The 3' region of Human Papillomavirus type 16 early mRNAs decrease expression

Vinther, Jeppe; Rosenstierne, Maiken Worsøe; Kristiansen, Karen; Norrild, Bodil

doi:10.1186/1471-2334-5-83

Cited by 12 publications

(13 citation statements)

References 40 publications

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“…While limiting levels of E2-TA and/or E8 E2 proteins appear to tightly control viral gene expression and genome replication during HPV persistence, steady-state levels of mRNA encoding E2-TA, E8 E2 (29), and P14-initiated E1 (30) in HPV-16 persistence may be significantly lower than those of E6-E7 mRNA, thus escaping detection in cells with unintegrated, persistent circular or integrated HPV genomes. An additional consequence of HPV integration may be the elimination of the viral 3Ј AU-rich destabilization sequence from the chimeric HPV E6-E7-cell mRNA transcripts (20,53). Nevertheless, we did not discern a clear difference in steadystate E6-E7 mRNA transcript levels between syngeneic keratinocyte clones harboring unintegrated or integrated HPV-16 genomes (Fig.…”

Section: Discussionmentioning

confidence: 47%

“…The integrated HR HPV fragments in high-grade precancerous cervical lesions, cervical carcinomas, and derived cell lines express the viral transforming genes E6 and E7 from chimeric virus-cell mRNAs, while the downstream early genes that are required for viral replication and regulated viral gene expression are disrupted or silenced (33,37,47,55). Further, chimeric virus-cell mRNAs may be more stable than the viral early mRNAs, which harbor a 3Ј destabilization motif (20,53). In addition, some integration sites in cervical cancer and precursor lesions have been found near potential growth control genes (11,40,55).…”

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confidence: 99%

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Human Papillomavirus Type 16 (HPV-16) Genomes Integrated in Head and Neck Cancers and in HPV-16-Immortalized Human Keratinocyte Clones Express Chimeric Virus-Cell mRNAs Similar to Those Found in Cervical Cancers

Lace

Anson

Klußmann

et al. 2011

J Virol

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Many human papillomavirus (HPV)-positive high-grade lesions and cancers of the uterine cervix harbor integrated HPV genomes expressing the E6 and E7 oncogenes from chimeric virus-cell mRNAs, but less is known about HPV integration in head and neck cancer (HNC).Mucosal high-risk (HR) human papillomavirus (HPV) types are found in nearly 100% of carcinomas of the uterine cervix, many anogenital cancers, and ϳ25% of head and neck cancers (HNC) (9, 13, 42). The most common HR HPV is type 16, found in over 50% of cervical cancers and 90 to 95% of HPVpositive HNCs. In persistent infection, HPV genomes are maintained as circular, unintegrated plasmids that persist in the nuclei of infected cells (see Fig. 1A). In contrast, HR HPV DNA found in cervical cancer specimens is frequently disrupted and integrated in the cellular genome in a way that potentially alters the expression program of the viral early gene region and/or the host genome (2,5,8,21,23,24,31,43). The integrated HR HPV fragments in high-grade precancerous cervical lesions, cervical carcinomas, and derived cell lines express the viral transforming genes E6 and E7 from chimeric virus-cell mRNAs, while the downstream early genes that are required for viral replication and regulated viral gene expression are disrupted or silenced (33,37,47,55). Further, chimeric virus-cell mRNAs may be more stable than the viral early mRNAs, which harbor a 3Ј destabilization motif (20,53). In addition, some integration sites in cervical cancer and precursor lesions have been found near potential growth control genes (11,40,55).Advances in keratinocyte culture techniques have permitted the study of the life cycle of HR HPV types that replicate efficiently and persist in primary human keratinocytes, such as 34,35), and to a more limited extent 36). However, relatively little is known about the progression of the infected cell toward a malignant phenotype in vivo or in culture. While some cervical cancers have been shown to harbor extrachromosomal HPV DNA, it is apparent that integration of viral DNA accompanied by disruption of the integrity of the HR HPV genomes represents a common, albeit not absolutely obligatory, step associated with carcinogenic progression associated with the genital tract (42, 57). The majority of cervical carcinomas caused by the two most common HR HPV types, HPV-16 and -18, contain integrated viral sequences (52) that express E6-E7 from chimeric, spliced virus-cell transcripts. However, the genetic structure and expres-

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Section: Discussionmentioning

confidence: 47%

mentioning

confidence: 99%

Human Papillomavirus Type 16 (HPV-16) Genomes Integrated in Head and Neck Cancers and in HPV-16-Immortalized Human Keratinocyte Clones Express Chimeric Virus-Cell mRNAs Similar to Those Found in Cervical Cancers

Lace

Anson

Klußmann

et al. 2011

J Virol

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“…Similarly, the E4 protein of HPV16 is able to inhibit mitosis by preventing the nuclear localization of cyclinB/Cdk1, and it is not surprising therefore that the expression of these proteins is abrogated in HPV-associated cancers. In addition to the loss of regulatory proteins, integration also leads to the loss of sequences at the 3 -end of the viral early transcripts that can suppress the production of viral mRNA species encoding E6 and E7 [133][134][135], contributing further to the deregulation of viral oncogene expression. Although integrated HPV DNA is found in the vast majority of cervical cancers, other factors are likely to influence the development of the precancerous changes seen in squamous intraepithelial neoplasia.…”

Section: Molecular Events During Cancer Progressionmentioning

confidence: 99%

Molecular biology of human papillomavirus infection and cervical cancer

Doorbar¹

2006

Clinical Science

878

701

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HPVs (human papillomaviruses) infect epithelial cells and cause a variety of lesions ranging from common warts/verrucas to cervical neoplasia and cancer. Over 100 different HPV types have been identified so far, with a subset of these being classified as high risk. High-risk HPV DNA is found in almost all cervical cancers (>99.7%), with HPV16 being the most prevalent type in both low-grade disease and cervical neoplasia. Productive infection by high-risk HPV types is manifest as cervical flat warts or condyloma that shed infectious virions from their surface. Viral genomes are maintained as episomes in the basal layer, with viral gene expression being tightly controlled as the infected cells move towards the epithelial surface. The pattern of viral gene expression in low-grade cervical lesions resembles that seen in productive warts caused by other HPV types. High-grade neoplasia represents an abortive infection in which viral gene expression becomes deregulated, and the normal life cycle of the virus cannot be completed. Most cervical cancers arise within the cervical transformation zone at the squamous/columnar junction, and it has been suggested that this is a site where productive infection may be inefficiently supported. The high-risk E6 and E7 proteins drive cell proliferation through their association with PDZ domain proteins and Rb (retinoblastoma), and contribute to neoplastic progression, whereas E6-mediated p53 degradation prevents the normal repair of chance mutations in the cellular genome. Cancers usually arise in individuals who fail to resolve their infection and who retain oncogene expression for years or decades. In most individuals, immune regression eventually leads to clearance of the virus, or to its maintenance in a latent or asymptomatic state in the basal cells.

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“…3 The high-risk human papillomavirus (HPV) E6/E7 early viral sequence merges into the host cell genome with integrated 5′-promoter and 3′-end host sequence preceded by the standard hexanucleotide polyadenylation signal (AATAAA). 4,5 E6 expression in host cells eliminates the cellular protective response to genotoxic stress such as DNA damage by interfering with p53-mediated cell cycle arrest. 6 Chemotherapeutic drugs such as VP-16 (DNA damage agent) and cisplatin (alkylating agent and DNA crosslinker) could restore p53 levels by decreasing E6 expression and usurp the E6/E6AP-mediated proteosomal degradation pathway in these cells.…”

Section: Introductionmentioning

confidence: 99%

Star-PAP controls HPV E6 regulation of p53 and sensitizes cells to VP-16

Anderson

2013

Oncogene

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Cervical cancer is the most common genital malignancy and the high-risk human papillomaviruses (HPV type 16, 18 and 31, and so on) are major agents for its cause. A key switch for the onset of cervical cancers by HPVs is the cellular degradation of the tumor-suppressor p53 that is mediated by the HPV-generated E6 protein. E6 forms a complex with the E3 ubiquitin-ligase E6-associated protein (E6AP) leading to p53 degradation. The components that control E6 expression and the mechanisms for regulation of the expression in host cells remain undefined. Here we show that the nuclear noncanonical poly(A) polymerase (PAP) speckle targeted PIPKIα regulated PAP (Star-PAP) controls E6 mRNA polyadenylation and expression and modulates wild-type p53 levels as well as cell cycle profile in high-risk HPV-positive cells. In the absence of Star-PAP, treatment of cells with the chemotherapeutic drug VP-16 dramatically reduced E6 and increased p53 levels. This diminished both cell proliferation and anchorage-independent growth required for cancer progression, indicating a synergism between VP-16 treatment and the loss of Star-PAP. This identifies Star-PAP as a potential drug target for the treatment of HPV-positive cancer cells. These data provide a mechanistic basis for increasing the sensitivity and efficiency of chemotherapy in the treatment of cancers that have low levels of wild-type p53.

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The 3' region of Human Papillomavirus type 16 early mRNAs decrease expression

Cited by 12 publications

References 40 publications

Human Papillomavirus Type 16 (HPV-16) Genomes Integrated in Head and Neck Cancers and in HPV-16-Immortalized Human Keratinocyte Clones Express Chimeric Virus-Cell mRNAs Similar to Those Found in Cervical Cancers

Human Papillomavirus Type 16 (HPV-16) Genomes Integrated in Head and Neck Cancers and in HPV-16-Immortalized Human Keratinocyte Clones Express Chimeric Virus-Cell mRNAs Similar to Those Found in Cervical Cancers

Molecular biology of human papillomavirus infection and cervical cancer

Star-PAP controls HPV E6 regulation of p53 and sensitizes cells to VP-16

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