Gene Summary

Gene:TMC6; transmembrane channel like 6
Aliases: EV1, EVER1, EVIN1, LAK-4P
Summary:Epidermodysplasia verruciformis (EV) is an autosomal recessive dermatosis characterized by abnormal susceptibility to human papillomaviruses (HPVs) and a high rate of progression to squamous cell carcinoma on sun-exposed skin. EV is caused by mutations in either of two adjacent genes located on chromosome 17q25.3. Both of these genes encode integral membrane proteins that localize to the endoplasmic reticulum and are predicted to form transmembrane channels. This gene encodes a transmembrane channel-like protein with 10 transmembrane domains and 2 leucine zipper motifs. [provided by RefSeq, Jul 2008]
Databases:OMIM, HGNC, Ensembl, GeneCard, Gene
Protein:transmembrane channel-like protein 6
Source:NCBIAccessed: 30 August, 2019


What does this gene/protein do?
TMC6 is implicated in:
- endoplasmic reticulum membrane
- integral to membrane
Data from Gene Ontology via CGAP

Cancer Overview

Research Indicators

Publications Per Year (1994-2019)
Graph generated 31 August 2019 using data from PubMed using criteria.

Literature Analysis

Mouse over the terms for more detail; many indicate links which you can click for dedicated pages about the topic.

  • Neoplasm Recurrence, Local
  • TMC6 protein, human
  • Head and Neck Cancers
  • Transplant Recipients
  • Skin
  • Cervical Cancer
  • Betapapillomavirus
  • Squamous Cell Carcinoma
  • fas Receptor
  • Pharyngeal Neoplasms
  • Single Nucleotide Polymorphism
  • Skin Cancer
  • Phenotype
  • Host-Pathogen Interactions
  • Genome-Wide Association Study
  • Squamous Cell Carcinoma of Head and Neck
  • Siblings
  • Restriction Fragment Length Polymorphism
  • Surveys and Questionnaires
  • Laryngeal Cancer
  • Reproducibility of Results
  • Case-Control Studies
  • Membrane Proteins
  • Chromosome 17
  • Linkage Disequilibrium
  • Epidermodysplasia Verruciformis
  • Risk Factors
  • Genotype
  • Papillomavirus Infections
  • Cervical Intraepithelial Neoplasia
  • Viral Proteins
  • Cancer DNA
  • Papillomaviridae
  • Severity of Illness Index
  • Logistic Models
  • Genetic Predisposition
  • SLC30A1 protein, human
  • Oral Cavity Cancer
  • Zinc
  • Mutation
Tag cloud generated 30 August, 2019 using data from PubMed, MeSH and CancerIndex

Specific Cancers (5)

Data table showing topics related to specific cancers and associated disorders. Scope includes mutations and abnormal protein expression.

Note: list is not exhaustive. Number of papers are based on searches of PubMed (click on topic title for arbitrary criteria used).

Latest Publications: TMC6 (cancer-related)

Pavlidou E, Daponte A, Egea R, et al.
Genetic polymorphisms of FAS and EVER genes in a Greek population and their susceptibility to cervical cancer: a case control study.
BMC Cancer. 2016; 16(1):923 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: The aim of the study was to evaluate the association of two SNPs of EVER1/2 genes' region (rs2290907, rs16970849) and the FAS-670 polymorphism with the susceptibility to precancerous lesions and cervical cancer in a Greek population.
METHODS: Among the 515 women who were included in the statistical analysis, 113 belong to the case group and present with precancerous lesions or cervical cancer (27 with persistent CIN1, 66 with CIN2/3 and 20 with cervical cancer) and 402 belong to the control group. The chi-squared test was used to compare the case and the control groups with an allelic and a genotype-based analysis.
RESULTS: The results of the statistical analysis comparing the case and the control groups for all the SNPs tested were not statistically significant. Borderline significant difference (p value = 0.079) was only found by the allelic model between the control group and the CIN1/CIN2 patients' subgroup for the polymorphism rs16970849. The comparison of the other case subgroups with the control group did not show any statistically significant difference.
CONCLUSIONS: None of the SNPs included in the study can be associated with statistical significance with the development of precancerous lesions or cervical cancer.

Antonsson A, Law MH, Neale RE, et al.
Variants of EVER1 and EVER2 (TMC6 and TMC8) and human papillomavirus status in patients with mucosal squamous cell carcinoma of the head and neck.
Cancer Causes Control. 2016; 27(6):809-15 [PubMed] Related Publications
PURPOSE: There is a growing association of human papillomavirus (HPV) with some cases of mucosal squamous cell carcinoma of the head and neck (HNSCC), particularly of the oropharynx. Persistent oral HPV infection is believed to increase the likelihood of malignancy, and it is possible that host genetic factors can determine susceptibility to persistent HPV infection. Polymorphisms in the two EV genes (EVER1 and EVER2, also known as transmembrane channel protein (TMC) 6 and 8) have been identified as strong candidate genes, since a small number of critical mutations in these genes have been shown to cause profound and florid skin HPV infections, and some of them have been linked to susceptibility to cervical cancer.
METHODS: We sought to determine whether there was a difference in the frequency of single nucleotide polymorphisms (SNPs) in EVER1 (rs2613516, rs12449858) and EVER2 (rs7205422, rs12452890) between HNSCC patients with HPV-positive and HPV-negative tumors, and healthy controls. We used logistic regression to analyze SNPs in 219 patients with histologically confirmed primary SCC of the oropharynx, oral cavity, hypopharynx, or larynx, and 321 healthy controls.
RESULTS: We did not find any associations with the EVER1/EVER2 SNPs and HPV status or being a HNSCC case or a control.
CONCLUSIONS: The present data do not provide evidence for a role of genetic variations in EVER1 or EVER2 for HPV status of mucosal HNSCC or between HNSCC patients and controls.

Burger B, Spörri I, Stegmann DA, et al.
Risk of Cutaneous Squamous Cell Carcinoma Development in Renal Transplant Recipients Is Independent of TMC/EVER Alterations.
Dermatology. 2015; 231(3):245-52 [PubMed] Related Publications
BACKGROUND: Renal transplant recipients (RTRs) have an increased risk of developing nonmelanoma skin cancer, mainly cutaneous squamous cell carcinoma (cSCC). Two genes (TMC6/EVER1 and TMC8/EVER2), mutated in epidermodysplasia verruciformis (EV) patients with an increased risk of cSCC development, contain numerous single-nucleotide polymorphisms (SNPs).
AIM: To evaluate the effect of SNPs in both TMC/EVER genes on the different susceptibilities of RTRs to cSCC.
METHOD: We determined the occurrence of cSCC in 105 RTRs who were transplanted at least 7 years previously and investigated the frequency of 26 SNPs within both TMC/EVER genes in severely affected (n = 16) as well as in nonaffected RTRs (n = 25).
RESULTS: Our data did not indicate a significant association between any SNP genotype and risk of cSCC development in RTRs.
CONCLUSION: To clarify the correlation between SNPs in both TMC genes and cSCC development in RTRs, integrated investigations of large cohorts including both RTRs and immunocompetent individuals with consideration of cSCC status, SNP genotype and human papillomavirus status might be necessary.

Kalinska-Bienias A, Kostrzewa G, Malejczyk M, et al.
Possible association between actinic keratosis and the rs7208422 (c.917A→T, p.N306l) polymorphism of the EVER2 gene in patients without epidermodysplasia verruciformis.
Clin Exp Dermatol. 2015; 40(3):318-23 [PubMed] Related Publications
BACKGROUND: Mutations of the EVER1 and EVER2 genes cause epidermodysplasia verruciformis (EV), a genodermatosis associated with squamous cell carcinoma (SCC). Recently, it has been found that the rs7208422 (c.917A→T, p.N306l) polymorphism in the EVER2 gene is related to an increased risk of SCC in patients with conditions other than EV. We hypothesized that this polymorphism might be also associated with actinic keratoses (AK).
AIM: To determine whether the rs7208422 polymorphism of the EVER2 gene is associated with AK in non-EV patients.
METHODS: We genotyped rs7208422 in 65 patients with AK and 274 controls, using reverse transcription PCR.
RESULTS: We detected a trend towards an association between AK and the TT genotype of rs7208422; the frequency of this genotype was 38.5% in patients with AK and 26.3% in controls (OR  =  1.75, P  <  0.06 for recessive model of inheritance). We also found an association between rs7208422 TT and both the age at which AK appeared and the extent of the AK. This variant was more frequent in patients who had AK onset before the age of 70 years compared with those whose age of onset was above 70 years (OR = 3.14, P = 0.03 for the recessive model; OR = 2.05, P = 0.04 for allelic comparison) and more frequent in AK involving > 3 body areas (OR = 3.14, P = 0.03 for the recessive model; OR = 2.34, P = 0.01 for allelic comparison). These associations remained significant in a multivariate regression analysis, showing that both parameters were independently associated with the TT genotype (P = 0.031).
CONCLUSIONS: This study indicates a potential role of the rs7208422 (c.917A→T, P.N306l) polymorphism of the EVER2 gene in AK.

Smola S
Human papillomaviruses and skin cancer.
Adv Exp Med Biol. 2014; 810:192-207 [PubMed] Related Publications
Human papillomaviruses (HPVs) infect squamous epithelia and can induce hyperproliferative lesions. More than 120 different HPV types have been characterized and classified into five different genera. While mucosal high-risk HPVs have a well-established causal role in anogenital carcinogenesis, the biology of cutaneous HPVs is less well understood. The clinical relevance of genus beta-PV infection has clearly been demonstrated in patients suffering from epidermodysplasia verruciformis (EV), a rare inherited disease associated with ahigh rate of skin cancer. In the normal population genus beta-PV are suspected to have an etiologic role in skin carcinogenesis as well but this is still controversially discussed. Their oncogenic potency has been investigated in mouse models and in vitro. In 2009, the International Agency for Research on Cancer (IARC) classified the genus beta HPV types 5 and 8 as "possible carcinogenic" biological agents (group 2B) in EV disease. This chapter will give an overview on the knowns and unknowns of infections with genus beta-PV and discuss their potential impact on skin carcinogenesis in the general population.

Madeleine MM, Carter JJ, Johnson LG, et al.
Risk of squamous cell skin cancer after organ transplant associated with antibodies to cutaneous papillomaviruses, polyomaviruses, and TMC6/8 (EVER1/2) variants.
Cancer Med. 2014; 3(5):1440-7 [PubMed] Free Access to Full Article Related Publications
Squamous cell skin cancer (SCSC) disproportionately affects organ transplant recipients, and may be related to increased viral replication in the setting of immune suppression. We conducted a nested case-control study among transplant recipients to determine whether SCSC is associated with antibodies to cutaneous human papillomaviruses (HPV), to genes associated with a rare genetic susceptibility to HPV (TMC6/TMC8), or to human polyomaviruses (HPyV). Cases (n = 149) had histologically confirmed SCSC, and controls (n = 290) were individually matched to cases on time since transplant, type of transplant, gender, and race. All subjects had serum drawn immediately prior to transplant surgery. Antibodies to 25 cutaneous HPVs and six HPyVs were assayed by detection of binding to virus-like particles, and 11 TMC6/8 variants were genotyped. After correction for multiple comparisons, only antibodies to HPV37 were associated with SCSC (OR 2.0, 95% CI 1.2-3.4). Common genetic variants of TMC6/8 were not associated with SCSC, but three variants in TMC8 (rs12452890, rs412611, and rs7208422) were associated with greater seropositivity for species 2 betapapillomaviruses among controls. This study suggests that some betaHPVs, but not polyomaviruses, may play a role in the excess risk of SCSC among transplant recipients.

Johanneson B, Chen D, Enroth S, et al.
Systematic validation of hypothesis-driven candidate genes for cervical cancer in a genome-wide association study.
Carcinogenesis. 2014; 35(9):2084-8 [PubMed] Related Publications
A large number of genetic associations with cervical cancer have been reported in hypothesis-driven candidate gene studies, but most studies have not included an independent replication or the results have been inconsistent between studies. In order to independently validate these associations, we reexamined 58 candidate gene/regions previously reported to be associated with cervical cancer using the gene-based Adaptive Rank Truncated Product test in a genome-wide association study (GWAS) of 1034 cervical cancer patients and 3948 controls from the Swedish population. Of the 58 gene/regions, 8 had a nominal P value < 0.05 [tumor necrosis factor (TNF), P = 5.0 × 10(-4); DEAD (Asp-Glu-Ala-Asp) box helicase 1 [DDX1], P = 2.2 × 10(-3); exonuclease 1 [EXO1], P = 4.7 × 10(-3); excision repair cross-complementing rodent repair deficiency, complementation group 1 [ERCC1], P = 0.020; transmembrane channel-like 6 and 8 genes [TMC6-TMC8], P = 0.023; secreted phosphoprotein 1 [SPP1], P = 0.028; v-erb-b2 avian erythroblastic leukemia viral oncogene homolog 2 [ERBB2], P = 0.033 and chloride channel, voltage-sensitive 7 [CLCN7], P = 0.047). After correction for multiple testing, only TNF remained statistically significant (P = 0.028). Two single-nucleotide polymorphisms that are in nearly perfect linkage disequilibrium (rs2857602 and rs2844484) contributed most to the association with TNF. However, they are not independent from the previously reported associations within the MHC region. The very low number of previously reported associations with cervical cancer that replicate in the Swedish population underscore the need to apply more stringent criteria when reporting associations, including the prerequisite of replicating the association as part of the original study.

Burger B, Itin PH
Epidermodysplasia verruciformis.
Curr Probl Dermatol. 2014; 45:123-31 [PubMed] Related Publications
Epidermodysplasia verruciformis (EV) is a rare genodermatosis that predisposes certain individuals to developing cutaneous malignancies caused by infectious agents. Mutations in the transmembrane channel gene TMC6 or TMC8 create patient susceptibility to infections by human papillomavirus (HPV) and the development of EV-typical plane warts. Mainly in the UV-exposed regions, affected individuals have a lifelong increased risk for the development of cutaneous malignancy, especially squamous cell carcinoma (SCC). EV is the first disease to correlate cancer and viral infection, therefore EV now serves as the cornerstone to our understanding of viral oncogenesis. The EV model of cutaneous SCC may be applied to the general population; it is suggested that the TMC mutations impair the immunity of the patients, supporting the amplification of specific HPV types. Despite several advances in our comprehension of EV, the pathogenesis of the disease is not well understood.

Sunohara M, Ozawa T, Morimoto K, et al.
Dye laser photodynamic therapy for Bowen's disease in a patient with epidermodysplasia verruciformis.
Osaka City Med J. 2012; 58(2):77-82 [PubMed] Related Publications
Epidermodysplasia verruciformis (EV) is a rare heritable skin disease that results in unusual susceptibility to infection with specific types of human papillomavirus (HPV). Here we report a 53-year-old man with EV who developed Bowen's disease on his lower eyelid and the chest. Mutation analysis of EVER1 gene revealed homozygous splice acceptor site mutation (IVS8-2, A > T). In this patient, HPV3, HPV14, and HPV38 had been identified from the skin lesions. The Bowen's skin lesion on the left lower eye-lid was treated by photodynamic therapy (PDT) using 5-aminolevulinic acid (ALA) and pulsed dye laser (PDL). After two rounds of the PDT treatment, the skin lesion disappeared and a skin biopsy confirmed the efficacy of the treatment. This method was simple, less invasive than other treatments, and achieved a satisfactory cosmetic result.

Castro FA, Ivansson EL, Schmitt M, et al.
Contribution of TMC6 and TMC8 (EVER1 and EVER2) variants to cervical cancer susceptibility.
Int J Cancer. 2012; 130(2):349-55 [PubMed] Free Access to Full Article Related Publications
Cervical cancer (CxCa) is caused by persistent human papillomavirus (HPV) infection; genetic predisposition is also suspected to play a role. Our study is a targeted candidate gene follow-up based on: (i) strong clinical evidence demonstrating that mutations in the TMC6 and TMC8 (EVER1 and EVER2) genes associate with the HPV-associated disease epidermodysplasia verruciformis (EV) and (ii) recent epidemiological data suggesting a genetic susceptibility conferred by polymorphisms in such genes for skin and CxCa. Clarifying the association of the TMC6/8 genes with risk of CxCa will help in understanding why some HPV-infected women develop persistent infection, cervical lesions and eventually cancer while others do not. Twenty-two single nucleotide polymorphisms (SNPs) harboring the TMC6/8 genes were genotyped in 2,989 cases with cervical intraepithelial neoplasia grade III or invasive CxCa and 2,281 controls from the Swedish population. Association was evaluated in logistic regression models. Two SNPs displayed association with cervical disease: rs2290907 [odds ratio (OR)(GGvsAA) = 0.6, 95% confidence interval (95% CI): 0.3-0.9, p = 0.02)] and rs16970849 (OR(AGvsGG) = 0.8, 95% CI: 0.66-0.98, p = 0.03). The present data support the involvement of the TMC6/8 region in CxCa susceptibility but further analyses are needed to replicate our findings, fully characterize the region and understand the function of the genetic variants involved.

Arnold AW, Burger B, Kump E, et al.
Homozygosity for the c.917A→T (p.N306l) polymorphism in the EVER2/TMC8 gene of two sisters with epidermodysplasia verruciformis Lewandowsky-Lutz originally described by Wilhelm Lutz.
Dermatology. 2011; 222(1):81-6 [PubMed] Related Publications
BACKGROUND: Epidermodysplasia verruciformis Lewandowsky-Lutz (EV) is a rare genodermatosis, characterised by development of numerous verrucous skin lesions caused by specific genotypes of human papillomaviruses belonging to the β-papillomavirus genus. The EV loci were mapped to chromosome 2p21-p24 (EV2) and 17q25 (EV1). On chromosome 17, 2 adjacent related genes--EVER1/TMC6 and EVER2/TMC8--were identified. We reinvestigated 2 patients originally described by Wilhelm Lutz in 1946 with the aim to document the natural course of the disease and confirm his diagnosis.
METHODS: PCR fragments specific for exons with short flanking intron sequences of EVER1/TMC6 and EVER2/TMC8 genes from patients' DNA were amplified using sequence information. The single-nucleotide polymorphism (SNP) rs7208422 was studied, using restriction fragment length polymorphism analysis.
RESULTS: In the index patient, we identified a homozygous TT genotype in exon 8 of the EVER2/TMC8 gene (c.917A→T, p.N306I). The same mutation could thereafter be detected in her sister from paraffin-embedded skin.
CONCLUSION: We have followed one of the first patients described with EV in Basel, Switzerland, in 1930 until today and demonstrated the TT genotype (SNP rs7208422) in the EVER2/TMC8 gene in this index patient and her sister. The results underline the possible relevance of SNP rs7208422 by influencing the susceptibility to β-papillomaviruses and their oncogenic potential.

Wang SS, Gonzalez P, Yu K, et al.
Common genetic variants and risk for HPV persistence and progression to cervical cancer.
PLoS One. 2010; 5(1):e8667 [PubMed] Free Access to Full Article Related Publications
HPV infrequently persists and progresses to cervical cancer. We examined host genetic factors hypothesized to play a role in determining which subset of individuals infected with oncogenic human papillomavirus (HPV) have persistent infection and further develop cervical pre-cancer/cancer compared to the majority of infected individuals who will clear infection.We evaluated 7140 tag single nucleotide polymorphisms (SNPs) from 305 candidate genes hypothesized to be involved in DNA repair, viral infection and cell entry in 416 cervical intraepithelial neoplasia 3 (CIN3)/cancer cases, 356 HPV persistent women (median: 25 months), and 425 random controls (RC) from the 10,049 women Guanacaste Costa Rica Natural History study. We used logistic regression to compute odds ratios and p-trend for CIN3/cancer and HPV persistence in relation to SNP genotypes and haplotypes (adjusted for age). We obtained pathway and gene-level summary of associations by computing the adaptive combination of p-values. Genes/regions statistically significantly associated with CIN3/cancer included the viral infection and cell entry genes 2',5' oligoadenylate synthetase gene 3 (OAS3), sulfatase 1 (SULF1), and interferon gamma (IFNG); the DNA repair genes deoxyuridine triphosphate (DUT), dosage suppressor of mck 1 homolog (DMC1), and general transcription factor IIH, polypeptide 3 (GTF2H4); and the EVER1 and EVER2 genes (p<0.01). From each region, the single most significant SNPs associated with CIN3/cancer were OAS3 rs12302655, SULF1 rs4737999, IFNG rs11177074, DUT rs3784621, DMC1 rs5757133, GTF2H4 rs2894054, EVER1/EVER2 rs9893818 (p-trends

Patel AS, Karagas MR, Pawlita M, et al.
Cutaneous human papillomavirus infection, the EVER2 gene and incidence of squamous cell carcinoma: a case-control study.
Int J Cancer. 2008; 122(10):2377-9 [PubMed] Free Access to Full Article Related Publications
The first evidence of an association between HPV and non-melanoma skin cancer comes from patients with epidermodysplasia verruciformis (EV). EV is a rare heritable disease characterized by cutaneous warts that display not only a high rate of progression to squamous cell carcinoma on sun-exposed sites, but also a strong predisposition to infection by beta-HPVs, for which HPV 5 and 8 predominate. Two EV genes (EVER1 and EVER2) have been identified, and we tested the hypothesis that variation in the EVER2 gene (rs7208422) is related to seropositivity to HPV (of the genus beta types) and risk of squamous cell carcinoma in a population-based case-control study of SCC (n = 239 cases and 432 controls). Among controls, variant genotype was associated with beta-HPV seropositvity (OR = 2.3, 95%CI = 1.2-4.3), specifically HPV5 or 8 seropositivity (OR = 2.4, 95%CI = 1.1-5.1) and seropositivity for multiple beta-HPV types (OR = 2.7, 95%CI = 1.1-6.6). Furthermore, variant genotype was also related to SCC risk [adjusted OR for homozygous variant versus homozygous wild type for the EVER2 polymorphism 1.7, 95% CI 1.1-2.7]. These data provide evidence for a role of genetic variation in the EVER2 gene in beta-HPV infection and risk of SCC, shedding light on the link between HPVs and skin cancers.

Berthelot C, Dickerson MC, Rady P, et al.
Treatment of a patient with epidermodysplasia verruciformis carrying a novel EVER2 mutation with imiquimod.
J Am Acad Dermatol. 2007; 56(5):882-6 [PubMed] Related Publications
Epidermodysplasia verruciformis (EV) is a rare disorder characterized by widespread human papillomavirus infection and malignant transformation. EV may be caused by mutations of the genes EVER1 or EVER2, which are located on the EV1 locus, 17q25. We describe a patient with EV and a novel homozygous gene mutation of EVER2 gene who was treated successfully with topical imiquimod.

Donfack J, Buchinsky FJ, Derkay CS, et al.
Four mutations in Epidermodysplasia verruciformis 1 (EVER1) gene are not contributors to susceptibility in RRP.
Int J Pediatr Otorhinolaryngol. 2006; 70(7):1235-40 [PubMed] Related Publications
OBJECTIVE: Epidermodysplasia verruciformis is a skin disease characterized by abnormal susceptibility to human papilloma viruses. Recently four mutations in the Epidermodysplasia verruciformis 1 gene (EVER1, also known as TMC6) have been associated with the disease. Because of the phenotypic similarity between Epidermodysplasia verruciformis and recurrent respiratory papillomatosis, we decided to investigate whether any of these mutations accounts for the susceptibility to human papilloma viruses in subjects with recurrent respiratory papillomatosis (RRP).
METHODS: Allele-specific PCR and restriction fragment length polymorphisms (RFLPs) were employed for genotyping a cohort of 101 patients with recurrent respiratory papillomatosis.
RESULTS: None of these four mutations were found in the studied subjects.
CONCLUSION: The absence of these mutations in RRP patients might indicate that EVER 1 alleles are not associated with susceptibility to RRP, or that other, as yet unidentified, mutations in the Epidermodysplasia verruciformis 1 gene, might account for the susceptibility to RRP.

Majewski S, Jablonska S
Possible involvement of epidermodysplasia verruciformis human papillomaviruses in the immunopathogenesis of psoriasis: a proposed hypothesis.
Exp Dermatol. 2003; 12(6):721-8 [PubMed] Related Publications
We have shown previously in psoriasis a very high prevalence of epidermodysplasia verruciforms-associated human papillomavirus 5 (EVHPV5) DNA and antibodies to human papillomavirus 5 (HPV5) virus-like particle (VLP) L1, and we suggested that this benign hyperproliferative disorder could be a reservoir for EVHPVs. Here we provide new data confirming the expression of EVHPVs in psoriasis and present our hypothesis on their possible involvement in the immunopathogenesis of the disorder. The new important finding was detection by radioimmunoprecipitation assay of a very high prevalence of antibodies to E6/E7 HPV5 oncoproteins, known to enhance keratinocyte proliferation. More recently, EV genes were identified, EVER1 and EVER2, whose mutations are responsible for epidermodysplasia verruciformis. Eidermodysplasia verruciforms-associated human papillomaviruses are harmless to the general population as a result of genetic restriction, which in psoriasis appears to be partly alleviated, and this may allow the viral gene expression. We hypothesize that induction of keratinocyte proliferation in psoriasis by various stimuli initiates the EVHPV life cycle with expression of early (E6/E7) and late (L1) viral proteins. The early proteins may, in turn, enhance the keratinocyte proliferation, and the late proteins could serve as target for specific-B- and T-cell-mediated responses. Immune responses against the viral antigens in the epidermis may result in the chemoattraction of leukocytes and Munro abscess formation, as well as in production of the psoriatic process. The novel immunomodulatory therapies could also inhibit immune responses against EVHPV proteins, leading to decreased cytokine production, keratinocyte proliferation and EVHPV expression. Thus the beneficial effect of these therapies is not discordant with the propose hypothesis of possible involvement of EVHPVs in the immunopathogenesis of psoriasis.

Huttunen P, Hyypiä T, Vihinen P, et al.
Echovirus 1 infection induces both stress- and growth-activated mitogen-activated protein kinase pathways and regulates the transcription of cellular immediate-early genes.
Virology. 1998; 250(1):85-93 [PubMed] Related Publications
We have previously shown that echovirus 1 (EV1) infection increases the mRNA levels of cellular immediate-early (IE) genes in host cells. Here we provide further evidence that the induction of junB, c-jun, and c-fos genes is due to active viral macromolecular synthesis rather than to the interaction of EV1 with its receptor, alpha2beta1 integrin. Nuclear run-on transcription assays indicated that differences in mRNA levels in infected and uninfected cells are brought about by regulation at the transcriptional level. EV1 infection induced the phosphorylation of both the stress-related p38 mitogen-activated protein kinase (MAPK) and the growth signal-related ERK1/2 MAPKs. Studies with selective MAPK inhibitors revealed that p38 was the main inducer of junB expression, whereas both MAPK pathways were involved in the induction of c-fos. Activation of AP-1 genes was also observed to occur during infections with other enteroviruses and with Semliki Forest A7(74) virus, suggesting that the phosphorylation of MAPKs and induction of AP-1 gene expression may be important regulators of host cell behavior during viral infections.

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