Disease relevance of Krt1

• Monospecific antikeratin antisera and specific complementary DNA probes were used to analyze expression of keratin genes in newborn mouse skin and skin papillomas and carcinomas by indirect immunofluorescence, immunoblotting, and in situ hybridization [1].
• Keratin expression in carcinomas is highly disturbed [1].
• Analysis of the lesional keratins of psoriasis patients showed that etretinate caused a reduction in keratin 16 and an increase in the keratin 14:keratin 16 ratio, although the magnitude of these changes and their correlation with clinical improvement was variable [2].
• Therefore, we analyzed 18 mouse skin tumors (nine papillomas and nine squamous cell carcinomas), induced either by two-stage carcinogenesis with 7,12-dimethylbenz[a]anthracene(DMBA)/12-O-tetradecanoylphorbol-13-acetat e or complete carcinogenesis with DMBA, by immunofluorescence with a monoclonal antibody to keratin (K) 8 (TROMA-1) [3].
• Cytokeratin accumulation as seen in alcoholic hepatitis could lead to the formation of Mallory bodies [4].

High impact information on Krt1

• To demonstrate function, we engineered one of these point mutations in a cloned human K14 cDNA, and showed that a K14 with an Arg-125----Cys mutation disrupted keratin network formation in transfected keratinocytes and perturbed filament assembly in vitro [5].
• Since we had previously shown that keratin network perturbation is an essential component of EBS diseases, these data suggest that the basis for the phenotype in this patient resides in this point mutation [5].
• 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 [5].
• Previously we demonstrated that transgenic mice expressing mutant basal epidermal keratin genes exhibited a phenotype resembling a group of autosomal dominant human skin disorders known as epidermolysis bullosa simplex (EBS) [5].
• With retrovirus-mediated gene transfer, we used intact and deleted keratin proteins to investigate the molecular basis of intermediate filament function [6].

Chemical compound and disease context of Krt1

• Ex vivo, caerulein-triggered pancreatitis caused protein degradation (actin approximately or = tubulin > keratins) and mRNA up-regulation that was blocked by actinomycin-D (act-D) (actin approximately or = tubulin approximately or = keratin) or by NF-kappaB inhibition (keratins > actin approximately or = tubulin) [7].
• Mouse hepatoma cell lines were studied using PS-341 to induce cytokeratin aggresome formation [8].
• In order to investigate the role that hyperplasia plays in the induction of the keratin modifications by the tumor promoter 12-O-tetradecanoylphorbol-13-acetate (TPA), the effects of several inhibitors of tumor promotion and cycloheximide on the TPA-induced protein changes were studied [9].
• These genes included the rat homologues of human galectin-7 gene, the human/mouse melanoma inhibitory activity/bovine chondrocyte-derived retinoic acid sensitive protein gene, the mouse stearoyl-CoA desaturase-2 gene, and the mouse endo B cytokeratin/human cytokeratin-18 gene [10].
• In addition, we evaluated pivotal keratinocyte functions necessary for the reparative hyperplasia, including proliferation by 5-bromo-2'deoxy-uridine labeling and differentiation by the expression of involucrin, keratin 1, and keratin 6 [11].

Biological context of Krt1

• 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].
• Transcriptional control of high molecular weight keratin gene expression in multistage mouse skin carcinogenesis [1].
• The effect of K18 on MB formation is independent of hepatocyte keratin filament organization or K18 Ser33/Ser52 phosphorylation [13].
• In benign tumors, distribution of K14 protein is similar to that in newborn skin, while the abundance of K1 and K10 appears to be somewhat reduced although the tissue distribution remains suprabasal [1].
• The mild phenotype of K10(-/-) mice suggests that there is a considerable redundancy in the keratin gene family [14].

Anatomical context of Krt1

• Notably, specific 'soft' keratins, Krt2-1 and Krt2-17, normally weakly expressed in the tongue but present at high levels in skin and in orthokeratinized oral dysplasia are up-regulated in the mutant tongue epithelium [15].
• Transient and stable transfectants, as well as heterokaryons produced by fusions with epithelial cells, were evaluated for expression of K1 and K10 proteins and filament formation using specific antibodies [12].
• Keratins 1 (K1) and 10 (K10) are the predominant cytoskeletal intermediate filaments of epidermal cells during transition from the proliferative to the terminal differentiation stage [12].
• The major differentiation products in suprabasal keratinocytes are keratins, K1 and K10 [16].
• The formation of a recombinant cytoskeleton was more restricted for K10 than for K1 and appeared to be related to a requirement for cessation of cell division before K10 could integrate [17].

Associations of Krt1 with chemical compounds

• Vitamin A deficiency also altered keratin expression and localization in squamous subjunctional epithelium [18].
• Retinoid status controls the appearance of reserve cells and keratin expression in mouse cervical epithelium [18].
• After estrogen treatment, K1 was expressed [19].
• In contrast, during the progestational stages (metaestrus and diestrus) or after progesterone treatment of ovariectomized mice, the most relevant change was the loss of K1 [19].
• Promotion of skin carcinogenesis by dimethylarsinic acid in keratin (K6)/ODC transgenic mice [20].

Physical interactions of Krt1

• We have used the keratin (K) 5 promoter to target the expression of stabilized N-terminally truncated beta-catenin to the basal cell layer of mouse mammary epithelium [21].
• Keratin binding to 14-3-3 proteins modulates keratin filaments and hepatocyte mitotic progression [22].
• One of two Ets-binding sites in the cytokeratin EndoA enhancer is essential for enhancer activity and binds to Ets-2 related proteins [23].
• Retinoic acid receptor alpha is located on mouse Chromosome (Chr) 11 near the homeobox-2 complex and the keratin type I gene complex, whereas retinoic acid receptor gamma is on mouse Chr 15 near the homeobox-3 complex and the keratin type II complex [24].

Enzymatic interactions of Krt1

• IgG binds to desmoglein 3 in desmosomes and causes a desmosomal split without keratin retraction in a pemphigus mouse model [25].

Co-localisations of Krt1

• We compared the distribution of alpha 8 with alpha-smooth muscle actin (alpha SMA), fibronectin (alpha 8 ligand), and cytokeratin. alpha 8 co-localized with alpha SMA and fibronectin in the peribronchial and perivascular regions [26].
• The transglutaminase-related antigen was shown by confocal microscopy to co-localize only with nonbasal cell specific keratin intermediate filaments [27].

Regulatory relationships of Krt1

• K14 protein and transcripts are highly expressed in all strata in carcinomas while protein and transcripts for K1 and K10 are essentially absent [1].
• A transgenic mouse line expressing a truncated form of the ornithine decarboxylase (ODC) dominant-negative mutant K69A/C360A under the control of the keratin 6 promoter has been established (K6/ODCdn mice) [28].
• With that purpose, we analyzed the keratin profiles of 16 DMBA-induced hamster skin tumors using monospecific antibodies against K1 and K13 [29].
• Impaired NF-kappa B activation and increased production of tumor necrosis factor alpha in transgenic mice expressing keratin K10 in the basal layer of the epidermis [30].
• Transgenic mice overexpressing Bcl-2 under the control of the keratin-1 promoter display multifocal epidermal hyperplasia and aberrant expression of keratin-6, while alterations of HF cycling have not been investigated [31].

Other interactions of Krt1

• In situ, formation of the K1/K10 intermediate filament network occurs in the cytoplasm of cells with a preexisting cytoskeleton composed of keratins 5 and 14 [12].
• The K1/K14 pair was capable of forming a cytoskeletal network, but the network was poorly developed, and usually perinuclear [12].
• The localization of both K5 and K1 proteins in these same cell layers, and above, is consistent with transcriptional regulation of these keratins [18].
• High constitutive ODC expression and decreased K1 and K10 expression will be useful phenotypic markers for studying the early stages of tumorigenesis in mouse skin [16].
• The integration of exogenous K1 filaments into the endogenous keratin network was compatible with sustained proliferation of SLC-1 carcinoma cells in vitro [17].

Analytical, diagnostic and therapeutic context of Krt1

• In the absence of its natural partner we observed the formation of a minor amount of novel K1/14/15 filaments as revealed by immunogold electron microscopy [14].
• On the other hand, K8 does not generally colocalize with K13, a keratin also aberrantly expressed by epidermal cell cultures when induced to differentiate by high Ca2+ medium [32].
• Keratin profiles were studied by quantitative gel electrophoresis of culture extracts, whereas the extent of envelope formation was assessed in an enzyme-linked immunosorbent assay (ELISA) using an antibody that specifically recognizes keratinocyte envelopes [2].
• RFLP was used for their genotyping, and possible keratin gene expression was examined by immunohistochemical staining, Western analysis, RT-PCR and Northern hybridization [33].
• Hepatocytes expressing high levels of the transgene were found to have abnormal keratin filament networks as detected by indirect immunofluorescence using an antibody specific for the transgene product [34].

References