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  • 1
    Keywords: APOPTOSIS ; CANCER ; EXPRESSION ; GROWTH ; human ; IN-VIVO ; PATHWAY ; PATHWAYS ; DEATH ; GENE ; GENES ; PROTEIN ; transcription ; MICE ; TIME ; MECHANISM ; CARCINOGENESIS ; SKIN ; E7 ; papillomavirus ; TRANSGENIC MICE ; p53 ; human papillomavirus ; E6 ; HUMAN-PAPILLOMAVIRUS ; RE ; TUMORIGENESIS ; downregulation ; function ; cutaneous HPV38 ; Delta Np73 ; E6 and E7
    Abstract: The E6 and E7 of the cutaneous human papillomavirus (HPV) type 38 immortalize primary human keratinocytes, an event normally associated with the inactivation of pathways controlled by the tumour suppressor p53. Here, we show for the first time that HPV38 alters p53 functions. Expression of HPV38 E6 and E7 in human keratinocytes or in the skin of transgenic mice induces stabilization of wild-type p53. This selectively activates the transcription of Delta Np73, an isoform of the p53-related protein p73, which in turn inhibits the capacity of p53 to induce the transcription of genes involved in growth suppression and apoptosis. Delta Np73 downregulation by an antisense oligonucleotide leads to transcriptional re-activation of p53-regulated genes and apoptosis. Our findings illustrate a novel mechanism of the alteration of p53 function that is mediated by a cutaneous HPV type and support the role of HPV38 and Delta Np73 in human carcinogenesis
    Type of Publication: Journal article published
    PubMed ID: 16397624
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  • 2
    Keywords: CANCER ; cell line ; DNA-DAMAGE ; STABILITY ; INDUCE APOPTOSIS ; REGULATES P73 ; HUMAN TUMORS ; C-ABL ; APOPTOTIC RESPONSE ; IKK-BETA ; P53-RELATED PROTEIN
    Abstract: Delta Np73 alpha, a dominant-negative inhibitor of p53 and p73, exhibits antiapoptotic and transforming activity in in vitro models and is often found to be upregulated in human cancers. The mechanisms involved in the regulation of Delta Np73 alpha protein levels in normal and cancer cells are poorly characterized. Here, we show that that I kappa B kinase beta (IKK beta) increases Delta Np73 alpha protein stability independently of its ability to activate NF-kappa B. IKK beta associates with and phosphorylates Delta Np73 alpha at serine 422 (S422), leading to its accumulation in the nucleus, where it binds and represses several p53-regulated genes. S422A mutation in Delta Np73 alpha abolished IKK beta-mediated stabilization and inhibition of p53-regulated gene expression. Inhibition of IKK beta activity by chemical inhibitors, overexpression of dominant-negative mutants, or gene silencing by siRNA also resulted in Delta Np73 alpha destabilization, which under these conditions was rapidly translocated into the cytoplasm and degraded by a calpain-mediated mechanism. We also present evidence for the IKK beta and Delta Np73 alpha cross talk in cancer-derived cell lines and primary cancers. Our data unveil a new mechanism involved in the regulation of the p73 and p53 network
    Type of Publication: Journal article published
    PubMed ID: 21482671
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  • 3
    Keywords: CANCER ; EXPRESSION ; IRRADIATION ; CELL ; human ; PATHWAY ; PATHWAYS ; GENE ; PROTEINS ; transcription ; ACCUMULATION ; MICE ; radiation ; CARCINOGENESIS ; KERATINOCYTES ; SKIN ; BIOLOGY ; CELL-CYCLE ; MOLECULAR-BIOLOGY ; papillomavirus ; MOUSE ; TRANSGENIC MICE ; MOUSE SKIN ; skin carcinogenesis ; genetics ; p53 ; human papillomavirus ; FRANCE ; HPV ; ONCOGENE ; HUMAN KERATINOCYTES ; HUMAN-PAPILLOMAVIRUS ; heredity ; molecular biology ; molecular ; ONCOLOGY ; RE ; LEVEL ; LOSSES ; Delta Np73 ; ENGLAND ; PROMOTES ; cell cycle checkpoints ; cell cycle arrest ; HPV38 ; SPONTANEOUS TUMORS ; UV irradiation
    Abstract: We have previously shown that human keratinocytes expressing E6 and E7 from the cutaneous human papillomavirus (HPV) type 38 have high levels of a specific form of p53, which in turn activate the transcription of Delta Np73 gene. Expression of HPV38 E6 and E7 in mouse skin also promotes p53 and Delta Np73 accumulation. Interestingly, keratinocytes of these mice do not undergo cell cycle arrest after skin ultraviolet (UV) irradiation. Here, we provide several lines of evidence that Delta Np73 expression and lack of the UV response are directly linked. Loss of p53 gene in HPV38E6/E7 transgenic mice abolished Delta Np73 expression and partially restored the UV-activated cell cycle checkpoints. Similarly, loss of p73, and consequently Delta Np73, led to restoration of the p53 pathways. In fact, keratinocytes of p73(-/-) HPV38 E6/E7 transgenic mice upon UV irradiation express high levels of p21(WAF1) and are cell cycle arrested. Thus, HPV38 E6 and E7, via Delta Np73 accumulation, are able to alter the regulation of cell cycle checkpoints activated by UV radiation. These data suggest that UV and HPV may cooperate in skin carcinogenesis
    Type of Publication: Journal article published
    PubMed ID: 18026133
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  • 4
    Keywords: SPECTRA ; CANCER ; human ; GENE ; HYBRIDIZATION ; microarray ; SAMPLE ; SAMPLES ; LINES ; DNA ; SKIN ; E7 ; papillomavirus ; AMPLIFICATION ; ASSAY ; skin cancer ; LINE ; PCR ; human papillomavirus ; HPV ; BETA ; DIVERSITY ; HUMAN-PAPILLOMAVIRUS ; sensitivity ; MUTATION DETECTION ; SKIN-CANCER ; SINGLE ; RE ; EXTENSION ; ARRAY ; EPIDERMODYSPLASIA-VERRUCIFORMIS ; development ; INTERVAL ; methods ; DNA-MICROARRAY ; technique ; USA ; PRIMER EXTENSION ; SPECTRUM ; microbiology ; BIOPSIES ; HUMAN-PAPILLOMAVIRUS TYPES ; MUCOSAL ; HPV types ; KAPPA
    Abstract: Emerging lines of evidence indicate that the cutaneous human papillomavirus (HPV) types that belong to the genus Betapapillomavirus (beta HPV) are involved in the development of nonmelanoma skin cancer. Unlike the situation for mucosal HPV types, highly sensitive and reliable methods to identify characterized cutaneous HPV types in a single assay are limited. Here, we describe a novel one-shot method for the detection of all characterized beta HPV types, namely, HPV type 5 (HPV5), 8, 9, 12, 14, 15, 17, 19, 20, 21, 22, 23, 24, 25, 36, 37, 38, 47, 49, 75, 76, 80, 92, 93, and 96. This assay combines two different techniques: multiplex PCR using HPV type-specific primers for amplification of each E7 gene and array primer extension (APEX) for typing. This method has been validated using clinical samples which were analyzed simultaneously for the presence of cutaneous HPV types by two additional methods, i.e., the FAP59/64 PCR protocol and a commercially available PCR-reverse hybridization assay (PM-PCR RHA). Our data show good agreement between the results obtained with the multiplex PCR/APEX assay and the PM-PCR RHA method (overall HPV positivity of 92.2% for multiplex PCR/APEX assay versus 90.6% with the PM-PCR RHA) (kappa value, 50; 95% confidence interval, 13 to 88). In addition, the multiplex PCR/APEX assay showed higher sensitivity than the PM-PCR RHA did. This favorable feature and the high-throughput potential make this assay ideal for large-scale clinical and epidemiological studies aimed at determining the spectrum of cutaneous types in skin cancer
    Type of Publication: Journal article published
    PubMed ID: 17581938
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  • 5
    Keywords: CANCER ; EXPRESSION ; proliferation ; tumor ; CELL ; human ; CLASSIFICATION ; SYSTEM ; GENE ; PROTEIN ; PROTEINS ; ACCUMULATION ; MICE ; ACTIVATION ; primary ; KERATINOCYTES ; SKIN ; BIOLOGY ; E7 ; MOLECULAR-BIOLOGY ; papillomavirus ; skin cancer ; ABERRATIONS ; p53 ; human papillomavirus ; FRANCE ; HPV ; BETA ; E6 ; HPV16 ; HUMAN-PAPILLOMAVIRUS ; ONCOPROTEIN ; SQUAMOUS-CELL CARCINOMAS ; OVEREXPRESSION ; GENOMIC INSTABILITY ; SKIN-CANCER ; ORDER ; molecular biology ; molecular ; RE ; TUMOR-SUPPRESSOR ; GENOMIC ABERRATIONS ; mRNA ; CHROMOSOMAL INSTABILITY ; LEVEL ; SUPPRESSOR ; TELOMERASE ACTIVITY ; USA ; Delta Np73 ; nonmelanoma skin cancer ; PREVENTS ; retinoblastoma ; telomere dysfunction ; viral ; REVERSE-TRANSCRIPTASE HTERT ; CELL BIOLOGY ; ECTOPIC EXPRESSION ; tumor suppressor ; viral proteins ; HPV38 ; genomic aberration ; chromosomal abnormalities ; HPV38 E6 and E7 ; telomere dysfunctions
    Abstract: The skin human papillomavirus (HPV) types belonging to the genus beta of the HPV phylogenetic tree appear to be associated with nonmelanoma skin cancer. We previously showed that the beta HPV type 38 E6 and E7 oncoproteins are able to inactivate the tumor suppressors p53 and retinoblastoma. Here, both viral proteins were expressed in primary human skin keratinocytes in order to study their effects on the telomere/telomerase system. We show that immortalization of skin keratinocytes induced by HPV38 E6/E7 is associated with hTERT gene overexpression. This event is, in part, explained by the accumulation of the p53-related protein, Delta Np73. Despite elevated levels of hTERT mRNA, the telomerase activity detected in HPV38 E6/E7 keratinocytes was lower than that observed in HPV16 E6/E7 keratinocytes. The low telomerase activation in highly proliferative HPV38 E6/E7 keratinocytes resulted in the presence of extremely short and unstable telomeres. In addition, we observed anaphase bridges, mitotic multipolarity, and dramatic genomic aberrations. Interestingly, the ectopic expression of hTERT prevents both telomere erosion and genomic instability. Thus, we showed that in HPV38 E6/E7 keratinocytes characterized by unscheduled proliferation, suboptimal activation of telomerase and subsequent extensive telomere shortening result in genomic instability facilitating cellular immortalization
    Type of Publication: Journal article published
    PubMed ID: 17898088
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  • 6
    Keywords: CANCER ; CLASSIFICATION ; DNA ; INFECTION ; papillomavirus ; NEOPLASIA ; prevention ; AMPLIFICATION ; WOMEN ; cervical cancer ; CERVICAL-CANCER ; PCR ; human papillomavirus ; HPV ; PREVALENCE ; WORLDWIDE ; METAANALYSIS ; CANCERS ; HUMAN PAPILLOMAVIRUSES ; Central India
    Abstract: Cervical cancer that is associated with high-risk human papillomaviruses (HPV) is the most common malignancy in Indian women. Therefore, the establishment of a prevention program is urgently required considering both vaccination and screening. However, relatively little is known about the prevalence of the different HPV types in cervical cancers in different regions of India, particularly central India. In this study, we have determined the HPV type distribution in 180 cervical cancers of women from Sevagram, a rural area from central India. In addition, we have analyzed other epithelial cancers that are known to be in part associated with high-risk HPV infection, i.e. oral (n = 65), vulva and vagina (n = 7) and penis (n = 7). Approximately 93% of cervical cancers were positive for one or more of the high-risk HPV types. HPV16 was the predominant type being present in 81.7% of the cases. The remaining most predominant high-risk HPV types were: 18, 31,35,45, 56 and 59. Oral and vulva/vagina cancers were exclusively associated with HPV16, 27.7% and 70%, respectively. None of penile cancers was found positive for any of the high-risk HPV types. These data show that HPV16 vaccination in this geographical region will have considerable impact on the prevention of cervical and other epithelial cancers. (C) 2008 Elsevier Ltd. All rights reserved
    Type of Publication: Journal article published
    PubMed ID: 19056450
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  • 7
    Keywords: LUNG-CANCER ; RISK-FACTORS ; BIOMARKERS ; POLYMORPHISMS ; SUSCEPTIBILITY LOCUS ; DNA methylation ; adenocarcinoma ; TRACT ; HELICOBACTER-PYLORI ; DIETARY FACTORS ; gastric cancer ; prospective study ; CPG ISLAND HYPERMETHYLATION ; GLYCINE N-METHYLTRANSFERASE
    Abstract: Epigenetic events have emerged as key mechanisms in the regulation of critical biological processes and in the development of a wide variety of human malignancies, including gastric cancer (GC), however precise gene targets of aberrant DNA methylation in GC remain largely unknown. Here, we have combined pyrosequencing-based quantitative analysis of DNA methylation in 98 GC cases and 64 controls nested within the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort and in cancer tissue and non-tumorigenic adjacent tissue of an independent series of GC samples. A panel of 10 cancer-associated genes (CHRNA3, DOK1, MGMT, RASSF1A, p14ARF, CDH1, MLH1, ALDH2, GNMT and MTHFR) and LINE-1 repetitive elements were included in the analysis and their association with clinicopathological characteristics (sex, age at diagnosis, anatomical sub-site, histological sub-type) was examined. Three out of the 10 genes analyzed exhibited a marked hypermethylation, whereas two genes (ALDH2 and MTHFR) showed significant hypomethylation, in gastric tumors. Among differentially methylated genes, we identified new genes (CHRNA3 and DOK1) as targets of aberrant hypermethylation in GC, suggesting that epigenetic deregulation of these genes and their corresponding cellular pathways may promote the development and progression of GC. We also found that global demethylation of tumor cell genomes occurs in GC, consistent with the notion that abnormal hypermethylation of specific genes occurs concomitantly with genome-wide hypomethylation. Age and gender had no significant influence on methylation states, but an association was observed between LINE-1 and MLH1 methylation levels with histological subtype and anatomical sub-site. This study identifies aberrant methylation patters in specific genes in GC thus providing information that could be exploited as novel biomarkers in clinics and molecular epidemiology of GC.
    Type of Publication: Journal article published
    PubMed ID: 21831520
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  • 8
    Keywords: CANCER ; EXPRESSION ; IN-VITRO ; proliferation ; tumor ; carcinoma ; human ; IN-VIVO ; MODEL ; VITRO ; EXPOSURE ; GENE ; GENES ; PROTEIN ; PROTEINS ; TUMORS ; LINES ; MICE ; CARCINOGENESIS ; CONTRAST ; KERATINOCYTES ; SKIN ; cell cycle ; CELL-CYCLE ; CYCLE ; E7 ; papillomavirus ; SUSCEPTIBILITY ; TRANSGENIC MICE ; PROGRESSION ; PROMOTER ; LINE ; human papillomavirus ; LIFE-SPAN ; E6 ; HUMAN KERATINOCYTES ; keratin ; SQUAMOUS-CELL CARCINOMA ; CARCINOMAS ; REPLICATION ; squamous cell carcinoma ; HUMAN-PAPILLOMAVIRUS TYPE-16 ; SQUAMOUS-CELL CARCINOMAS ; epidermis ; immunosuppression ; RE ; immortalization ; keratinocyte ; CARCINOGEN ; ONCOGENESIS ; CHECKPOINT ; EPIDERMODYSPLASIA-VERRUCIFORMIS ; LIFE ; HYPERPLASIA ; LEVEL ; EVENTS ; BOVINE ; chemical carcinogenesis ; CYCLE ARREST ; DYSPLASIA
    Abstract: The oncoproteins E6 and E7 of human papillomavirus type 38 (HPV38) display several transforming activities in vitro, including immortalization of primary human keratinocytes. To evaluate the oncogenic activities of the viral proteins in an in vivo model, we generated transgenic mice expressing HPV38 E6 and E7 under the control of the bovine homologue of the human keratin 10 (K10) promoter. Two distinct lines of HPV38 E6/E7-expressing transgenic mice that express the viral genes at different levels were obtained. In both lines, HPV38 E6 and E7 induced cellular proliferation, hyperplasia, and dysplasia, in the epidermis. The rate of occurrence of these events was proportional to the levels of HPV38 E6 and E7 expression in the two transgenic lines. Exposure of the epidermis of nontransgenic mice to UV led to p21(WAF1) accumulation and cell cycle arrest. In contrast, keratinocytes from transgenic mice continued to proliferate and were not positive for p21(WAF1), indicating that cell cycle checkpoints are altered in keratinocytes expressing the viral genes. Although the HPV38 E6/E7-expressing transgenic mice did not develop spontaneous tumors during their life span, two-stage carcinogen treatment led to a high incidence of papillomas, keratoacanthomas, and squamous-cell carcinomas in HPV38 mice compared with nontransgenic animals. Together, these data show that HPV38 E6 and E7 display transforming properties in vivo, providing further support for the role of HPV38 in carcinogenesis
    Type of Publication: Journal article published
    PubMed ID: 16282489
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  • 9
    ISSN: 0378-1119
    Keywords: B2 mouse repeat ; Recombinant DNA ; cloning ; enhancers ; nucleotide sequencing ; origin of replication ; recombination
    Source: Elsevier Journal Backfiles on ScienceDirect 1907 - 2002
    Topics: Biology
    Type of Medium: Electronic Resource
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  • 10
    ISSN: 0888-7543
    Source: Elsevier Journal Backfiles on ScienceDirect 1907 - 2002
    Topics: Biology , Medicine
    Type of Medium: Electronic Resource
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