Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:2.7.7.6 (RNA polymerase)
34,946 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Erythema multiforme follows administration of several drugs or infection with various agents, including herpes simplex virus, a syndrome designated herpes simplex virus associated erythema multiforme. Lesional skin from 21 of 26 (81%) herpes simplex virus associated erythema multiforme patients was positive for herpes simplex virus gene expression as evidenced by reverse transcriptase-polymerase chain reaction with primers for DNA polymerase and/or immunohistochemistry with DNA polymerase antibody. Reverse transcriptase-polymerase chain reaction and immunohistochemistry studies indicated that herpes simplex virus associated erythema multiforme lesional skin from 16 of 21 (76%) DNA polymerase positive herpes simplex virus associated erythema multiforme patients was also positive for interferon-gamma, a product of T cells involved in delayed-type hypersensitivity (p < 0. 0001 by Pearson correlation coefficient). Interferon-gamma signals were in infiltrating mononuclear cells and in intercellular spaces within inflammatory sites in the epidermis and at the epidermis/dermis junction. Herpes simplex virus lesional skin was also positive for DNA polymerase [five of five (100%)] and interferon-gamma [four of five (80%)], but lesional skin from drug-induced erythema multiforme patients was negative. Lesional herpes simplex virus associated erythema multiforme keratinocytes also stained with antibody to transforming growth factor-beta [14 of 23 (61%)] and cyclin-dependent kinase inhibitor waf [12 of 18 (67%)]. Staining was also seen in keratinocytes from herpes simplex virus lesions [five of five (100%)], but not in normal skin. By contrast, staining with antibody to tumor necrosis factor-alpha, another pro-inflammatory cytokine, was seen in seven of 11 (64%) drug-induced erythema multiforme patients, but not in herpes simplex virus or herpes simplex virus associated erythema multiforme patients, and lesional keratinocytes from drug-induced erythema multiforme patients were negative for transforming growth factor-beta and cyclin-dependent kinase inhibitor waf. We interpret the data to indicate that herpes simplex virus associated erythema multiforme pathology includes a delayed-type hypersensitivity component and is mechanistically distinct from drug-induced erythema multiforme.
J Invest Dermatol 1999 Nov
PMID:Herpes simplex virus associated erythema multiforme (HAEM) is mechanistically distinct from drug-induced erythema multiforme: interferon-gamma is expressed in HAEM lesions and tumor necrosis factor-alpha in drug-induced erythema multiforme lesions. 1057 38

An autosomal recessive disorder, generalized atrophic benign epidermolysis bullosa, is a rare form of nonlethal type junctional epidermolysis bullosa. It is associated not only with skin fragility but also with other unique clinical features including widespread atrophic skin changes, alopecia, reduced axillary and pubic hair, dysplastic teeth, and dystrophic nails. The majority of generalized atrophic benign epidermolysis bullosa cases are caused by mutations in the COL17A1 gene coding for type XVII collagen (or the 180 kDa bullous pemphigoid antigen). Another candidate gene for mutations in some forms of generalized atrophic benign epidermolysis bullosa is LAMB3 encoding the beta3 chain of laminin 5. This report documents compound heterozygosity for novel mutations in LAMB3 of a Japanese patient showing typical clinical features of generalized atrophic benign epidermolysis bullosa. One is an A-to-G transversion at the splice acceptor site of intron 14, which is designated as a 1977-2A-->G mutation; the other is a deletion of 94 bp located at the junction of intron 18 and exon 19, which is a 2702-29del94 mutation. Reverse transcriptase polymerase chain reaction analysis suggested skipping of exon 19 in LAMB3 mRNA produced from the allele with 2702-29del94 and impaired stability of the aberrant mRNA transcribed from the second allele with the 1977-2A-->G mutation.
J Invest Dermatol 2000 Aug
PMID:Compound heterozygosity for a point mutation and a deletion located at splice acceptor sites in the LAMB3 gene leads to generalized atrophic benign epidermolysis bullosa. 1095 Dec 52

Histamine has been implicated as one of the mediators involved in regulation of proliferation in both normal and neoplastic tissues. Histidine decarboxylase, the only enzyme that catalyzes the formation of histamine from L-histidine, is an essential regulator of histamine levels. In this study, we investigated the gene and protein expression of histidine decarboxylase in melanoma. Reverse transcriptase polymerase chain reaction and in situ hybridization studies of WM-35, WM-983/B, HT-168, and M1 human melanoma cell lines both resulted in positive signals for histidine decarboxylase messenger RNA. A polyclonal chicken antibody was developed against human histidine decarboxylase and protein expression was confirmed by western blot analysis of the cell lysates, revealing a predominant immunoreactive band at approximately 54 kDa corresponding to monomeric histidine decarboxylase. Protein expression of histidine decarboxylase was also shown by flow cytometric analysis and strong punctate cytoplasmic staining of melanoma cell lines. Moreover, both primary and metastatic human melanoma tissues were brightly stained for histidine decarboxylase. When compared with the very weak or no reactions on cultivated human melanocytes both western blot and immunohistochemical studies showed much stronger histidine decarboxylase expression in melanoma cells. These findings suggest that expression of histidine decarboxylase is elevated in human melanoma.
J Invest Dermatol 2000 Sep
PMID:Histidine decarboxylase expression in human melanoma. 1095 Dec 67

The circadian clock is a cellular machine composed of proteins with regulated expression that gives rise to circadian rhythms. Two main new concepts have arisen from recent research in the field in the last few years: (i) at least three to five key genes are involved in maintaining the basic circadian cellular rhythms, and (ii) their expression is fairly ubiquitous, extending beyond the traditionally considered pacemaker in mammals, the suprachiasmatic nucleus. We have demonstrated the expression of two circadian clock genes, clock and period1, in human skin cells. Reverse transcriptase polymerase chain reaction revealed the presence of clock and period1 mRNA in cultured human keratinocytes, melanocytes, and dermal fibroblasts, as well as in the human keratinocyte cell line HaCaT and the human melanoma line A375. In addition, antibodies to these two proteins produced immuno-positive staining in these cell types. Our investigations demonstrate for the first time that skin cells express circadian clock proteins constitutively although regulation of their expression and activity has not been elucidated. These proteins may have a role in cutaneous and/or systemic circadian biology and the skin and skin cells may provide an attractive model for the study of circadian rhythms.
J Invest Dermatol 2000 Oct
PMID:Expression of the circadian clock genes clock and period1 in human skin. 1099 56

The vascular endothelial growth factor is produced by a large variety of human tumors, including melanoma, in which it appears to play an important role in the process of tumor-induced angiogenesis. Little information is available on the role of placenta growth factor, a member of the vascular endothelial growth factor family of cytokines, in tumor angiogenesis, even though placenta growth factor/vascular endothelial growth factor heterodimers have been recently isolated from tumor cells. To investigate the role of placenta growth factor and vascular endothelial growth factor homodimers and heterodimers in melanoma angiogenesis and growth, 19 human melanoma cell lines derived from primary or metastatic tumors were characterized for the expression of these cytokines and their receptors. Release of placenta growth factor and vascular endothelial growth factor polypeptides into the supernatant of human melanoma cells was demonstrated. Reverse transcriptase polymerase chain reaction analysis showed the presence of mRNAs encoding at least three different vascular endothelial growth factor isoforms (VEGF(121), VEGF(165), and VEGF(189)) and transcripts for two placenta growth factor isoforms (PlGF-1 and PlGF-2) in human melanoma cells. In addition, placenta growth factor expression in human melanoma in vivo was detected by immunohistochemical staining of tumor specimens. Both primary and metastatic melanoma cells were found to express the mRNAs encoding for vascular endothelial growth factor and placenta growth factor receptors (KDR, Flt-1, neuropilin-1, and neuropilin-2), and exposure of melanoma cells to these cytokines resulted in a specific proliferative response, supporting the hypothesis of a role of these angiogenic factors in melanoma growth. J Invest Dermatol 115:1000-1007 2000
J Invest Dermatol 2000 Dec
PMID:Human melanoma cells secrete and respond to placenta growth factor and vascular endothelial growth factor. 1112 Nov 33

This study examines endothelin-induced modulation of extracellular matrix synthesis and remodeling by fibroblasts, and its potential role in the pathogenesis of systemic sclerosis (scleroderma). Endothelin-1 promoted fibroblast synthesis of collagen types I and III, but not fibronectin, by a mechanism dependent upon both ETA and ETB receptors. Conversely, endothelin-1 inhibited both protein expression of matrix metalloproteinase 1 and zymographic activity exclusively via ETA receptors. A dual regulatory role for endothelin-1 in transcriptional regulation was suggested by the ability of endothelin-1 to enhance steady-state levels of collagen mRNA and activate the proalpha2(I) collagen (Col1a2) promoter, but in contrast to reduce matrix metalloproteinase 1 transcript expression and suppress transcription of a human matrix metalloproteinase 1 promoter reporter construct in transient transfection assays. Although endothelin-1 significantly enhanced remodeling of three-dimensional collagen lattices populated by normal fibroblasts, this was not observed for lattices populated by systemic sclerosis fibroblasts. Promotion of matrix remodeling was dependent upon ETA receptor expression and was blocked by specific inhibitors of tyrosine kinases or protein kinase C. Reverse transcriptase polymerase chain reaction, S1 nuclease, and functional cell surface binding studies showed that normal and systemic sclerosis fibroblasts express both ETA and ETB receptors (predominantly ETA), but that ETA receptor mRNA levels and ETA binding sites on fibroblasts cultured from systemic sclerosis skin biopsies are reduced by almost 50%. Endothelin-1 is thus able to induce a fibrogenic phenotype in normal fibroblasts that is similar to that of lesional systemic sclerosis fibroblasts. Moreover, reduced responsiveness to exogenous endothelin-1 in systemic sclerosis suggests that downstream pathways may have already been activated in vivo. These data further implicate dysregulated endothelin-receptor pathways in fibroblasts in the pathogenesis of connective tissue fibrosis.
J Invest Dermatol 2001 Mar
PMID:Fibroblast matrix gene expression and connective tissue remodeling: role of endothelin-1. 1123 16

CC chemokine receptors are expressed on hematopoietic cells, and these may impart selective homing of monocyte, leukocyte, and lymphocyte subsets to sites of inflammation. CC chemokine receptor 3 is the major receptor on eosinophils and is also expressed on other inflammatory cells suggesting its important role for allergic diseases such as atopic dermatitis and bronchial asthma. Eotaxin, eotaxin-2 and eotaxin-3 have been identified as ligands that only activate CC chemokine receptor 3. CC chemokine receptor 3 is also activated by other promiscuous ligands, however, such as RANTES and monocyte chemotactic protein 4. To date, CC chemokine receptor 3 has not been reported to be expressed on nonhematopoietic cells. In this study, we investigated whether keratinocytes possess autocrine and paracrine mechanisms for CC chemokine secretion and receptor expression as reported for the expression of interleukin 8 and its receptors. Reverse transcriptase polymerase chain reaction analysis demonstrated that CC chemokine receptor 3 mRNA is expressed constitutively in cultured keratinocytes. The signal quantities of the CC chemokine receptor 3 amplicons showed lower intensities for keratinocytes than for eosinophils. In situ hybridization techniques exhibited that basal cell layers of the epidermis were stained homogeneously for CC chemokine receptor 3 mRNA with a decreasing signal to the upper epidermis showing that differentiating and proliferating keratinocytes did express mRNA specific for CC chemokine receptor 3. Immunohistochemical studies confirmed low expression of CC chemokine receptor 3 protein on epidermal keratinocytes compared to the high level observed on infiltrating eosinophils. Furthermore, stimulation of cultured keratinocytes with eotaxin resulted in an increased [3H]thymidine incorporation indicating a role of CC chemokine receptor 3 in epidermal proliferation and differentiation. These data demonstrate that CC chemokine receptor 3 is expressed not only on hematopoietic cells but also on keratinocytes as nonhematopoietic cells with ectodermal origin. Therefore, the identification of CC chemokine receptor 3 on epidermal keratinocytes may indicate a role for CC chemokine receptor 3 and its ligands in skin physiology and pathophysiology.
J Invest Dermatol 2001 Apr
PMID:Characterization of the CC chemokine receptor 3 on human keratinocytes. 1128 22

Little is known about the mechanism(s) underlying hyperpigmentation in lentigo senilis. We have previously reported that keratinocyte-derived endothelins are intrinsic paracrine mitogens and melanogens for human melanocytes and that they play an essential role in stimulating ultraviolet-B-induced melanogenesis. In this study, we have used immunohistochemistry and reverse transcriptase polymerase chain reaction analysis to clarify the role of the endothelin cascade, including endothelin production, processing by endothelin-converting enzyme, and expression of the endothelin B receptor, in the hyperpigmentary mechanism(s) involved in lentigo senilis. The number of tyrosinase immunopositive melanocytes in lentigo senilis lesional skin was increased 2-fold over the perilesional epidermis. Immunohistochemistry using antibodies to endothelin-1 demonstrated relatively stronger staining in the lesional epidermis than in the perilesional epidermis. Reverse transcriptase polymerase chain reaction analysis concomitantly demonstrated accentuated expression of transcripts for endothelin-1 and for the endothelin B receptor in lentigo senilis lesional skin, which was accompanied by a similar accentuated expression of tyrosinase mRNA compared with the perilesional control. The endothelin-1-inducible cytokine, tumor necrosis factor alpha, was consistently upregulated in the lentigo senilis lesional epidermis as determined at the transcriptional level and by immunostaining, whereas interleukin-1alpha was downregulated. In contrast, endothelin-converting enzyme 1alpha mRNA was not substantially increased in the lesional epidermis. These findings suggest that an accentuation of the epidermal endothelin cascade, especially with respect to expression of endothelin and the endothelin B receptor, plays an important role in the mechanism involved in the hyperpigmentation of lentigo senilis.
J Invest Dermatol 2001 Apr
PMID:The role of the epidermal endothelin cascade in the hyperpigmentation mechanism of lentigo senilis. 1128 25

To investigate the regulatory mechanisms of telomerase activity in human melanoma cells, we assessed the enzyme's catalytic activity and the expression of the telomerase subunits, the human telomerase RNA, the human telomerase-associated protein, and the human telomerase reverse transcriptase, in 52 melanoma lesions. Eight normal skin specimens were also studied. Telomerase activity was detected in 84.6% of melanomas, whereas all skin specimens were telomerase negative. Human telomerase-associated protein mRNA and human telomerase RNA were constitutively expressed in all melanoma and skin specimens. Although at a variable level of expression, human telomerase reverse transcriptase mRNA was detected in all but one melanomas, whereas it was never present in skin samples. Reverse transcriptase-polymerase chain reaction experiments were performed using primers within the reverse transcriptase domain of human telomerase reverse transcriptase and revealed the presence of multiple alternatively spliced transcripts in melanoma specimens. Among the 44 telomerase-positive melanomas, one showed the full-length transcript alone whereas in all other specimens a full-length message was present with different combinations of alternatively spliced variants. In these tumors the expression of the full-length transcript was generally equal to or higher than that of the alternatively spliced variants. The ratio full-length transcript to alternatively spliced species ranged from 0.6 to 5.26, with a median value of 1.18. Among the seven telomerase-negative melanomas, one displayed the beta deletion transcript alone, whereas in the remaining six tumors weak expression of the full-length transcript and a more abundant level of alternatively spliced transcripts were found. In these cases human telomerase reverse transcriptase ratio ranged from 0.09 to 1.1, with a median value of 0.40. The results suggest that transcription and alternative splicing of human telomerase reverse transcriptase are regulatory mechanisms controlling telomerase activity in melanoma.
J Invest Dermatol 2001 Jun
PMID:Possible regulation of telomerase activity by transcription and alternative splicing of telomerase reverse transcriptase in human melanoma. 1140 73

The human homolog of KET, p63, bears strong homology to the tumor suppressor p53 and plays an essential role in epithelial development. CUSP, the most abundant cutaneous product of p63, has been identified as an autoantigen in chronic ulcerative stomatitis (CUS). The original report of KET expression at least partially contradicts p63 expression subsequently reported by many different groups. We have examined p63 expression by Northern analysis of RNA from multiple human tissues and by indirect immunofluorescence of rat tissue with CUS patient sera. Northern analysis reveals p63 RNA in skin, thymus, placenta, skeletal muscle, kidney, and lung, with non-transactivating p63 RNA in skin, thymus, and placenta. Reverse transcriptase polymerase chain reaction (rtPCR) assays show abundant non-transactivating p63 RNA, and little to no transactivating p63 RNA, in human basal cell carcinoma as well as in normal skin adjacent to the tumors. p63 RNA expression was not detected in brain, heart, colon, spleen, liver, or small intestine. Immunofluorescence reveals p63 expression in skin, oral epithelium, tongue, kidney, and trachea, but not in liver, large intestine, testis, skeletal muscle, or heart. Focal p63 expression within tissues, the complex array of isoforms encoded by the gene, and the specificity of the probes and antibodies utilized, may all contribute to contradictory accounts of CUSP/p63 expression.
J Dermatol Sci 2001 Oct
PMID:CUSP/p63 expression in rat and human tissues. 1153 71


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