Disease relevance of KRT4

• A glutamine insertion in the 1A alpha helical domain of the keratin 4 gene in a familial case of white sponge nevus [1].
• Serial sections were stained with Genta or El-Zimaity triple stain, and biopsies with intestinal metaplasia were stained with antibodies against CK 4, 13, 7, and 20 [2].
• Three NKSCCs were associated with a Schneiderian papilloma, and the results of the immunostaining were similar in the two components, with the exception of CK4 and CK7, which were expressed by the papilloma and not by the carcinoma [3].
• All the typical and atypical medullary carcinomas and the metastases (10 cases) stained negatively for CK4 and positively for CK8-18 (CAM5.2) [4].
• Differential expression of the keratin-4, -13, -14, -17 and transglutaminase 3 genes during the development of oral squamous cell carcinoma from leukoplakia [5].

High impact information on KRT4

• We have now confirmed this hypothesis and report here a three base-pair (bp) deletion in the helix initiation peptide of K4 in affected members from two families with this condition [6].
• CYK-4 and ECT2 interact, and this interaction is cell cycle regulated via ECT2 phosphorylation [7].
• Central spindle localization of CYK-4 could accelerate GTP hydrolysis by RhoA, thereby allowing contractile ring disassembly and completion of cytokinesis [8].
• CYK-4: A Rho family gtpase activating protein (GAP) required for central spindle formation and cytokinesis [8].
• CYK-4 and a CYK-4:GFP fusion protein localize to the central spindle and persist at cell division remnants [8].

Chemical compound and disease context of KRT4

• Furthermore, in addition to androgens, hK4 expression is regulated by estrogen and progesterone in prostate cancer cells [9].
• The data indicate that mesothelial cells undergoing metaplastic changes finally resulting in ovarian cystadenomas (and carcinomas) initiate the synthesis of a 200-kd glycoprotein recognized by MAb (BW 495/36), the production of ovarian carcinoma associated antigens, in addition to focal production of keratin 4 and/or 13, as seen in several samples [10].
• In addition, intracellular hK4 levels, as detected on Western blot analysis, were induced by 100 nM estrogen treatment of the estrogen receptor positive ovarian carcinoma cell line OVCAR-3, >8-24 h [11].

Biological context of KRT4

• Mutation analysis revealed a heterozygous missense mutation 1345G-->A in KRT4, predicting an amino acid change, E449K, in the 2B domain of the K4 polypeptide [12].
• Allelic variations of human keratins K4 and K5 provide polymorphic markers within the type II keratin gene cluster on chromosome 12 [13].
• The genes for human cytokeratins 4 and 15 (KRT4 and 15) are assigned to the p11.2----q12 region of chromosome 12 (cytokeratin 4) and to the q21----q23 region of chromosome 17 (cytokeratin 15), respectively [14].
• A panel of K4 promoter deletions were found in transient transfection assays to be predominantly active in esophageal and corneal cell lines [15].
• The extended substrate specificity profiles are in good agreement with known substrate cleavage sites but also in accord with experimentally solved (hK4, hK6, and hK7) or modeled structures [16].

Anatomical context of KRT4

• Hybridization in situ with antisense riboprobes and/or synthetic oligonucleotides shows the presence of cytokeratin 15 mRNA in all layers of esophagus, whereas cytokeratin 4 mRNA tends to be suprabasally enriched, although to degrees varying in different regions [17].
• The promoter of the HaCaT keratinocyte differentiation-related gene keratin 4 contains a functional AP-2 binding site [18].
• In situ hybridization study of cytokeratin 4, 13, 16 and 19 mRNAs in human developing junctional epithelium [19].
• Two electrophoretic variants for each of the human keratins K4 and K5 that are expressed in squamous nonkeratinizing epithelia lining the upper digestive tract could be distinguished on SDS-PAGE [20].
• CK 4 was expressed by 5-10% of pancreas duct cells in all specimens of normal pancreas [21].

Associations of KRT4 with chemical compounds

• Of all known proteins, the context of the K8 S73 motif (LLS/TPL) is unique to type II keratins and is conserved in epidermal K5/K6, esophageal K4, and type II hair keratins, except that serine is replaced by threonine [22].
• Starting from the X-ray crystallographic structure of HPg K4 and the intermolecular 1H-NMR NOE data, two models of the K2 lysine binding site complexed to 6-AHA have been derived which differ mainly in the extent of electrostatic pairing between the K2 Arg56 and Glu57 side chains [23].
• Reverse transcription-polymerase chain reaction experiments showed that the K4 expression was the one most overtly induced by 2 wk of open treatment with 0.05% of retinoic acid and tazarotene [24].
• Finally, a dose-response study showed that the de novo appearance of K4 can be utilized as a sensitive test for retinoid bioactivity in epidermis in vivo [24].
• As is the case for the HPg K1, K4, and K5, among the tested ligands, AMCHA is the one which interacts most firmly with r-K2 (Ka approximately 7.3 mM-1) while the aromatic ligands BASA, benzylamine, and benzamidine exhibit Ka values of approximately 4.0, approximately 0.04, and approximately 0.03 mM-1, respectively [23].

Regulatory relationships of KRT4

• CK4 was rarely and only lightly expressed while CK18 and 19 (characteristic of junctional epithelium) were very strongly expressed in the older (2 and 3 weeks) cultures [25].
• When keratinocytes were continuously treated with 1 microM retinoic acid (RA), the upregulation of AhR- and ARNT-mRNA levels was inhibited as was keratin 4-expression, a marker of HaCaT-keratinocyte differentiation [26].

Other interactions of KRT4

• OBJECTIVES: To search for possible mutations in KRT4 and KRT13 [12].
• In order to understand transcriptional regulatory mechanisms mediated by ELF3, we investigated its effect on the human keratin 4 gene promoter based upon the role of keratin 4 in early differentiation of the esophageal squamous epithelium [27].
• CK4 and CK16 were not found in the placenta [28].
• These cells were also immunoreactive with K 4 and K 10 MoAbs [29].
• Using real-time quantitative polymerase chain reaction (TaqMan) and normalization of the mRNA values to beta-actin, the increase in K4 was found to be 100-1000-fold [24].

Analytical, diagnostic and therapeutic context of KRT4

• Subchromosomal localization of two human cytokeratin genes (KRT4 and KRT15) by in situ hybridization [14].
• Sequence analysis revealed a 3 bp (ACA) heterozygous insertion localized in the helix initiation motif of the 1A alpha helical domain of K4 [1].
• Extraction, two-dimensional electrophoresis and western blotting showed that this transitional JE during eruption also contained CK 6, 16 and perhaps CK 4 [30].
• In addition to detailed mapping of the KLK4 mRNA 5' end by RT-PCR, this conclusion is supported by predominantly nuclear localization of the hK4 protein in the cell, documented by both immunofluorescence and cell fractionation experiments [9].
• The binding of alpha-, omega-amino acids, which are important effectors of human plasminogen activation, to the isolated kringle 4 (K4) peptide region of this protein has been investigated by high sensitivity titration calorimetry [31].

References