Human Papillomavirus Type 8 E2 Protein Unravels JunB/Fra-1 as an Activator of the β4-Integrin Gene in Human Keratinocytes

Ołdak, Monika; Maksym, Radosław; Sperling, Tanya; Yaniv, Moshe; Smola, Hans; Pfister, Herbert; Malejczyk, Jacek; Smola, Sigrun

doi:10.1128/jvi.01220-09

Cited by 21 publications

(21 citation statements)

References 48 publications

(56 reference statements)

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“…However, to date only a limited number of genes are validated to be regulated by E2. These include MMP-9 (Behren et al, 2005), hTERT (Lee et al, 2002), SF2/ASF (Klymenko et al, 2016; Mole et al, 2009), IL-10 (Bermudez-Morales et al, 2011), p21 (Steger et al, 2002), involucrin (Hadaschik et al, 2003), β 4-integrin (Oldak et al, 2010) and most recently c-Fos (Delcuratolo et al, 2016). Brd4 is necessary for E2’s function as a transcriptional activator when E2BS is positioned away from the promoter-proximal region in an enhancer-like sequence context (Lee and Chiang, 2009) as found in CRPV (see Fig.…”

Section: Brd4 and E2 In The Regulation Of Cellular Genes And Theirmentioning

confidence: 99%

Involvement of Brd4 in different steps of the papillomavirus life cycle

Iftner¹,

Haedicke‐Jarboui²,

et al. 2017

Virus Research

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Bromodomain-containing protein 4 (Brd4) is a cellular chromatin-binding factor and transcriptional regulator that recruits sequence-specific transcription factors and chromatin modulators to control target gene transcription. Papillomaviruses (PVs) have evolved to hijack Brd4’s activity in order to create a facilitating environment for the viral life cycle. Brd4, in association with the major viral regulatory protein E2, is involved in multiple steps of the PV life cycle including replication initiation, viral gene transcription, and viral genome segregation and maintenance. Phosphorylation of Brd4, regulated by casein kinase II (CK2) and protein phosphatase 2A (PP2A), is critical for viral gene transcription as well as E1- and E2-dependent origin replication. Thus, pharmacological agents regulating Brd4 phosphorylation and inhibitors blocking phospho-Brd4 functions are promising candidates for therapeutic intervention in treating human papillomavirus (HPV) infections as well as associated disease.

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Section: Brd4 and E2 In The Regulation Of Cellular Genes And Theirmentioning

confidence: 99%

Involvement of Brd4 in different steps of the papillomavirus life cycle

Iftner¹,

Haedicke‐Jarboui²,

et al. 2017

Virus Research

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“…RTS3b cells were seeded onto 10-cm dishes (1 ϫ 10 6 ), transfected with 1.3 g pALuc-HPV8NCR and 12 g IRF-7⌬247-467 in pFlag-CMV2 or the respective control vectors, using Fugene 6 transfection reagent (Roche) according to the manufacturer's protocol, and used for chromatin immunoprecipitation (ChIP) analysis. After 24 h, cells were trypsinized and then pelleted at 240 ϫ g for 5 min, and ChIP was performed according to the protocol of the ChIP assay kit from Upstate Biotechnology (Lake Placid, NY), as described previously (30). The cleared supernatant was incubated overnight at 4°C with 2 g of anti-IRF-7 (H-246) (sc-9083; Santa Cruz) or rabbit IgG (Chromopure, Dianova, Germany) antibodies.…”

Section: Methodsmentioning

confidence: 99%

Differential Regulation of Human Papillomavirus Type 8 by Interferon Regulatory Factors 3 and 7

Ołdak

Tolzmann

Wnorowski

et al. 2011

J Virol

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The genus ␤ human papillomavirus (HPV) type 8 is associated with nonmelanoma skin cancer in patients with epidermodysplasia verruciformis, and evidence for its protumorigenic potential in the general population increases. To date, strategies to suppress genus ␤ HPV infections are limited. Interferon regulatory factors IRF-3 and IRF-7 play key roles in the activation of the innate immune response to viral infections. In this study, we show for the first time that both IRF-3 and IRF-7 regulate transcription of a papillomavirus, but with opposing effects. IRF-7, expressed in the suprabasal layers of human epidermis, increased HPV8 late promoter activity via direct binding to viral DNA. UV-B light-induced activation of the HPV8 promoter involved IRF-7 as a downstream effector. In contrast, IRF-3, expressed in all layers of human epidermis, induced strong HPV8 suppression in primary keratinocytes. IRF-3-mediated suppression prevailed over IRF-7-induced HPV8 transcription. Unlike the E6 oncoprotein of the mucosal high-risk HPV16, the HPV8 E6 protein did not bind to IRF-3 and only weakly antagonized its activity. Strong antiviral activity was also observed, when keratinocytes were treated with potent IRF-3 activators, poly(I:C) or RNA bearing 5 phosphates. In conclusion, we show that IRF-3 activation induces a state of cell-autonomous immunity against HPV in primary human keratinocytes. Our study suggests that local application of IRF-3-activating compounds might constitute an attractive novel therapeutic strategy against HPV8-associated diseases, particularly in epidermodysplasia verruciformis patients.Human papillomaviruses (HPVs) are small DNA viruses that infect epithelial cells of skin and mucosa. Depending on the oncogenic potential of particular HPV types and specific sites of infection, lesions induced by HPVs range from benign warts to invasive carcinoma. High-risk mucosal HPV types 16 and 18 have a well-established role in anogenital carcinogenesis, in particular in the development of cervical carcinoma (47). Anogenital condylomas are caused by HPV types 6 and 11. Infection with cutaneous genus ␤ HPV (i.e., type 5 or 8) is involved in the development of nonmelanoma skin cancer at sites exposed to the sun. This was first discovered in patients with the inherited disease epidermodysplasia verruciformis (EV). However, there is increasing evidence that genus ␤ HPV types play a role in the development of squamous and basal cell carcinoma in immunocompromised individuals and in the general population (16a, 34). The carcinogenic potential of HPV8 has been documented in a HPV8-transgenic mouse model (40). In the murine epidermis, the HPV8 E6 protein represents the major oncoprotein necessary and sufficient to induce spontaneous tumor development (25).The life cycle of HPVs is tightly linked to the differentiation program of epithelial cells. To indicate the sequence of viral gene expression during the HPV life cycle, viral gene products have been classified as early (E) and late (L) proteins. Their transcription is i...

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“…Nuclear extracts from stimulated monocytes were prepared and NF-kB or AP-1 binding activities were determined in electromobility shift analysis as previously described (23,24).…”

Section: Electromobility Shift Analysismentioning

confidence: 99%

Molecular Pathobiology of Human Cervical High-Grade Lesions: Paracrine STAT3 Activation in Tumor-Instructed Myeloid Cells Drives Local MMP-9 Expression

et al. 2011

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In many tumors, the switch from precancerous lesions to malignancy critically relies on expression of the matrix-metalloprotease MMP-9, which is predominantly provided by infiltrating inflammatory cells. Our study defines a novel molecular cascade, how human neoplastic cells instruct tumor-associated myeloid cells to produce MMP-9. In biopsies of human papillomavirus-associated precancerous cervical intraepithelial neoplasia (CIN III lesions), we show broad activation of the transcription factor STAT3 and coexpression of MMP-9 in perivascular inflammatory cells. For the first time, we establish a causative link between tumor-mediated paracrine STAT3 activation and MMP-9 production by human tumor-instructed monocytes, whereas NF-kB activation is dispensable for this response. Our data provide evidence that STAT3 does not directly induce MMP-9 but first leads to a strong production of the monocyte chemoattractant protein-1 (CCL2) in the nanogram range. In a second phase, autocrine stimulation of the CCR2 receptor in the tumor-instructed monocytes amplifies MMP-9 expression via intracellular Ca 2þ signaling. These findings elucidate a critical mechanism in the molecular pathobiology of cervical carcinogenesis at the switch to malignancy. Particularly in tumors, which are associated with infectious agents, STAT3-driven inflammation may be pivotal to promote carcinogenesis, while at the same time limit NF-kB-dependent immune responses and thus rejection of the infected preneoplastic cells. The molecular cascade defined in this study provides the basis for a rational design of future adjuvant therapies of cervical precancerous lesions.

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Human Papillomavirus Type 8 E2 Protein Unravels JunB/Fra-1 as an Activator of the β4-Integrin Gene in Human Keratinocytes

Cited by 21 publications

References 48 publications

Involvement of Brd4 in different steps of the papillomavirus life cycle

Involvement of Brd4 in different steps of the papillomavirus life cycle

Differential Regulation of Human Papillomavirus Type 8 by Interferon Regulatory Factors 3 and 7

Molecular Pathobiology of Human Cervical High-Grade Lesions: Paracrine STAT3 Activation in Tumor-Instructed Myeloid Cells Drives Local MMP-9 Expression

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