Disease relevance of LOR

• Characterization of the loricrin (LOR) gene as a positional candidate for the PSORS4 psoriasis susceptibility locus [1].
• High levels of loricrin were found in hypergranulotic and hyperorthokeratotic epidermis as observed in lichen planus, benign papillomas, and pseudocarcinomatous hyperplasia [2].
• In contrast to involucrin, loricrin expression was consistently down-regulated in agranulotic, parakeratotic keratinization as observed in psoriasis, dermatitis, pityriasis lichenoides, porokeratosis, or precancerous and malignant squamous lesions [2].
• In contrast, insertional mutations resulting in a frameshift in the C-terminal domain of loricrin produce the characteristic ichthyosis of loricrin keratoderma in mouse and man [3].
• But in contrast to lamellar ichthyosis, the CE scaffold partially normalizes in the outer SC in loricrin keratoderma [3].

High impact information on LOR

• 3. Sequencing of the loricrin gene revealed an insertion that shifts the translation frame of the C-terminal Gly- and Gln/Lys-rich domains, and is likely to impair cornification [4].
• Radiolabel sequence analysis of cyanogen bromide fragments of p42 led to the conclusion that this antigen is encoded in part by LOR, a conserved portion of the "X" region that is flanked by the envelope gene and the 3' long terminal repeat of HTLV-I [5].
• Furthermore, in a chemical carcinogen-induced skin carcinogenesis setting, mice overexpressing human IKKalpha in the epidermis under the control of a truncated loricrin promoter developed significantly fewer SCCs and metastases than did wild-type mice [6].
• Hyperplasia was a result of a disturbed program of epidermal differentiation rather than an increased proliferation rate, as reflected by the strong suppression of keratin 10, involucrin, and loricrin expression in suprabasal cells [7].
• Satisfactory features of stratification were obtained, but the expression of epidermal differentiation products, such as keratin K10 and loricrin, was delayed and reduced [8].

Chemical compound and disease context of LOR

• The reactivities for both loricrin and loricrin mRNAs were abolished by a treatment of the cultures with a retinoic acid concentration (10(-6) M) provoking a complete inhibition of terminal epidermal differentiation (parakeratosis) [9].
• Loricrin is expressed in the granular layer of all mammalian orthokeratinizing epithelia tested including oral, esophageal and fore-stomach mucosa of rodents, tracheal squamous metaplasia of vitamin A deficient hamster and estrogen induced squamous vaginal epithelium of ovary ectomized rats [10].
• In a blind cross-over study, 12 patients with ventricular arrhythmias (VPC's; Lown Grades II-IVB) resistant to a daily dose of quinidine 1.2 g, disopyramide 0.8 g, N-propyl-ajmaline 0.1 g were randomly given, each dose for one week, placebo (PL), mexiletine (MEX; 400, 600, 800 mg daily) and lorcainide (LOR; 200, 300, 400 mg daily) [11].

Biological context of LOR

• Our results demonstrate that loricrin expression is closely linked to an orthokeratotic phenotype of human epidermal keratinization [2].
• We have previously shown that an AP1 site located in the proximal promoter region (position -55) is essential for human loricrin promoter activity (Rossi, A., Jang, S-I., Ceci, R., Steinert, P. M., and Markova, N. G. (1998) J. Invest. Dermatol. 110, 34-40) [12].
• NO was also found to inhibit DNA-binding activity of activating protein 1 in keratinocyte nuclear extracts, and to interfere with the transactivation of activating protein 1 responsive genes such as transglutaminase 1, involucrin, and loricrin, whose expression is regulated during epidermal differentiation [13].
• Sequencing of the loricrin gene has disclosed heterozygous mutations; insertion of one nucleotide (730insG, 709insC) that shifts the reading frame in these patients [14].
• Elucidation of the molecular biology of "loricrin keratodermas" adds to our understanding of the complexity and biological significance of the CE [14].

Anatomical context of LOR

• The cytoplasmic surface of intact purified CEs consists of filaggrin, loricrin, SPRs and keratin intermediate filaments [15].
• Loricrin is the major protein of the cornified cell envelope of terminally differentiated epidermal keratinocytes which functions as a physical barrier [16].
• Loricrin is the major protein of the cornified cell envelope, a structure that replaces the plasma membrane during keratinocyte terminal differentiation [17].
• Reduction in loricrin was most apparent in regions of epithelium containing abundant HPV 59 DNA [18].
• In the hair peg (85-104 days EGA) (corresponding to the stage 3 of murine hair follicle morphogenesis), loricrin and TGase 2 were seen in cells of the upper part of the hair peg while TGase 1, 3 and LGP were observed in the inner cells of the hair peg [19].

Associations of LOR with chemical compounds

• Involucrin expression starts in the upper spinous layers in normal human epidermis and precedes loricrin expression, which is restricted to the granular layer [20].
• Subsequently, loricrin becomes cross-linked by the activity of transglutaminases TGK/E as a major component of the cornified cell envelope by N epsilon-(gamma-glutamyl)lysine isopeptide bonds [2].
• Loricrin is a glycine-, serine-, and cysteine-rich protein expressed very late in epidermal differentiation in the granular layers of normal human epidermis [2].
• Loricrin, profilaggrin and filaggrin were present in the stratum granulosum of orthokeratinised sites, but expression was abruptly lost at the junction between the vermilion and the intermediate zone [21].
• Polymerase chain reaction analyses of genomic DNAs from different individuals show that human loricrin consists of two allelic size variants, due to sequence variations in its second glycine loop domain, and these variants segregate in the human population by normal Mendelian mechanisms [22].

Enzymatic interactions of LOR

• Epidermal transglutaminase-K is believed to catalyze the covalent linking of loricrin and involucrin to form cross-linked (CE) envelopes [23].

Regulatory relationships of LOR

• Loricrin and SPRR2 are expressed in the stratum granulosum and SPRR3 is absent [24].
• These results suggest that Ca++, cell density, and RA are crucial regulators of loricrin expression in vitro and that the transcriptional control of loricrin and filaggrin expression in the epidermis are closely coordinated [25].

Other interactions of LOR

• Biochemical, structural, and transglutaminase substrate properties of human loricrin, the major epidermal cornified cell envelope protein [16].
• This rules out the LOR gene as a candidate for the PSORS4 locus [1].
• SPRR 4, loricrin, and LEP 6 transcripts were not detected [26].
• In the presence of anti-E-cadherin antibody, both loricrin and profilaggrin levels were dramatically enhanced compared to the high Ca(2+) control cells, while addition of antibody to P-cadherin slightly attenuated the Ca(2+)-induced increase [27].
• Thus, in undifferentiated cells, loricrin expression is suppressed by Jun B, Sp3, and KSR-1 proteins [12].

Analytical, diagnostic and therapeutic context of LOR

• By use of a specific loricrin antibody, we show by immunogold electron microscopy that loricrin initially appears in the granular layer of human epidermis and forms composite keratohyalin granules with profilaggrin, but localizes to the cell periphery (cell envelope) of fully differentiated stratum corneum cells [22].
• In control cultures (incubated with no antibody or with antibodies to other cell surface molecules), Ca(2+) elevation induced an increase in type 1 transglutaminase, profilaggrin, and loricrin, as measured by western blotting and in agreement with previous results [27].
• Immunoelectron microscopy demonstrated that both major cornified cell envelope precursor proteins, involucrin and loricrin, were restricted to the cornified cell envelope in periderm cells at this stage of development [28].
• Patterns of loricrin and involucrin expression were examined by immunohistochemistry [29].
• We then measured the steady-state mRNA levels for several S100 genes, small proline rich region-1, -2, and -3, loricrin, and involucrin by Northern blotting [30].

References