The human papillomavirus type 16 E7 protein is associated with the nucleolus in mammalian and yeast cells

Зацепина, О. В.; Braspenning, Joris; Robberson, Donald L.; Hajibagheri, M. A.; Blight, Ken; Ely, Susan; Hibma, Merilyn; Spitkovsky, Dimitri D.; Trendelenburg, Michael F.; Crawford, L. V.; Tommasino, Massimo

doi:10.1038/sj.onc.1200946

Cited by 33 publications

(24 citation statements)

References 21 publications

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“…It was shown that in the HPV16-positive Caski cervical carcinoma cells, E7 localizes to the nucleolus (Zatsepina et al, 1997). This is also true for E7 encoded by the bovine papillomavirus BPV-1.…”

Section: Discussionmentioning

confidence: 73%

“…In bovine fibropapillomas, E7 encoded by BPV-1 localizes in the cytoplasm and in the nucleolus (Bohl et al, 2001). Moreover, the HPV16 E7 protein localizes in the nucleolus when expressed in the fission yeast Saccharomyces pombe (Zatsepina et al, 1997). However, E7 does not possess a nucleolar localization signal.…”

Section: Discussionmentioning

confidence: 99%

“…However, E7 does not possess a nucleolar localization signal. It was proposed that a common cellular mechanism is responsible for the nucleolar localization of E7 in various cell types (Zatsepina et al, 1997). The nucleolar localization of E7 is surprising because it is known to target proteins that are in the nucleoplasm.…”

Section: Discussionmentioning

confidence: 99%

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P19ARF inhibits the functions of the HPV16 E7 oncoprotein

et al. 2003

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The E7 oncoprotein encoded by high-risk types of human papillomavirus (HPV) plays a significant role in the development of HPV-related cancers. E7 is a potent stimulator of S phase and host DNA replication. These functions of E7 are linked to the deregulation of the Rb family of proteins. For example, E7 binds and induces proteolysis of Rb through the ubiquitin-proteasome pathway. Despite advances in our understanding of E7, reagents that inhibit E7 with promise in therapy have not been developed or identified. Here, we provide evidence that the tumor suppressor ARF can inhibit E7. We show that the expression of ARF causes a relocalization of E7 from the nucleoplasm to the nucleolus. Two distinct regions in ARF overlapping with the MDM2-binding sites are necessary for the relocalization of E7. Furthermore, we show that ARF blocks the proteolysis of Rb induced by E7. In addition, ARF expression inhibits DNA replication induced by E7. Although it is not known whether the endogenous ARF, which is expressed at a low level, interferes with E7, our results suggest that ARF is an effective inhibitor of E7. We speculate that ARF or an ARF-derived molecule might have a significant impact in therapy against HPV-related tumors.

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Section: Discussionmentioning

confidence: 73%

Section: Discussionmentioning

confidence: 99%

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P19ARF inhibits the functions of the HPV16 E7 oncoprotein

et al. 2003

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“…on May 11, 2018 by guest http://jvi.asm.org/ localized E7 to nucleoli and to the cytoplasm in HPV-transformed CaSki cells (38). In overexpression experiments, HPV E7 cytoplasmic expression can be prominent, and E7 has been shown associate with actin stress fibers in the cytoplasm when expressed by vaccinia virus (25).…”

Section: Vol 75 2001mentioning

confidence: 96%

Cooperative Transformation and Coexpression of Bovine Papillomavirus Type 1 E5 and E7 Proteins

Bohl

Hull

Pol

2001

J Virol

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Productively infected bovine fibropapillomas were examined for bovine papillomavirus type 1 (BPV-1) E7 localization. BPV-1 E7 was observed in the cytoplasm of basal and lower spinous epithelial cells, coexpressed in the cytoplasm of basal cells with the E5 oncoprotein. E7 was also observed in nucleoli throughout the basal and spinous layers but not in the granular cell layer. Ectopic expression of E7 in cultured epithelial cells gave rise to localization similar to that seen in productive fibropapillomas, with cytoplasmic and nucleolar expression observed. Consistent with the coexpression of E7 and E5 in basal keratinocytes, BPV-1 E7 cooperated with E5 as well as E6 in an anchorage independence transformation assay. While E5 is expressed in both basal and superficial differentiating keratinocytes, BPV-1 E7 is only observed in basal and lower spinous epithelial cells. Therefore, BPV-1 E7 may serve to modulate the cellular response of basal epithelial cells to E5 expression.Papillomaviruses are causative agents for a variety of epithelial neoplasms in vertebrates. Typically, virus-induced epitheliomas are benign lesions containing episomal viral DNA in proliferative basal epithelial cells, producing virus within superficial differentiated epithelial cells. The role of virus-encoded oncogenes (E5, E6, and E7) in the maintenance of viral DNA within proliferative basal epithelial cells and/or the role of these oncogenes in the transition to vegetative viral DNA amplification and virus production has yet to be fully defined. The separation of papillomavirus oncogenes into at least three separate polypeptides (E5, E6, and E7) may reflect a requirement for separate regulation of expression and activity of each product in the virus life cycle. One area of uncertainty in papillomavirus biology has been the location of each oncoprotein within the stratified epithelium of a virus-induced epithelioma.While bovine papillomavirus type 1 (BPV-1) encodes E5, E6, and E7 oncoproteins, only mutation of BPV-1 E5 decreases transformed cell focus formation by BPV-1 viral DNA. Mutations in the BPV-1 E6 or E7 genes have little effect upon focus formation or viral DNA replication, although there is a decrease in anchorage-independent growth and tumorigenicity (12,15,20). The modest oncogenic potency of BPV-1 E6 and BPV-1 E7 expressed from the wild-type BPV-1 genome is due to repression by two separate repressor mechanisms that, when mutated, reveal cooperative transformation by BPV-1 E6 and BPV-1 E7 (35). Since both BPV-1 E6 and BPV-1 E7 are thought to be translated from the same mRNA transcript, it was unproven if BPV-1 E7 had a direct role in transformation together with BPV-1 E6. Correlating with this observation, BPV-1 E6 strongly transforms murine C127 cells when expressed from retroviral long terminal repeats, whereas E7 did not (27).The E6 proteins of human papillomavirus type 16 (HPV-16) (16E6) and BPV-1 E6 bind to the cellular targets E6AP, ERC-55, and paxillin through interaction with homologous peptide sequences found on the t...

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“…Samples were mounted in Citifluor mounting medium (Agar Scientific), and images were captured using a SenSys monochrome camera and IPLab imaging software (Roper Scientific). Immunofluorescence staining was also attempted with TVGY701 and TVGY703 (anti-E7 [94]), C1P5 and 618 (anti-E6 [4,47]), E1-N1 and E1-C1 (anti-E1 [55]), and TVG 261 and TVG 271 (anti-E2 [40]) by using the approach described above. HPV16 L1 protein and the E4 proteins of HPV types other than HPV16 were detected by using secondary antibodies (Amersham) conjugated to either fluorescein isothiocyanate, Alexa 488, or Texas red.…”

Section: Methodsmentioning

confidence: 99%

Organization of Human Papillomavirus Productive Cycle during Neoplastic Progression Provides a Basis for Selection of Diagnostic Markers

Middleton

Peh

Southern

et al. 2003

J Virol

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227

214

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The productive cycle of human papillomaviruses (HPVs) can be divided into discrete phases. Cell proliferation and episomal maintenance in the lower epithelial layers are followed by genome amplification and the expression of capsid proteins. These events, which occur in all productive infections, can be distinguished by using antibodies to viral gene products or to surrogate markers of their expression. Here we have compared precancerous lesions caused by HPV type 16 (HPV16) with lesions caused by HPV types that are not generally associated with human cancer. These include HPV2 and HPV11, which are related to HPV16 (supergroup A), as well as HPV1 and HPV65, which are evolutionarily divergent (supergroups E and B). HPV16-induced low-grade squamous intraepithelial lesions (CIN1) are productive infections which resemble those caused by other HPV types. During progression to cancer, however, the activation of late events is delayed, and the thickness of the proliferative compartment is progressively increased. In many HPV16-induced high-grade squamous intraepithelial lesions (CIN3), late events are restricted to small areas close to the epithelial surface. Such heterogeneity in the organization of the productive cycle was seen only in lesions caused by HPV16 and was not apparent when lesions caused by other HPV types were compared. By contrast, the order in which events in the productive cycle were initiated was invariant and did not depend on the infecting HPV type or the severity of disease. The distribution of viral gene products in the infected cervix depends on the extent to which the virus can complete its productive cycle, which in turn reflects the severity of cervical neoplasia. It appears from our work that the presence of such proteins in cells at the epithelial surface allows the severity of the underlying disease to be predicted and that markers of viral gene expression may improve cervical screening.

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The human papillomavirus type 16 E7 protein is associated with the nucleolus in mammalian and yeast cells

Cited by 33 publications

References 21 publications

P19ARF inhibits the functions of the HPV16 E7 oncoprotein

P19ARF inhibits the functions of the HPV16 E7 oncoprotein

Cooperative Transformation and Coexpression of Bovine Papillomavirus Type 1 E5 and E7 Proteins

Organization of Human Papillomavirus Productive Cycle during Neoplastic Progression Provides a Basis for Selection of Diagnostic Markers

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