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  • 1
    Keywords: PEPTIDE ; APOPTOSIS ; TUMOR-CELLS ; Germany ; human ; INHIBITION ; PROTEIN ; PROTEINS ; MECHANISM ; DOMAIN ; CYCLE ; virus ; E6 ; ONCOPROTEIN ; REPLICATION ; BODY ; INHIBITORS ; AGGREGATION ; LIFE ; GENETIC SELECTION ; BLOCKS ; function ; SIGNALS ; E6 PROTEIN ; CORE-PROTEIN
    Abstract: Peptide aptamers (PAs) can be employed to block the intracellular function of target proteins. Little is known about the mechanism of PA-mediated protein inhibition. Here, we generated PAs that specifically bound to the duck hepatitis B virus (HBV) core protein. Among them, PA34 strongly blocked duck HBV replication by inhibiting viral capsid formation. We found that PA34 led to a dramatic intracellular redistribution of its target protein into perinuclear inclusion bodies, which exhibit the typical characteristics of aggresomes. As a result, the core protein is efficiently removed from the viral life cycle. Corresponding findings were obtained for bioactive PAs that bind to the HBV core protein or to the human papillomavirus-16 (HPV16) E6 protein, respectively. The observation that PAs induce the specific sequestration of bound proteins into aggresomes defines a novel mechanism as to how this new class of intracellular inhibitors blocks the function of their target proteins
    Type of Publication: Journal article published
    PubMed ID: 16717089
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  • 2
    Keywords: CANCER ; CANCER CELLS ; CELLS ; EXPRESSION ; tumor ; carcinoma ; CELL ; Germany ; human ; INHIBITION ; GENE ; PROTEIN ; TISSUE ; CARCINOGENESIS ; DOWN-REGULATION ; E7 ; papillomavirus ; TARGET ; virus ; ELEMENT ; LESIONS ; PROMOTER ; cervical cancer ; CERVICAL-CANCER ; p53 ; GROWTH-INHIBITION ; human papillomavirus ; CANCER-CELLS ; HPV ; E6 ; ONCOGENE ; HPV16 ; HUMAN-PAPILLOMAVIRUS ; CARCINOMAS ; POSITIVE CANCER-CELLS ; TRANSLOCATION ; OVEREXPRESSION ; REPRESSION ; RETINOIC ACID ; E6 ONCOPROTEIN ; TUMOR-SUPPRESSOR ; papillomaviruses ; LEVEL ; tumor suppressor gene ; EPITHELIUM ; USA ; oncogenes ; B-CELL ; HUMAN PAPILLOMAVIRUSES ; tumor suppressor genes ; NOV ; tumor suppressor ; Luciferase reporter ; BTG2 ; cervical cancers ; viral carcinogenesis
    Abstract: Human papillomavirus (HPV)-induced carcinogenesis is critically dependent on the activities of the viral E6 and E7 oncogenes. Here, we demonstrate that expression of the putative tumor suppressor gene B-cell translocation gene-2 (BTG2) is reinduced in HPV16- and HPV18-positive cancer cells on silencing of viral oncogene expression, indicating that BTG2 is repressed by oncogenic HPVs. Inhibition of BTG2 expression was mediated by the HPV E6 oncogene and occurred in a p53-dependent manner. Luciferase reporter gene analyses revealed that BTG2 repression takes place at the transcriptional level and is dependent on the integrity of the major p53-response element within the BTG2 promoter. Ectopic expression of BTG2 acted antiproliferative in cervical cancer cells. Tissue specimens commonly exhibited reduced BTG2 protein levels in HPV-positive high-grade lesions (CIN2/3) and cervical carcinomas, when compared with normal cervical epithelium. These findings identify the antiproliferative BTG2 gene as a novel cellular target blocked by the HPV E6 oncoprotein. (C) 2009 UICC
    Type of Publication: Journal article published
    PubMed ID: 19551855
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  • 3
    Keywords: APOPTOSIS ; PROTEIN ; INDUCTION ; ASSOCIATION ; CERVICAL-CANCER ; p53 ; POSITIVE CANCER-CELLS ; NUCLEAR-LOCALIZATION ; E6-MEDIATED DEGRADATION ; AGGRESOMES
    Abstract: Oncogenic types of human papillomaviruses (HPVs) cause cervical cancer and other malignancies in humans. The HPV E6 oncoprotein is considered to be an attractive therapeutic target since its inhibition can lead to the apoptotic cell death of HPV-positive cancer cells. The HPV type 16 (HPV16) E6-binding peptide pep11, and variants thereof, induce cell death specifically in HPV16-positive cancer cells. Although they do not encompass the LxxLL binding motif found in cellular HPV16 E6 interaction partners, such as E6AP, the pep11 variants strongly bind to HPV16 E6 by contacting the recently identified E6AP binding pocket. Thus, these peptides can serve as prototype E6-inhibitory molecules which target the E6AP pocket. We here analyzed their intracellular interaction with HPV16 E6. By comprehensive intracellular binding studies and GST pull-down assays, we show that E6-binding competent pep11 variants induce the formation of a trimeric complex, consisting of pep11, HPV16 E6 and p53. These findings indicate that peptides, which do not contain the LxxLL motif, can reshape E6 to enable its interaction with p53. The formation of the trimeric HPV16 E6 / peptide / p53 complex was associated with an increase of endogenous HPV16 E6 protein amounts. Yet, total cellular p53 amounts were also increased, indicating that the E6 / E6AP-mediated degradation of p53 is blocked. These findings suggest that inhibition of oncogenic activities by targeting the E6AP pocket on HPV16 E6 could be a strategy for therapeutic intervention.
    Type of Publication: Journal article published
    PubMed ID: 26151636
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  • 4
    Keywords: CANCER ; CELLS ; EXPRESSION ; GROWTH ; GROWTH-FACTOR ; carcinoma ; Germany ; INHIBITION ; GENE ; PROTEIN ; PROTEINS ; LINES ; INFECTION ; MECHANISM ; prognosis ; CARCINOGENESIS ; mechanisms ; CELL-LINES ; E7 ; DELETION ; LESIONS ; PROGRESSION ; CARCINOMA CELLS ; WOMEN ; COLORECTAL-CANCER ; CERVICAL-CANCER ; LINE ; TUMOR-SUPPRESSOR GENE ; human papillomavirus ; CARCINOMA-CELLS ; BETA ; CERVICAL-CARCINOMA ; CARCINOMAS ; squamous cell carcinoma ; intraepithelial neoplasia ; UTERINE CERVIX ; GROWTH-FACTOR-BETA ; POOR-PROGNOSIS ; cell lines ; GENOMIC INSTABILITY ; FACTOR-BETA ; molecular ; DEFICIENCY ; TUMOR-SUPPRESSOR ; TUMOR-GROWTH ; TGF-BETA ; MOLECULAR-MECHANISMS ; RESPONSIVENESS ; carcinoma cell ; CIN lesion ; cytogenetic ; DPC4 INACTIVATION ; multistep carcinogenesis ; PAPILLOMAVIRUS INFECTIONS ; SUPPRESSOR ; TGF beta ; tumor suppressor gene
    Abstract: Squamous cell carcinoma of the uterine cervix is one of the most frequent cancers affecting women worldwide. Carcinomas arise from cervical intraepithelial lesions, in which infection with high-risk human papillomavirus types has led to deregulated growth control through the actions of the viral E6 and E7 oncoproteins. The molecular mechanisms underlying progression to invasive tumor growth are poorly understood. One important feature, however, is the escape from growth inhibition by transforming growth factor beta (TGF-beta). Loss of chromosomal arm 18q is among the most frequent cytogenetic alterations in cervical cancers and has been associated with poor prognosis. Since the TGF-beta response is mediated by Smad proteins and the tumor suppressor gene Smad4 resides at 18q21, we have analysed the Smad4 gene for cervical cancer-associated alterations in cell lines and primary carcinomas. Here, we report Smad4 deficiency in four out of 13 cervical cancer cell lines which is due to an intronic rearrangement or deletions of 30 exons. All cell lines, however, showed either absent or moderate responsiveness to TGF-beta irrespective of their Smad4 status. In 41 primary squamous cervical carcinomas analysed, 10 samples showed loss of Smad4 protein expression and 26 samples a reduced expression. Altogether, our results strongly suggest that Smad4 gene alterations are involved in cervical carcinogenesis
    Type of Publication: Journal article published
    PubMed ID: 15531914
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  • 5
    Keywords: DNA ; hepatocytes ; X-PROTEIN ; cytomegalovirus ; CORE-PROTEIN ; P38 MAP KINASE ; MOFETIL ; IMMUNOSUPPRESSIVE AGENT LEFLUNOMIDE ; KINASE SIGNALING PATHWAYS ; HUMAN HEPATOMA-CELL
    Abstract: The inhibitors of pyrimidine synthesis, leflunomide and FK778, have been reported to exert broad antiviral effects, in addition to their immunosuppressive activities. Their possible therapeutic benefit for transplantation medicine is currently discussed, because they also block the replication of human cytomegalovirus and human polyomavirus BK, which both cause important complications in transplant recipients. Here, we show that leflunomide and FK778 strongly enhance hepatitis B virus (HBV) replication in vitro. This activity is shared by mycophenolic acid (MPA), an inhibitor of purine biosynthesis. Stimulation of HBV replication by these agents was linked to their inhibitory effects on de novo nucleotide biosynthesis because it could be efficiently counteracted by external nucleoside supply. Mechanistically, we found that mitogen-activated protein kinase p38 played a key role for the enhancement of HBV replication by leflunomide, FK778, and MPA. All three HBV-activating compounds increased p38 phosphorylation, in contrast to the HBV inhibitors, telbivudine and cyclosporine A. Moreover, silencing of p38 expression through RNA interference efficiently counteracted the stimulatory effect of leflunomide, FK778, and MPA on HBV replication. Conclusion: Our data indicate that, in contrast to their reported inhibitory effects on other viruses, both leflunomide and FK778 can augment HBV replication. Treatment with leflunomide, FK778, or MPA may bear the risk to enhance HBV replication in infected patients.
    Type of Publication: Journal article published
    PubMed ID: 22271223
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  • 6
    Keywords: IN-VITRO ; PROSTATE-CANCER ; POSITIVE CANCER-CELLS ; OXIDATIVE STRESS ; TRANSCRIPTIONAL REGULATION ; RNA INTERFERENCE ; NUCLEAR-LOCALIZATION SIGNAL ; HIV-1 INTEGRASE ; INTEGRASE INTERACTOR LEDGF/P75 ; DNA-END RESECTION
    Abstract: The expression of the human papillomavirus (HPV) E6/E7 oncogenes is crucial for HPV-induced malignant cell transformation. The identification of cellular targets attacked by the HPV oncogenes is critical for our understanding of the molecular mechanisms of HPV-associated carcinogenesis and may open novel therapeutic opportunities. Here, we identify the Lens Epithelial-Derived Growth Factor (LEDGF) gene as a novel cellular target gene for the HPV oncogenes. Elevated LEDGF expression has been recently linked to human carcinogenesis and can protect tumor cells towards different forms of cellular stress. We show that intracellular LEDGF mRNA and protein levels in HPV-positive cancer cells are critically dependent on the maintenance of viral oncogene expression. Ectopic E6/E7 expression stimulates LEDGF transcription in primary keratinocytes, at least in part via activation of the LEDGF promoter. Repression of endogenous LEDGF expression by RNA interference results in an increased sensitivity of HPV-positive cancer cells towards genotoxic agents. Immunohistochemical analyses of cervical tissue specimens reveal a highly significant increase of LEDGF protein levels in HPV-positive lesions compared to histologically normal cervical epithelium. Taken together, these results indicate that the E6/E7-dependent maintenance of intracellular LEDGF expression is critical for protecting HPV-positive cancer cells against various forms of cellular stress, including DNA damage. This could support tumor cell survival and contribute to the therapeutic resistance of cervical cancers towards genotoxic treatment strategies in the clinic.
    Type of Publication: Journal article published
    PubMed ID: 24604027
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  • 7
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  • 9
    Keywords: CANCER ; tumor ; carcinoma ; Germany ; DIAGNOSIS ; HYBRIDIZATION ; TISSUE ; TUMORS ; PATIENT ; DNA ; INFECTION ; E7 ; papillomavirus ; ASSOCIATION ; PROGRESSION ; METASTASIS ; CERVICAL-CANCER ; metastases ; PCR ; human papillomavirus ; TYPE-16 ; HPV ; SQUAMOUS-CELL CARCINOMA ; HEAD ; CARCINOMAS ; POLYMERASE-CHAIN-REACTION ; NECK ; squamous cell carcinoma ; UTERINE CERVIX ; PREVALENCE ; CYCLE CONTROL ; NECK CANCERS ; NECK-CANCER ; CELL-CARCINOMA ; TISSUE SAMPLES ; head and neck squamous cell carcinoma ; Waldeyer's tonsillar ring
    Abstract: Conclusion. The results of this study corroborate earlier findings that human papillomavirus (HPV) 16 is the most prevalent type of HPV in squamous cell carcinomas of the head and neck (SCCHNs) and reinforce a possible influence of HPV on SCCHN progression by showing that the majority of HPV-positive patients harbor HPV16 ( or HPV33) both in their primary tumors and in lymph node neck metastases (LNNMs). Objective. HPVs are causally associated with carcinomas of the uterine cervix and have also been linked to a subset of SCCHNs. In order to further investigate the predicted causative role of HPV in SCCHNs, we analyzed pairs of primary tumors and LNNMs or LNNMs alone for the presence of HPV DNA using polymerase chain reaction (PCR). Material and methods. DNA was extracted from fresh frozen tissue samples of primary tumors and the corresponding LNNMs of 18 patients and from LNNMs alone in 17 patients. For the detection and typing of HPV, PCR was performed using both type-specific and consensus primer pairs, followed by Southern hybridization and, in selected cases, sequencing of the PCR products. Results. Of the 35 patients investigated, 22 (63%) were found to have HPV DNA in their tumors: HPV16 DNA in 21 cases and HPV33 in 1. The highest HPV prevalence was detected in tumors of Waldeyer's tonsillar ring (8/9 patients; 89%). Of the 18 patients in whom primary tumors and LNNMs were analyzed, 7 (39%) were HPV-positive in both samples ( HPV16, n = 6; HPV33, n = 1), in 3 (17%) the primary tumors were HPV-negative and the LNNMs HPV16-positive and in 1 (5.5%) the primary tumor contained HPV16 and the LNNM was negative. Interestingly, of the 7 patients in whom LNNMs had been detected only several months after diagnosis and treatment of the primary tumors, only 1 showed infection with HPV (HPV33)
    Type of Publication: Journal article published
    PubMed ID: 15823814
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  • 10
    Keywords: CANCER ; radiotherapy ; SURVIVAL ; carcinoma ; COMBINATION ; Germany ; human ; THERAPY ; DIAGNOSIS ; FOLLOW-UP ; TIME ; PATIENT ; DNA ; INFECTION ; prognosis ; tumour ; ASSOCIATION ; METASTASIS ; human papillomavirus ; PROGNOSTIC-FACTORS ; HPV ; HEAD ; CARCINOMAS ; POLYMERASE-CHAIN-REACTION ; PROGNOSTIC FACTORS ; NECK ; squamous cell carcinoma ; SQUAMOUS-CELL CARCINOMAS ; PREVALENCE ; CANCER PATIENTS ; PROGNOSTIC FACTOR ; LOCATION ; NECK-CANCER ; SUBSET ; head and neck cancer ; overall survival ; HNSCC ; PROGNOSTIC-FACTOR ; CELL-CARCINOMA ; statistical analysis ; Waldeyer's tonsillar ring ; lymph node neck metastasis ; prognosis of survival
    Abstract: Depending on the primary tumour's anatomical location, squamous cell carcinoma of the head and neck (HNSCC) shows HPV prevalences between 20 and 30% for oro-, hypopharyngeal as well as laryngeal SCC and up to over 50% for SCC of the Waldeyer's tonsillar ring. There is persistent controversy on the role of HPV infection in HNSCC-progression, and on the influence of these infections on the final clinical outcome. To evaluate the possible relevance of HPV infection on survival and prognosis, 73 patients with HNSCC were investigated statistically with a median follow-up time of 28 (0.3-94) months. The statistical analysis revealed no differences in the overall survival of HPV-positive and HPV-negative cancer patients. A correlation between decreased survival and increased lymph node status was expected. Patients with carcinomas of the Waldeyer's tonsillar ring with a high HPV prevalence rate as compared to tumours of other anatomical locations revealed a better survival. Moreover, an association between HPV positivity and higher lymph node status at time of first diagnosis, and a better survival of HPV-positive patients compared to HPV-negative patients given the same initial nodal status (N0 vs. N1-N2b vs. N2c-N3) could be demonstrated. The influence of HPV on the patient's survival can only be observed statistically in combination with other prognostic factors, as the lymph nodal status of the patients. The better prognosis of survival of HPV-positive vs. the HPV-negative patients with lymph node neck metastasis is attributable to a better response of the HPV-positive group to therapy, especially radiotherapy. (C) 2004 Elsevier Ireland Ltd. All rights reserved
    Type of Publication: Journal article published
    PubMed ID: 15670897
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