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Crusius, Kerstin; Rodriguez, Isabel; Alonso, Ángel

doi:10.1023/a:1008112207824

Cited by 58 publications

(13 citation statements)

References 20 publications

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“…Although p-p38MAPK could be detected in the basal and parabasal layers in both WT and E4KO rafts, the WT rafts showed a marked elevated p-p38 MAPK in the middle and upper layers where E4 accumulation was seen (Fig 5B). Previous studies using undifferentiated monolayer cell culture systems have shown that both E4 and E5 can activate p38 MAPK [49, 50], which is compatible with our observations (S4 Fig). Interestingly, loss of 16E4’s keratin-binding motif (Δ16N), as occurs in the upper epithelial layers where p38 MAPK activation was observed (Fig 5A), did not significantly compromise E4s ability to activate p38 MAPK in this system (S4 Fig), although as expected, N-terminal deletion led to E4 accumulation because of its increased ability to assemble into amyloid-like fibrils [19, 51].…”

Section: Resultssupporting

confidence: 93%

HPV16 and 18 genome amplification show different E4-dependence, with 16E4 enhancing E1 nuclear accumulation and replicative efficiency via its cell cycle arrest and kinase activation functions

et al. 2017

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To clarify E1^E4’s role during high-risk HPV infection, the E4 proteins of HPV16 and 18 were compared side by side using an isogenic keratinocyte differentiation model. While no effect on cell proliferation or viral genome copy number was observed during the early phase of either virus life cycle, time-course experiments showed that viral genome amplification and L1 expression were differently affected upon differentiation, with HPV16 showing a much clearer E4 dependency. Although E4 loss never completely abolished genome amplification, its more obvious contribution in HPV16 focused our efforts on 16E4. As previously suggested, in the context of the virus life cycle, 16E4s G2-arrest capability was found to contribute to both genome amplification success and L1 accumulation. Loss of 16E4 also lead to a reduced maintenance of ERK, JNK and p38MAPK activity throughout the genome amplifying cell layers, with 16E4 (but not 18E4) co-localizing precisely with activated cytoplasmic JNK in both wild type raft tissue, and HPV16-induced patient biopsy tissue. When 16E1 was co-expressed with E4, as occurs during genome amplification in vivo, the E1 replication helicase accumulated preferentially in the nucleus, and in transient replication assays, E4 stimulated viral genome amplification. Interestingly, a 16E1 mutant deficient in its regulatory phosphorylation sites no longer accumulated in the nucleus following E4 co-expression. E4-mediated stabilisation of 16E2 was also apparent, with E2 levels declining in organotypic raft culture when 16E4 was absent. These results suggest that 16E4-mediated enhancement of genome amplification involves its cell cycle inhibition and cellular kinase activation functions, with E4 modifying the activity and function of viral replication proteins including E1. These activities of 16E4, and the different kinase patterns seen here with HPV18, 31 and 45, may reflect natural differences in the biology and tropisms of these viruses, as well as differences in E4 function.

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Section: Resultssupporting

confidence: 93%

HPV16 and 18 genome amplification show different E4-dependence, with 16E4 enhancing E1 nuclear accumulation and replicative efficiency via its cell cycle arrest and kinase activation functions

et al. 2017

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“…16E5 can stimulate ERK1/2, p38 MAP kinases, and phospholipase Cγ-1 independently of the EGFR in human keratinocytes (Crusius et al, 1999; Crusius, Rodriguez, and Alonso, 2000). Venuti et al reported that 16E5 enhanced endothelin-1-induced mitogenic signaling, resulting in the growth of primary human keratinocytes (Venuti et al, 1998).…”

Section: Human Papillomavirus E5 Proteinsmentioning

confidence: 99%

The E5 proteins

2013

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The E5 proteins are short transmembrane proteins encoded by many animal and human papillomaviruses. These proteins display transforming activity in cultured cells and animals, and they presumably also play a role in the productive virus life cycle. The E5 proteins are thought to act by modulating the activity of cellular proteins. Here, we describe the biological activities of the best-studied E5 proteins and discuss the evidence implicating specific protein targets and pathways in mediating these activities. The primary target of the 44-amino acid BPV1 E5 is the PDGF β receptor, whereas the EGF receptor appears to be an important target of the 83-amino acid HPV16 E5 protein. Both E5 proteins also bind to the vacuolar ATPase and affect MHC class I expression and cell-cell communication. Continued studies of the E5 proteins will elucidate important aspects of transmembrane protein-protein interactions, cellular signal transduction, cell biology, virus replication, and tumorigenesis.

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“…Furthermore, miR-324-5p was constantly repressed in E5-expressing cells, whereas its putative target, E-cadherin, was increased at the protein level. These data are interesting as the function of E5 in cell transformation is still not fully understood [63], and one additional mechanism by which HPV16 E5 might contribute to the carcinogenic process in cervical epithelial cells could be controlled by miR-324-5p [61]. …”

Section: Global Mirna Analysismentioning

confidence: 99%

A Decade of Global mRNA and miRNA Profiling of HPV-Positive Cell Lines and Clinical Specimens

Kaczkowski

Morevati²,

Rossing³

et al. 2012

TOVJ

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For more than a decade, global gene expression profiling has been extensively used to elucidate the biology of human papillomaviruses (HPV) and their role in cervical- and head-and-neck cancers. Since 2008, the expression profiling of miRNAs has been reported in multiple HPV studies. Two major strategies have been employed in the gene and miRNA profiling studies: In the first approach, HPV positive tumors were compared to normal tissues or to HPV negative tumors. The second strategy relied on analysis of cell cultures transfected with single HPV oncogenes or with HPV genomes compared to untransfected cells considered as models for the development of premalignant and malignant transformations.In this review, we summarize what we have learned from a decade of global expression profiling studies. We performed comprehensive analysis of the overlap of the lists of differentially expressed genes and microRNAs, in both tissue samples and cell culture based studies. The review focuses mainly on HPV16, however reports from other HPV species are used as references. We discuss the low degree of consensus among different studies and the limitation of differential expression analysis as well as the fragmented miRNA-mRNA target correlation evidence. Furthermore, we propose an approach for future research to include more comprehensive miRNA-mRNA target correlation analysis and to apply systems biology/gene networks methodology.

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Untitled

Cited by 58 publications

References 20 publications

HPV16 and 18 genome amplification show different E4-dependence, with 16E4 enhancing E1 nuclear accumulation and replicative efficiency via its cell cycle arrest and kinase activation functions

HPV16 and 18 genome amplification show different E4-dependence, with 16E4 enhancing E1 nuclear accumulation and replicative efficiency via its cell cycle arrest and kinase activation functions

The E5 proteins

A Decade of Global mRNA and miRNA Profiling of HPV-Positive Cell Lines and Clinical Specimens

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