis from leukocyte genomic DNA, obviating the need for a skin sample or keratinocyte culture for cDNA synthesis [1].
• Keratin 5 (K5) mRNA and protein are shown to be expressed in normal mammary epithelial cells in culture and are absent from tumor-derived cell lines [22].
• Epidermolysis bullosa simplex: a keratin 5 mutation is a fully dominant allele in epidermal cytoskeleton function [14].
• However, this part of the K5 head domain is likely to protrude on the filament surface, perhaps leading to additional aberrations in intermediate filament architecture and/or in melanosome distribution that are seen ultrastructurally in patients with the mutation [20].
• To confirm this in vitro, we transfected mutant keratin 5 cDNA into cultured cells [23].

Associations of KRT5 with chemical compounds

• We describe a novel K5 mutation (V186L) that produces a conservative amino acid change (valine to leucine) at position 18 of the 1A helix [24].
• Direct sequencing of polymerase chain reaction products revealed a T to C transition within codon 323 of K5 in affected individuals, resulting in a valine to alanine substitution of the seventh residue within the L12 linker domain [25].
• Only keratins K5, K14, and K15, which are synthesized by epidermal basal cells, were solubilized in 2 M urea [26].
• Our studies revealed that the epidermal keratins, K5, K6, K14, and K16, their mRNAs, and their transcripts were diminished relative to actin as a consequence of retinoic acid (RA) treatment [27].
• Repression was also observed when 5' upstream sequences of K14 or K5 genes were used to drive expression of a chloramphenicol acetyltransferase reporter gene in SCC-13 keratinocytes [27].

Enzymatic interactions of KRT5

• K5 and K6 become phosphorylated in vitro on threonine by the stress-activated kinase p38 [18].

Co-localisations of KRT5

• Aggregation is purely a function of the K5-1649delG tail domain; in contrast, the cloned 109 residue-long tail domain from wild type K5 is distributed throughout the cytoplasm and colocalizes partly with keratin IFs [28].
• Immunohistochemical analysis showed that TSC-22 protein expression in NP is restricted to the basal cells and colocalizes with the basal cell marker cytokeratin 5 [29].

Regulatory relationships of KRT5

• K5 was expressed in all organotypic epithelia but K14 was absent in SVpgC2a [30].
• Furthermore, pretreatment with neutralizing anti-EGF receptor antibody also suppressed UVB-induced keratin 5 and keratin 14 expression by SVHK, NHK and HaCaT cells [31].
• In addition, RXR-specific ligands suppress cytokeratin K5 mRNA levels slightly, compared to RAR-specific ligands that strongly suppress K5 mRNA levels [32].

Other interactions of KRT5

• In immortalized cells, which are preneoplastic or partially transformed, the levels of K5 mRNA and protein are lower than in normal cells, whereas the amount of K18 is increased [22].
• All but six cases (91%) showed the typical immunoprofile of basal-like tumours (ER- and HER2-, EGFR+ and/or CK5/6+) [33].
• Biochemically, using 2-DE and immunoblotting, stratified epithelial keratins K5/K14 and large amounts of K17 were present in all cases [34].
• In the epidermis overlying tumour tissue, there was positive immunoreactivity with anti-CK 1-8, CK 5/6/18, CK 10 and CK 14 antibodies in all biopsy specimens [35].
• 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 [36].

Analytical, diagnostic and therapeutic context of KRT5

• 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 [37].
• Using Northern (RNA) blot analysis and in situ hybridization with cRNA probes for both K5 and K14, we examined the expression of these mRNAs in the epidermis and in cultured epidermal cells [38].
• To unambiguously determine whether intermediate luminal cells in PIA show increased proliferative activity and decreased p27(kip1) expression, double-staining immunofluorescence of Ki-67 and K5, as well as p27(Kip1) and K5 was performed [39].
• Expression was determined by immunocytochemistry staining using antibodies to the luminal cytokeratins (CKs) 7/8, 18 and 19 and the basal markers CK 5/6 and CK 14 [40].
• Value of p63 and cytokeratin 5/6 as immunohistochemical markers for the differential diagnosis of poorly differentiated and undifferentiated carcinomas [41].

References