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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Psoriasis is a common chronic inflammatory disorder of the skin. To further understand the pathogenesis of psoriasis we have chosen to investigate the molecular genetic basis of the disorder. We have used a two-stage approach to search the human genome for the location of genes conferring susceptibility to psoriasis, using a total of 106 affected sibling pairs identified from 68 independent families. As over a third of the extended kindreds included affected relatives besides siblings, in addition to an analysis of allele sharing between affected sibling pairs, a novel linkage strategy was applied that extracts full non-parametric information. Four principal regions of possible linkage were identified on chromosomes 2, 8, 20 (p <0.005) and markers from the MHC region at 6p21 (p <0.0000006) for which significant evidence of linkage disequilibrium was also observed (p <0.00002). Whilst data from limited case control associations exist to implicate the MHC, the results of this genome wide analysis demonstrate that, at least in the population studied, a gene or genes located within the MHC and close to the class 1 HLA loci, represent the major determinant of the genetic basis of psoriasis.
Hum Mol Genet 1997 May
PMID:Identification of a major susceptibility locus on chromosome 6p and evidence for further disease loci revealed by a two stage genome-wide search in psoriasis. 915 58

In a meeting dedicated to a single common complex disease such as psoriasis, it is not surprising that many unanswered questions were raised. However, the meeting highlighted the impressive progress being made in psoriasis research at both the investigative and the therapeutic levels. A follow-up meeting is to take place in 1999, when further characterization of susceptibility gene loci should be available, together with data concerning the selective nature of disease-causing T cells and the antigens that trigger the disease. Identification of these critical factors should allow development of highly specific therapeutic agents, some of which are beginning to find their way into clinical development.
Mol Med Today 1997 May
PMID:Progress in psoriasis. Psoriasis: from gene to clinic. London, UK, 5-7 December 1996. 917 81

In a 12.5 cM genome-wide scan for psoriasis susceptibility loci, recombination-based tests revealed linkage to the HLA region (Zmax = 3.52), as well as suggestive linkage to two novel regions: chromosome 16q (60-83.1 cM from pter, Zmax = 2.50), and chromosome 20p (7.5-25 cM from pter, Zmax = 2.62). All three regions yielded P values < or = 0.01 by non-parametric analysis. Recombination-based and allele sharing methods also confirmed a previous report of a dominant susceptibility locus on distal chromosome 17q (108.2 cM from pter, Zmax = 2.09, GENEHUNTER P = 0.0056). We could not confirm a previously reported locus on distal chromosome 4q; however, a broad region of unclear significance was identified proximal to this proposed locus (153.6-178.4 cM from pter, Zmax = 1.01). Taken together with our recent results demonstrating linkage to HLA-B and -C, this genome-wide scan identifies a psoriasis susceptibility locus at HLA, confirms linkage to 17q, and recommends two novel genomic regions for further scrutiny. One of these regions (16q) overlaps with a recently-identified susceptibility locus for Crohn's disease. Psoriasis is much more common in patients with Crohn's disease than in controls, suggesting that an immunomodulatory locus capable of influencing both diseases may reside in this region.
Hum Mol Genet 1997 Aug
PMID:Evidence for two psoriasis susceptibility loci (HLA and 17q) and two novel candidate regions (16q and 20p) by genome-wide scan. 925 83

The dialysate fluid of uremic patients exhibits, in vitro, an inhibitory effect on cell growth, owing to urea, guanidino compounds, and substances named middle molecules. The polyamines are compounds which exhibit high levels in biological fluids during either normal development or disease such as psoriasis, uremia, and tumors. Dialysate and middle molecules show toxicity and degeneration of the organotype cultures, whereas the free polyamines and nonrecirculated dialysate do not have any toxic effect. The aim of this study is to analyze the effects of polyamines, nonrecirculated dialysate, and middle molecules of uremic patients in periodic hemodialysis on cultured VERO (fibroblast-like cells) growth. These cells show an inhibition of growth in middle molecules or 2 x 10(-4) M putrescine and a stimulation with nonrecirculated dialysate and 2 x 10(-8) M putrescine. The effect is different because the cultures with middle molecules begin growth again after 24 hr, whereas in the presence of 2 x 10(-4) M putrescine no further growth is observed. Cells maintained in middle molecules + 2 x 10(-8) M putrescine show an irreversible degeneration, attesting a toxic effect due to the low molarities of putrescine. The electron microscopy shows alteration of cytoplasmic, mitochondrial, and nuclear membranes, but no chromatin fragmentation with either middle molecules or 2 x 10(-4) M putrescine: this suggests that the cells do not die of apoptosis. In conclusion, during uremia the polyamines could cause toxic effects, even at low concentrations, on cells stressed by other toxic stimuli.
Exp Mol Pathol 1997
PMID:Direct inhibitory effect of uremic toxins and polyamines on proliferation of VERO culture cells. 943 80

Establishing guidelines and experimental models preclinical and clinical evaluations of new agents for treatment, and/or prevention of human diseases has become a task of crucial importance. Psoriasis is such one disease holding great interest for dermatology owing to its high rate of incidence and complexity of treatment. However the absence of psoriatic lesions in animals and the inability to induce them, calls for experimental techniques both in vitro and in vivo. The purpose of this study was to evaluate experimentally the effects of tacalcitol on cell proliferation and differentiation process. Thereafter a human pilot study on psoriatic patients has been developed.
Cell Mol Biol (Noisy-le-grand) 1997 Dec
PMID:An experimental pilot study of tacalcitol activities during modulation of parakeratotic skin features. 948 47

Photochemotherapy employing 8-methoxypsoralen and ultraviolet radiation (PUVA) is widely used in the treatment of psoriasis. The photoactivation of psoralens in skin cells leads to DNA photoadduct formation which may be responsible for the efficacy of PUVA. Subsequent mutations may lead to the increased incidence of squamous cell carcinoma (SCC). Mutations in the p53 tumor suppressor gene have been detected in many human cancers. In this review, p53 mutation spectra in murine and human SCC are compared to those obtained from murine cells and skin treated with PUVA as well as to the p53 mutation spectrum in human solar SCC. While the expected psoralen-type mutations at alternating AT sites were detected in the treated cells and murine SCC (average frequency > 40%), such mutations were not commonly detected in the human SCC (< 10%). Other common mutations in the human SCC included: CG-->TA transitions (18%) and CG-->AT and TA-->GC transversions (17 and 25%, respectively). In addition, the frequency of UVB-type mutations at dipyrimidine sites (CC-->TT) in the SCC PUVA-treated psoriasis patients was comparable to that in patients with SCC from only solar exposure. A review of therapeutic history of these patients showed that many had also received UVB phototherapy. Furthermore, because sunlight is thought to be beneficial for psoriasis, nontherapeutic, casual UVB exposure cannot be excluded. Thus, the PUVA SCC may have arisen from the solar mutations and PUVA may enhance tumor progression by other epigenetic effects.
Environ Mol Mutagen 1998
PMID:Psoralen photochemotherapy, clinical efficacy, and photomutagenicity: the role of molecular epidemiology in minimizing risks. 954 88

Mast cells are traditionally known for mediating allergic reactions. In addition, these cells have been implicated in the pathogenesis of a variety of clinical conditions such as atopic and contact dermatitis, bullous pemphigoid, fibrotic lung disease, neurofibromatosis, psoriasis, scleroderma, rheumatoid arthritis, interstitial cystitis, ulcerative colitis, and Crohn's disease, but their role in host defense was an enigma until recently. Owing to the strategic location of mast cells at the host environment interface, their role in bacterial infections has been studied by a number of investigators. Latest reports show that mast cells have an ability to modulate the host's innate immune response to infectious agents. This review discusses the clinical implications of mast cell-bacteria interactions.
J Mol Med (Berl) 1998 Aug
PMID:Clinical implications of mast cell-bacteria interaction. 972 64

In the last few years, molecular genetics analyses have permitted novel insights into psoriasis, a disease characterized by uncontrolled proliferation of keratinocytes and recruitment of T cells into the skin. The disease affects approximately 1-2% of the Caucasian population and can occur in association with other inflammatory diseases such as Crohn's disease and in association with human immunodeficiency virus (HIV) infection. Given that psoriasis has characteristics of an autoimmune disease, it is not surprising that HLA studies revealed an association with certain alleles, notably HLA-Cw6. Despite this HLA component, psoriasis in some families is inherited as an autosomal dominant trait with high penetrance. Loci at chromosome 17q25 and 4q have been identified following genome-wide linkage scans of large, multiply affected families. In the case of at least the susceptibility locus at 17q25, the development of psoriasis does not require the presence of HLA-Cw6. Sib-pair analyses have confirmed the association with HLA-Cw6, confirmed the existence of a locus at 17q25 and identified other possible susceptibility loci. Two independent groups have reported a third region on chromosome 20p. Despite these findings, the extent of genetic heterogeneity and the role of environmental triggers and modifier genes is still not clear. The precise role of HLA also still needs to be defined. The isolation of novel susceptibility genes will provide insights into the precise biochemical pathways that control this disease. Such pathways will also reveal additional candidate genes that can be tested for molecular alterations resulting in disease susceptibility.
Hum Mol Genet 1998
PMID:The genetics of psoriasis: a complex disorder of the skin and immune system. 973 74

M proteins are receptor proteins and one of the virulence factors of streptococci. M proteins seem to play a role in inflammatory skin disorders such as psoriasis. It is however unknown whether M proteins have a direct influence on proliferative activity of human keratinocytes. In the present study human HaCaT keratinocytes were exposed to M proteins (M1, M3, M5, M12) and the proliferative and proinflammatory response was analyzed. We found a dose-dependent inhibition of keratinocyte proliferation with crude extract of strain M3 4/55. Following affinity chromatography we found inhibitory activity for keratinocyte proliferation with a maximum of 80% at 10-8 M in the M protein. Additionally tested M1 protein preparation showed an inhibitory activity of 55% whereas other M preparations (5 and 12) did not show any effect. In supernatants from HaCaT cultures IL-1alpha, IL-1beta, IL-6, IL-8, TNFalpha and ICAM-1 were measured by ELISA. The levels of IL-8 were high and TNFalpha was upregulated, whereas ICAM-1 was decreased from around 20 ng/ml to almost zero. In contrast to the streptococcal-derived M3 protein preparation the recombinant M3 did not interfere with the proliferation of HaCaT cells. Because neither recombinant M3 protein nor M3 protein purified by ion exchange chromatography on a Q-resource column had any antiproliferative activity on keratinocytes we suggest, that a component different from M3 protein was responsible.
Int J Mol Med 1998 Apr
PMID:Keratinocyte growth inhibition by streptococcal proteins. 985 94

Retinoids are therapeutically effective in the treatment of psoriasis, photoaging, acne, and certain cancers. Some of the therapeutic actions of retinoids can be ascribed to retinoic acid receptor (RAR)-mediated antagonism of AP1-dependent gene expression. The increased activity of transcription factor AP1, a complex of oncoproteins Jun and Fos, is associated with cell growth and proliferation. Retinoids, on the other hand, inhibit cell proliferation and affect differentiation, activities that possibly stem from an antagonism of AP1-mediated gene expression by RARs. To gain insight into the molecular mechanism of RAR-AP1 interaction, we have identified the regions of the RAR required for AP1 antagonism. We demonstrate that the AP1 antagonism domain of RAR is a complex of the core of the DNA binding domain and the hydrophobic zipper region. Further, both monomeric RAR and RAR-RXR heterodimers inhibit the expression of an AP1 reporter. CREB binding protein (CBP) has been described as a cofactor for AP1, various nuclear hormone receptor proteins including RARs, and certain other transcription factors and is required for their transactivation properties. Therefore, CBP has been proposed as a common limiting cofactor that can account for inhibition of AP1-dependent gene expression by RARs. Interestingly, however, our results along with previously reported observations suggest that in addition to CBP, there may be other limiting cofactor(s) responsible for mutual transrepression of RAR and AP1.
Mol Cell Biol Res Commun 1999 Apr
PMID:Identification of the AP1-antagonism domain of retinoic acid receptors. 1032 71


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