Transcriptional Control and Cell Type Specificity of HPV Gene Expression

Bernard, Hans‐Ulrich; Apt, Doris

doi:10.1001/archderm.1994.01690020076013

Cited by 37 publications

(13 citation statements)

References 48 publications

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“…Moreover, mutation of the AP1 site (AP1-5) inactivates the promoter. AP1 has been shown to be an important regulator in several genes that are expressed in a differentiation-dependent manner in surface epithelia (38,40,(43)(44)(45)(46)(47)(48)(49)(50)(51)(52)(53)(54)(55). Based on these results and the observation that the DRR is necessary and sufficient for expression, we hypothesize that the DRR AP1 site (AP1-5) is required for expression.…”

Section: Regulation Of Hinv Expression In Epidermis-identifyingmentioning

confidence: 87%

The Distal Regulatory Region of the Human Involucrin Promoter Is Required for Expression in Epidermis

Crish¹,

Zaim²,

Eckert³

1998

Journal of Biological Chemistry

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Epidermal keratinocytes undergo a program of differentiation that results in assembly of the epidermis (1). This differentiation process involves a series of morphological and biochemical changes that are tightly controlled and involve specific temporal and spatial changes in gene expression (1-3). These changes include activation of the gene that encodes human involucrin (hINV).1 Involucrin is not expressed in the basal epidermal layer, but expression is activated in the late spinous layer and continues in the granular layer (4, 5). Involucrin is an ␣-helical, rod-shaped, 68 kilodalton, glutamine-and glutamic acid-rich structural protein that is an efficient transglutaminase substrate (6 -9). During the final stages in keratinocyte differentiation, involucrin is incorporated, via the formation of interprotein ⑀-(␥-glutamyl)lysine cross-links with other proteins, into the keratinocyte cornified envelope (10). This envelope provides an essential protective barrier (11)(12)(13)(14). Involucrin play a similar role in other stratifying epithelia, including esophagus, cornea, ectocervix, vagina, etc. (15, 16). In each tissue, expression is confined to the suprabasal layers. We are interested in the regulation of hINV expression and identification of the regulatory elements responsible for the tissuespecific and differentiation-appropriate expression in these tissues. Recent studies indicate that a 6-kb segment of the hINV gene, including the hINV upstream regulatory region, the intron, and the coding sequence, targets expression to the appropriate tissues (16). Targeted expression is also observed when the upstream regulatory region is linked to the SV40 intron and ␤-galactosidase (17). In vitro studies show that the promoter is expressed in cells derived from stratifying epithelia (18,19), is regulated by agents that modulate differentiation (18 -20), and is not expressed in fibroblasts (18). Deletion mapping and point mutation studies identify two regions of the upstream regulatory region, the proximal regulatory region (PRR) and the distal regulatory region (DRR), that are required for optimal expression in cultured cells (18,19). Both the DRR and PRR contain AP1 sites, AP1-5 and AP1-1, respectively, that are required for optimal promoter activity (18). In addition, the PRR contains an Sp1 site that synergistically activates expression in conjunction with the AP1-5 site (19). In the present study, we evaluate the role of the DRR in mediating in vivo expression using a transgenic mouse model. Among other findings, we demonstrate that the DRR is necessary and sufficient for expression of the transgene in epidermis and other stratifying epithelia. MATERIALS AND METHODS Construction of hINV Transgenes-E13E was constructed byEcoRI digestion of phage, Charon 4AI-3 (21). A 13-kb EcoRI fragment was then subcloned into pBKS(ϩ) to yield pBKS-E13E. The EcoRI insert from this plasmid is shown in Fig. 1. The H6B transgene is a 6-kb HindIII/BamHI fragment that was derived by restricting Charon 4AI-3 with HindIII/BamHI and subcl...

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Section: Regulation Of Hinv Expression In Epidermis-identifyingmentioning

confidence: 87%

The Distal Regulatory Region of the Human Involucrin Promoter Is Required for Expression in Epidermis

Crish¹,

Zaim²,

Eckert³

1998

Journal of Biological Chemistry

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“…Regarding host regulatory proteins that bind to the viral URR, the transcription factor AP-1 plays an essential role in determining both the efficiency of HPV expression (4,16,63) and the phenotype of HPV-positive cells in nude mice (5,29). Monitoring AP-1 in comparison with other transcription factors within the viral enhancer and promoter region, decreased binding was only detectable for AP-1, whereas Oct-1/KRF-1 and Sp-1, each participating in the transcriptional regulation of the E6/E7 promoter (4), were not affected (Fig.…”

Section: Kipmentioning

confidence: 99%

“…AP-1 is a key element in a regulatory network, playing not only a fundamental role in transcriptional regulation of various HPVs (15,16), but also in cell proliferation and tumor induction (5,17). In the presence of ligands, RARs or RAR/RXR can negatively affect AP-1 either by a direct interaction with Jun/Fos family members (18) or by disrupting Jun-Fos dimerization (19).…”

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confidence: 99%

Retinoic Acid Receptor β Silences Human Papillomavirus-18 Oncogene Expression by Induction of de Novo Methylation and Heterochromatinization of the Viral Control Region

Arce

Göckel-Krzikalla

Rösl

2007

Journal of Biological Chemistry

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Retinoic acid receptor ␤2 (RAR␤2) is often down-regulated during the multistep process to cervical cancer. In that way, its inhibitory function on the transcription factor AP-1, indispensable to maintain human papillomavirus (HPV) gene expression is relieved. Using HPV-18 positive HeLa cells as a model system, we show that ectopic expression of RAR␤2 is able to down-regulate HPV-18 transcription by selectively abrogating the binding of AP-1 to the viral regulatory region in a ligandindependent manner. This resulted in down-regulation of the viral mRNAs at the level of initiation of transcription. Decreased oncogene expression was accompanied by a re-induction of cell cycle inhibitory proteins such as p53, p21 CIP1 , and p27 KIP as well as by a cessation of cellular growth. Reduced transcriptional activity as a consequence of AP-1 reduction by selective c-Jun degradation apparently targets the HPV-18 regulatory region for epigenetic modification such as de novo methylation and nucleosomal condensation. This mechanism is otherwise counterbalanced by active and abundant viral transcription in malignant cells, because RAR␤2 itself becomes inactivated during cervical carcinogenesis. Hence, our study shows that the temporal co-existence of a potential repressor and viral oncoproteins is mutually exclusive and provides evidence of a cross-talk between a nuclear receptor, AP-1, and the epigenetic machinery.Cancer is a multistep process that is characterized by accumulation of various cell-damaging events such as chromosomal instabilities, inactivation of cell cycle regulatory proteins, and epigenetic modifications (1, 2). In the case of cervical cancer, the second leading malignancy in women worldwide, certain types of human papillomaviruses (HPV) 2 have been identified as etiological agents being involved both in initiation and maintenance of the transformed phenotype (3). The transcription of the viral oncogenes E6 and E7 is controlled by the viral upstream regulatory region (URR), harboring the tissue-specific enhancer and promoter elements (4). Here, beside other cellular transcription factors, activator protein-1 (AP-1) is the main regulator determining the efficiency of expression and in turn the intracellular net amount of the viral oncoproteins E6/E7 (5).As shown for many malignant cells, including HPV-positive cervical cancer cells, the retinoic acid receptor (RAR) ␤2 gene (RAR␤2), the most potent RAR involved in suppression of tumor-related phenotypes (6, 7), is epigenetically silenced via de novo methylation and chromatin remodeling (8). In other words, the absence of RAR␤ provides a selective advantage during multistep progression to cervical cancer, because the gene is obviously not compatible with unscheduled cell proliferation (9, 10). Indeed, re-introduction of RAR␤ into malignant cells interferes with anchorage-independent growth (6, 11) and diminishes tumor formation upon heterotransplantation into immunocompromised animals (12). Together with other isotypes of retinoid acid receptors (␣ and ␥) or reti...

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“…This is of particular interest in the context of HPV-induced cancer, where AP-1 plays a major role both in viral transcriptional regulation and in proliferation of cervical cancer cells (11,12,28,29). Considering that both RAR␤ clones showed reduced steadystate levels of endogenous HPV18 E6/E7 expression that corresponded to slower growth rates when compared with parental HeLa cells (data not shown), we reasoned that constitutive expression of nonliganded RAR␤ might act via this pathway, namely by negatively affecting AP-1 activity.…”

Section: Ectopic Rar␤ Expression In Helamentioning

confidence: 99%

“…This important trans-repressive function is mediated by inhibition of the AP-1 (activator protein 1) (10). The transcription factor AP-1, which consists of a complex of homo-or heterodimers of the Jun/Fos family members, is a central regulatory key element, playing not only a fundamental role in transcriptional regulation of human papillomaviruses (11,12) but also exhibiting enhanced activity during cell proliferation and tumor progression (13,14). AP-1 activity is mainly determined by its composition as a dimer, by its affinity to a responsive element within a particular promoter, and by post-translational modification through mitogen-activated protein (MAP) kinases (15).…”

mentioning

confidence: 99%

Ectopic Expression of Nonliganded Retinoic Acid Receptor β Abrogates AP-1 Activity by Selective Degradation of c-Jun in Cervical Carcinoma Cells

Arce

Soto

Riggelen

et al. 2004

Journal of Biological Chemistry

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Transcriptional Control and Cell Type Specificity of HPV Gene Expression

Cited by 37 publications

References 48 publications

The Distal Regulatory Region of the Human Involucrin Promoter Is Required for Expression in Epidermis

The Distal Regulatory Region of the Human Involucrin Promoter Is Required for Expression in Epidermis

Retinoic Acid Receptor β Silences Human Papillomavirus-18 Oncogene Expression by Induction of de Novo Methylation and Heterochromatinization of the Viral Control Region

Ectopic Expression of Nonliganded Retinoic Acid Receptor β Abrogates AP-1 Activity by Selective Degradation of c-Jun in Cervical Carcinoma Cells

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