Mechanism of translation of the bicistronic mRNA encoding human papillomavirus type 16 E6-E7 genes

Tan, Theresa May Chin; Gloss, Bernd; Bernard, Hans‐Ulrich; Ting, R. C.

doi:10.1099/0022-1317-75-10-2663

Cited by 25 publications

(25 citation statements)

References 36 publications

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“…This difference in the molecular mass between the expected and experimental value is explained by the extremely acid character of E7 protein, which has 9 aspartate and 10 glutamate residues out of 98 aminoacids (17)(18)(19)(20).…”

Section: Resultsmentioning

confidence: 92%

Modulation of HPV16 E7 translation by tRNAs in eukaryotic cell‐free translation systems

Pasquale

Kanduc

1998

IUBMB Life

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Summary. Translational regulation of HPV 16 E7 mRNA is of particular interest since the viral E7 protein has oncogenic activity. Here we report that additional supplementation of cell-free reticulocyte/wheat-germ translation systems with rat liver tRNA pool favors the expression of the viral oncoprotein E7 which otherwise is scarcely translatable. The translational activation is explained by the positive correlation between the frequency of the glutamic and aspartic codons in E7 mRNA, and the increased concentration of the corresponding tRNAs following tRNA supplementation. The present in vitro data suggest a link between E7 expression and cell conditions conducive to tRNA changes such as development, cell proliferation and aging.

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Section: Resultsmentioning

confidence: 92%

Modulation of HPV16 E7 translation by tRNAs in eukaryotic cell‐free translation systems

Pasquale

Kanduc

1998

IUBMB Life

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“…The selective advantage of the frequent loss of E2 in cervical cancers induced by HPV16 or 18 has been explained by E2-mediated suppression of the viral E6/7 promotor, which is not relevant in transgenic mice, and by the induction of senescence or apoptosis (38)(39)(40). Interestingly, HPV8 E2 expressing keratinocytes do not undergo apoptosis (41), which may suggest that it has at least no inhibitory effect on carcinogenesis.…”

Section: Resultsmentioning

confidence: 99%

Development of Skin Tumors in Mice Transgenic for Early Genes of Human Papillomavirus Type 8

et al. 2005

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The cutaneous human papillomavirus (HPV) 8 is clearly involved in skin cancer development in epidermodysplasia verruciformis patients and its early genes E2, E6, and E7 have been implicated in cell transformation in vitro. To examine the functions of these genes in vivo we integrated the complete early region of HPV8 into the genome of DBA/Bl6 mice. To target their expression to the basal layer of the squamous epithelia the transgenes were put under the control of the keratin-14 promoter. Transgenic mice were back-crossed for up to six generations into both FVB/N and Bl6 mouse strains. Whereas none of the HPV8 transgene-negative littermates developed lesions in the skin or any other organ, 91% of HPV8-transgenic mice developed single or multifocal benign tumors, characterized by papillomatosis, acanthosis, hyperkeratosis, and varying degrees of epidermal dysplasia. Squamous cell carcinomas developed in 6% of the transgenic FVB/N mice. Real-time reverse transcription-PCR showed highest expression levels for HPV8-E2, followed by E7 and E6. There was no consistent difference in relative viral RNA levels between healthy or dysplastic skin and malignant skin tumors. Whereas UV-induced mutations in the tumor suppressor gene p53 are frequently detected in human skin carcinomas, mutations in p53 were not observed either in the benign or malignant mouse tumors. Nonmelanoma skin cancer developed in HPV8-transgenic mice without any treatment with physical or chemical carcinogens. This is the first experimental proof of the carcinogenic potential of an epidermodysplasia verruciformis-associated HPV-type in vivo. (Cancer Res 2005; 65(4): 1394-400)

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“…In several instances, for example E7, E2, and E5 in HPV-16, no RNAs have been defined in which the ORF is not preceded by an upstream coding ORF. Numerous investigators have noted that these polycistronic papillomavirus RNAs appear to be capable of producing more than one protein concurrently (2,5,22,49,51,72), but the mechanisms underlying this have remained obscure. Termination-reinitiation (65,72), leaky scanning (69), and shunting (49) have all been suggested previously as potential mechanisms.…”

Section: Discussionmentioning

confidence: 99%

Leaky Scanning Is the Predominant Mechanism for Translation of Human Papillomavirus Type 16 E7 Oncoprotein from E6/E7 Bicistronic mRNA

Stacey

Jordan

Williamson

et al. 2000

J Virol

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Human papillomaviruses (HPV) are unique in that they generate mRNAs that apparently can express multiple proteins from tandemly arranged open reading frames. The mechanisms by which this is achieved are uncertain and are at odds with the basic predictions of the scanning model for translation initiation. We investigated the unorthodox mechanism by which the E6 and E7 oncoproteins from human papillomavirus type 16 (HPV-16) can be translated from a single, bicistronic mRNA. The short E6 5 untranslated region (UTR) was shown to promote translation as efficiently as a UTR from Xenopus ␤-globin. Insertion of a secondary structural element into the UTR inhibited both E6 and E7 expression, suggesting that E7 expression depends on ribosomal scanning from the 5 end of the mRNA. E7 translation was found to be cap dependent, but E6 was more dependent on capping and eIF4F activity than E7. Insertion of secondary structural elements at various points in the region upstream of E7 profoundly inhibited translation, indicating that scanning was probably continuous. Insertion of the E6 region between Renilla and firefly luciferase genes revealed little or no internal ribosomal entry site activity. However when E6 was located at the 5 end of the mRNA, it permitted over 100-fold-higher levels of downstream cistron translation than did the Renilla open reading frame. Internal AUGs in the E6 region with strong or intermediate Kozak sequence contexts were unable to inhibit E7 translation, but initiation at the E7 AUG was efficient and accurate. These data support a model in which E7 translation is facilitated by an extreme degree of leaky scanning, requiring the negotiation of 13 upstream AUGs. Ribosomal initiation complexes which fail to initiate at the E6 start codon can scan through to the E7 AUG without initiating translation, but competence to initiate is achieved once the E7 AUG is reached. These findings suggest that the E6 region of HPV-16 comprises features that sponsor both translation of the E6 protein and enhancement of translation at a downstream site.

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Mechanism of translation of the bicistronic mRNA encoding human papillomavirus type 16 E6-E7 genes

Cited by 25 publications

References 36 publications

Modulation of HPV16 E7 translation by tRNAs in eukaryotic cell‐free translation systems

Modulation of HPV16 E7 translation by tRNAs in eukaryotic cell‐free translation systems

Development of Skin Tumors in Mice Transgenic for Early Genes of Human Papillomavirus Type 8

Leaky Scanning Is the Predominant Mechanism for Translation of Human Papillomavirus Type 16 E7 Oncoprotein from E6/E7 Bicistronic mRNA

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