TAp63α indirectly regulates a cutaneous HPV promoter through complex formation with Jun family members

Fei, J-W; Angel, Peter; Wei, Q-X; Villiers, E-M de

doi:10.1038/sj.onc.1209420

Cited by 5 publications

(5 citation statements)

References 60 publications

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“…We suspect this may be due directly or indirectly to the action of ⌬Np63. While no miR-203 or ⌬Np63 binding sites are present in high-risk HPV types 31 and 16, ⌬Np63 has been shown to bind to sequences in the upstream regulatory region of the cutaneous, low-risk HPV type 20 (10,11). In HPV type 20, ⌬Np63 binding resulted in transcriptional activation, but it is possible that in other HPV types, p63 may act as a negative regulator.…”

Section: Discussionmentioning

confidence: 92%

Human Papillomaviruses Modulate Expression of MicroRNA 203 upon Epithelial Differentiation to Control Levels of p63 Proteins

Melar-New

Laimins

2010

J Virol

154

140

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Human papillomaviruses (HPV) link their life cycles to epithelial differentiation and induce productive replication of viral DNA in suprabasal cells. Viral-DNA amplification requires cells to remain active in the cell cycle upon differentiation. This is in contrast to normal cells, which lose proliferative capability upon differentiation. One factor that negatively regulates proliferative capability upon differentiation is microRNA 203 (miR-203), which is expressed primarily in suprabasal epithelial cells. Although HPVs do not encode their own microRNAs (miRNAs), they modulate expression of cellular miRNAs to regulate the activities of cellular proteins. We show that the HPV E7 protein downregulates miR-203 expression upon differentiation, which may occur through the mitogen-activated protein (MAP) kinase/protein kinase C (PKC) pathway. One target of miR-203 is the p63 family of transcription factors, and we demonstrate that HPV-positive cells maintain significantly higher levels of these factors upon differentiation than do normal keratinocytes. Several downstream targets of p63, CARM-1, p21, and Bax, were also increased in E7-expressing cells, and their levels were inversely correlated with amounts of miR-203. Introduction of expression vectors for miR-203 into keratinocytes that stably maintain HPV episomes resulted in short-term elevation of HPV genome copy numbers, but these were rapidly lost upon subsequent passage. When HPV-positive cells expressing high levels of miR-203 were induced to differentiate in methylcellulose, impaired genome amplification was observed. We conclude that high levels of miR-203 are inhibitory to HPV amplification and that HPV proteins act to suppress expression of this microRNA to allow productive replication in differentiating cells.

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Section: Discussionmentioning

confidence: 92%

Human Papillomaviruses Modulate Expression of MicroRNA 203 upon Epithelial Differentiation to Control Levels of p63 Proteins

Melar-New

Laimins

2010

J Virol

154

140

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“…In vitro studies demonstrated that activation of the HPV 20 promoter by p53 family members ΔNp63α and TAp63α, was mediated by complex formation of these proteins with c‐Jun. Wild type p53 or mutp52R248W suppressed this activation 38, 39. We continued to investigate interactions of HPV20E6 with cellular proteins in particular wtp53, mtp53R248W and ΔNp63α.…”

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confidence: 99%

Degradation of HPV20E6 by p53: ΔNp63α and mutant p53R248W protect the wild type p53 mediated caspase‐degradation

Fei

Villiers

2008

Intl Journal of Cancer

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The E6 and E7 proteins of human papillomaviruses (HPV) play a crucial role in the pathogenesis of malignant tumors. E6 protein of high-risk mucosal papillomaviruses targets a number of proteins for proteosomal degradation through complex formation with ubiquitin ligase E6AP. These proteins include, amongst others, p53, paxillin and PDZ-domain proteins e.g. Dlg and MAGUK. The mechanism by which the E6 protein of cutaneous HPV types interacts with cellular proteins to induce either benign or malignant cutaneous lesions, has not been elucidated, although extensive ultraviolet exposure and mutated p53 (hot-spot mutations) are known to be associated with non-melanoma skin cancer. We demonstrate two mechanisms in which HPV20E6 may be involved in the infected cell. One pathway is the wtp53 mediated degradation of HPV20E6 through caspase-3. Mutated p53R248W and DNp63a, as well as other unknown proteins involved in proteosome-dependent degradation, convey a protective effect on HPV20E6 under these conditions. This unveils a remarkable opposite regulation to the well-known mechanism of E6-E6AP mediated degradation of p53 for mucosal HPV types. In a second interaction, ectopically expressed HPV20E6 induces cleavage of procaspase-3 to active caspase-3. We demonstrate, in addition, in vivo binding of HPV20E6 to the intermediate filament vimentin.

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“…Our previous studies demonstrated interplay between UV-induced mutp53R248W, ΔNp63α and wtp53 in relation to the expression of HPV20E6. Wtp53 mediated the caspase-3-dependent degradation of HPV20E6 protein [13], [40], [59]. We now extended these investigations to other HPV types of the genera Beta-, Gamma-and Nu-papillomavirus.…”

Section: Discussionmentioning

confidence: 76%

“…Transfection efficiency was controlled for by β-galactosidase expression. (E) RT-PCR [40], [59] demonstrating the respective mRNA of c-terminal HA-tagged HPVE6 genes.…”

Section: Resultsmentioning

confidence: 99%

Differential Regulation of Cutaneous Oncoprotein HPVE6 by wtp53, Mutant p53R248W and ΔNp63α is HPV Type Dependent

Fei

Villiers

2012

PLoS ONE

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UV exposure and p53 mutations are major factors in non-melanoma skin cancer, whereas a role for HPV infections has not been defined. Previous data demonstrated the wtp53-mediated degradation of cutaneous HPV20E6 by caspase-3. ΔNp63α and hot-spot mutant p53R248W conveyed a protective effect on HPV20E6 under these conditions. We demonstrate a differential regulation by wtp53 of the E6 genes of cutaneous types HPV4, HPV5, HPV7, HPV27, HPV38, HPV48, HPV60 and HPV77. Caspase- or proteasome-mediated down-regulation was HPV type dependent. Mutant p53R248W up-regulated expression of all these E6 proteins as did ΔNp63α except for HPV38E6 which was down-regulated by the latter. None of these cellular proteins affected HPV41E6 expression. Ectopic expression of both mutp53R248W and ΔNp63α in the normal NIKS keratinocyte cell line harbouring endogenous p53 and p63however led to a down-regulation of HPV20E6. We demonstrate that HPV20E6 expression in these cells is modulated by additional, yet unidentified, cellular protein(s), which are not necessarily involved in apoptosis or autophagy. We further demonstrate proliferation of HPV20E6-expressing keratinocytes. Levels of proteins involved in cell cycle control, cyclin-D1, cdk6 and p16INK4a, phosphorylated pRB, as well as c-Jun and p-c-Jun, were all increased in these cells. HPV20E6 did not compete for the interaction between p16INK4a with cyclin-D1 or cdk6. Phosphorylation of pRB in the HPV20E6 expressing cells seems to be sufficient to override the cytokenetic block induced by the p16INK4a/pRB pathway. The present study demonstrates the diverse influence of p53 family members on individual cutaneous HPVE6 proteins. HPV20E6 expression also resulted in varying protein levels of factors involved in proliferation and differentiation.

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TAp63α indirectly regulates a cutaneous HPV promoter through complex formation with Jun family members

Cited by 5 publications

References 60 publications

Human Papillomaviruses Modulate Expression of MicroRNA 203 upon Epithelial Differentiation to Control Levels of p63 Proteins

Human Papillomaviruses Modulate Expression of MicroRNA 203 upon Epithelial Differentiation to Control Levels of p63 Proteins

Degradation of HPV20E6 by p53: ΔNp63α and mutant p53R248W protect the wild type p53 mediated caspase‐degradation

Differential Regulation of Cutaneous Oncoprotein HPVE6 by wtp53, Mutant p53R248W and ΔNp63α is HPV Type Dependent

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