HPV-18 E6*I protein modulates the E6-directed degradation of p53 by binding to full-length HPV-18 E6

Pim, David; Banks, Lawrence

doi:10.1038/sj.onc.1203134

Cited by 84 publications

(80 citation statements)

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“…Nonetheless, decreased E6 levels can be deduced from enhanced p53 stabilization (Fig. 1B), which is consistent with the finding that E6* can counteract full-length E6-mediated p53 degradation (11).…”

Section: Discussionsupporting

confidence: 77%

“…The 8-kDa E6* protein was shown to modulate E6 functions. Studies show that HPV18 E6* can counteract E6 protein functions by rescuing p53 levels in vivo (11). Furthermore, though interaction of HPV16 E6 with procaspase-8 accelerates its degradation, binding of E6* results in procaspase-8 stabilization and therefore may sensitize the cells to tumor necrosis factor-alpha (TNFα)-mediated apoptosis (12).…”

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confidence: 99%

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Alternative splicing of human papillomavirus type-16 E6/E6* early mRNA is coupled to EGF signaling via Erk1/2 activation

Rosenberger

Arce

Langbein

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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Certain types of human papillomaviruses (HPVs) are etiologically linked to cervical cancer. Their transforming capacity is encoded by a polycistronic premRNA, where alternative splicing leads to the translation of functional distinct proteins such as E6, E6*, and E7. Here we show that splicing of HPV16 E6/E7 ORF cassette is regulated by the epidermal growth factor (EGF) pathway. The presence of EGF was coupled to preferential E6 expression, whereas depletion of EGF, or treatment with EGF receptor (EGFR) neutralizing antibodies or the EGFR inhibitor tyrphostin AG1478, resulted in E6 exon exclusion in favor of E6*. As a consequence, increased p53 levels and enhanced translation of E7 with a subsequent reduction of the retinoblastoma protein pRb could be discerned. E6 exon exclusion upon EGF depletion was independent from promoter usage, mRNA stability, or selective mRNA transport. Time-course experiments and incubation with cycloheximide demonstrated that E6 alternative splicing is a direct and reversible effect of EGF signal transduction, not depending on de novo protein synthesis. Within this process, Erk1/2-kinase activation was the critical event for E6 exon inclusion, mediated by the upstream MAP kinase MEK1/2. Moreover, siRNA knockdown experiments revealed an involvement of splicing factors hnRNPA1 and hnRNPA2 in E6 exon exclusion, whereas the splicing factors Brm and Sam68 were found to promote E6 exon inclusion. Because there is a natural gradient of EGF and EGF receptor expression in the stratified epithelium, it is reasonable to assume that EGF modulates E6/E7 splicing during the viral life cycle and transformation.P articular types of human papillomaviruses (HPVs) such as HPV16, 18, 31, and 33, respectively, are the etiological agents for the development of anogenital tumors. Their transforming potential is encoded by the viral oncoproteins E6 and E7, where among other functions, E6 labilizes p53 and prevents apoptosis, and E7 promotes cell cycle progression by degrading the retinoblastoma protein pRb (1). HPV gene transcription is regulated by two main promoters, the early p97 and the late p670 promoter (2). Activation of either promoter is regulated by differentiation, resulting in the synthesis of polycistronic mRNAs, which are further regulated by differential splicing (3, 4). For polycistronic mRNAs, it is known that only the first ORF is translated efficiently when intercistronic distances are short (5).Alternative splicing can be regulated dependent on the developmental stage or by extracellular stimuli, where an increasing number of pathways and splicing factors have been identified (6). For splicing reaction, the spliceosome recognizes exon-intron boundaries of the 5′-donor and 3′-acceptor splice site. Furthermore, specific sequence motifs within exons can positively or negatively influence the recognition of nearby splice sites (7). The activity of so-called exonic splicing enhancers or exonic splicing silencers can be modulated by splicing factors like SR proteins or hnRNPs, which in turn all...

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Section: Discussionsupporting

confidence: 77%

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confidence: 99%

Alternative splicing of human papillomavirus type-16 E6/E6* early mRNA is coupled to EGF signaling via Erk1/2 activation

Rosenberger

Arce

Langbein

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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“…6,24) In most cervical cancers, the function of p53 is down-regulated by the E6 protein of HPV 16; E6 binds to p53 and leads to degradation of E6-p53 complexes. [10][11][12] Exogenous p53 overexpression results in degradation of viral E6 proteins and decreases the survival of cancer cells. 25) A previous study also showed that p53 binds E6 oncoprotein to decrease the tumorigenic properties of E6.…”

Section: Discussionmentioning

confidence: 99%

“…9) In most cervical cancers, however, the function of p53 is down-regulated by the E6 protein of HPV 16, whereby E6 binds to p53, resulting in degradation of E6-p53 complexes through the ubiquitin pathway. [10][11][12] For instance, human cervical cancer cell lines, such as CaSki (HPV 16), SiHa (HPV 16), HeLa (HPV 18) and HeLaS3 (HPV 18) express intact p53 protein. However, the viral E6 protein is required for the continuous growth of HPV-immortalized cells, in which E6 reduces the level of p53 protein, resulting in loss of G 1 arrest.…”

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confidence: 99%

Differential Suppression of Human Cervical Cancer Cell Growth by Adenovirus Delivery of p53 in vitro: Arrest Phase of Cell Cycle Is Dependent on Cell Line

Ahn

Han

Bae

et al. 2002

Japanese Journal of Cancer Research

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It has been reported that overexpression of wild-type p53 protein induces suppression of tumor cell growth in vivo and in vitro. In this study, we further evaluated the differential effects of p53 delivered in an adenovirus vector on the cell growth, apoptosis and cell cycle progression in cervical cancer cell lines. We constructed a recombinant adenovirus expressing p53 and then delivered this into cervical carcinoma cell lines (CaSki, SiHa, and HeLa, HeLaS3) along with adenovirus expressing β β β β-galactosidase as a negative control. Adenovirus-delivered p53 overexpression resulted in a more significant suppression of cell growth in HPV 18-infected cells (HeLa and HeLaS3) and a lesser suppression in HPV 16-infected cells (CaSki and SiHa). However, no suppression was observed in cells infected with a negative control virus. p53 overexpression also induced apoptosis and cell cycle arrest, as determined by annexin V and propidium iodide staining. In particular, the cell cycle was arrested in the G 2 /M phase in CaSki cells. In contrast, cell cycles were arrested in the G 1 phase in HeLa cells, suggesting that the arrest phase is dependent upon the cervical cancer cell line. Taken together, these data support the idea that overexpressed p53 protein plays a differential role in suppressing cervical cancer cell growth through apoptosis and cell cycle arrest in either G 1 or G 2 /M phase, depending on the cancer cell line.

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“…Moreover, ectopic expression of the HPV-18 E6*I protein was found to have an antiproliferative effect in cell lines derived from cervical tumors. 18,19 These results led us to further examine the modulatory effects of E6*I on E6. Because no information is available on the patterns of expression of E6*I, we have used epitope-tagged versions of both HPV-18 E6 and HPV-18 E6*I to investigate their respective subcellular distribution.…”

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confidence: 99%

HPV‐18 E6*I modulates HPV‐18 full‐length E6 functions in a cell cycle dependent manner

Guccione

Pim

Banks

2004

Intl Journal of Cancer

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The E6 ORFs of the high-risk Human Papillomavirus (HPV) Types 16 and 18 have been shown to encode (besides the full-length product) several truncated forms, termed E6*. We have reported previously that the HPV-18 E6*I protein interacts with the full-length E6 protein as well as with the ubiquitin ligase E6-AP and, as a result of this, E6* can inhibit E6-mediated degradation of p53. Moreover, ectopic expression of the HPV-18 E6*I protein has an antiproliferative effect in cervical cancer-derived cell lines. These results led us to investigate further the modulatory functions of E6*I on E6. Using epitope tagged versions of the 2 proteins we have analyzed the sub-cellular distribution of the full-length HPV18 E6 and HPV18 E6*I, as well as their respective cellular abundance during the cell cycle, and show specific upregulation of E6*I during G2/M. We also investigated the effect of E6*I overexpression in cell lines derived from cervical tumors, with respect to the expression levels of E6 target proteins, such as p53, hDlg and Scribble and find a corresponding increase in p53 expression also during G2/M. In addition we show that the overexpression of E6*I reduces the amount of E6 in the insoluble nuclear and membrane fractions of the cell. E6 levels can, however, be restored by the addition of a specific proteasome inhibitor, suggesting that the interaction between E6 and E6*I leads to the destabilization of a subset of the E6 protein. These results suggest that the E6*I protein can function as a fine regulator of the fulllength E6 protein by direct interaction that leads both to changes in its cellular abundance as well as its distribution during particular phases of the cell cycle. © 2004 Wiley-Liss, Inc. Key words: E6*I; E6; cell cycle; HPV; proteasome degradationHuman papillomaviruses (HPVs) are linked to the development of a number of human malignancies. 1 These include squamous cell carcinomas (SCCs) in immunosuppressed individuals and in patients with epidermodysplasia verruciformis (EV), head and neck cancers, anogenital cancers and, most notably, carcinoma of the uterine cervix. 2 Although more than 130 HPV types have been described so far, infection by only a small subset of virus types (high-risk HPVs) is associated with the aforementioned malignancies, whereas others give rise to benign condylomas, and cutaneous plantar and palmar warts (low-risk HPVs). 3 High-risk mucosal HPVs encode 2 major oncoproteins, E6 and E7, both of which have oncogenic activity in a variety of cell transformation assays. 4 -7 E7 has the major role of deregulating the cell cycle, uncoupling it from differentiation, 8 and it plays a critical role in tumor promotion. In contrast E6 contributes more strongly during tumor progression, accelerating the malignant conversion of benign tumors. 9 High-risk, but not low-risk HPVs transcribe both E6 and E7 as bicistronic and polycistronic mRNAs. 10 -13 The resulting transcripts encode the 2 full-length proteins and 4 shorter peptides termed E6*. 14 These alternatively spliced transcripts ...

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HPV-18 E6*I protein modulates the E6-directed degradation of p53 by binding to full-length HPV-18 E6

Cited by 84 publications

References 26 publications

Alternative splicing of human papillomavirus type-16 E6/E6* early mRNA is coupled to EGF signaling via Erk1/2 activation

Alternative splicing of human papillomavirus type-16 E6/E6* early mRNA is coupled to EGF signaling via Erk1/2 activation

Differential Suppression of Human Cervical Cancer Cell Growth by Adenovirus Delivery of p53 in vitro: Arrest Phase of Cell Cycle Is Dependent on Cell Line

HPV‐18 E6*I modulates HPV‐18 full‐length E6 functions in a cell cycle dependent manner

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