THE GENETIC PROGRAM OF GENITAL HUMAN PAPILLOMAVIRUSES IN INFECTION AND CANCER

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Papillomaviral Particles

Papillomavirus particles, also referred to as virions, are nonenveloped, icosahedral structures approximately 54 nm in diameter, and thus slightly larger than the remotely related small DNA tumor viruses, polyoma viruses. The outer shell of the particle is made up of two different peptides encoded in the papillomaviral late genes, L1 and L2. The genetic information of the virus, the viral genome, is an approximately 8000-nucleotide long closed circle of double-stranded DNA. The intact DNA is

The E5 Polypeptide

The E5 genes of papillomaviruses encode unusually short, highly hydrophobic polypeptides anchored in the cell membrane. The overexpression of E5 proteins alone can modify cell growth and result in overt neoplastic transformation in some experimental systems.9, 74, 75, 78, 93, 105, 122 E5s interact with and modulate the function of other membrane associated proteins.

One major target of their action is transmembrane growth factor receptors: the epidermal growth factor (EGF) receptor in

VIRAL GENES INVOLVED IN HPV DNA REPLICATION: E1 AND E2

The papillomaviral life cycle, from the introduction of virus into the cell to the recovery of infectious virions that could be assayed in a second round of infection, has not been reproduced in cell culture, thus frustrating attempts to define viral replication genes by mutagenesis.29, 131 Using efficient techniques to slip (transfect) recombinant DNA clones into cells in culture in transient replication assays, Ustav, Stenlund and co-workers have identified two viral proteins, the full-length

REGULATION OF VIRAL GENE EXPRESSION

The precise program of papillomaviral gene expression is understood only partly.130 Viral protein levels in the cell are determined by their stability and their de novo translation, which in turn depends on the concentrations of specific mRNA in the cell. Control of viral RNA levels is largely responsible for several important aspects of HPV infection, including (1) the restricted cellular host range of HPV infection, (2) activation of late genes and virus particle production, and (3) the fine

CONCLUSION

Two HPV genes, E6 and E7, are retained and expressed selectively in clinical samples of cervical carcinomas and derived cell lines and increase the lifespan and alter the growth pattern of uninfected cells in culture. Although multifunctional in nature, the E6 and E7 proteins surprisingly target the same critical step in the transcriptional control of cell cycle progression: the activation of the E2F family of transcription factors. Free E2F complexes turn on a set of E2F-dependent cellular

ACKNOWLEDGMENTS

Research in the authors' laboratories was supported by funds from the Department of Veterans Affairs (LPT), the National Institutes of Health (EMS and LPT), and the American Cancer Society (LPT). The authors wish to thank laboratory members for comments on the manuscript and apologize to many colleagues whose seminal contributions could not be cited owing to space constraints.

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  • Cited by (33)

    • Cellular factors are required to activate bovine papillomavirus-1 early gene transcription and to establish viral plasmid persistence but are not required for cellular transformation

      2009, Virology
      Citation Excerpt :

      The HPV enhancers are active in keratinocytes, cervical carcinoma cells and in some epithelial tumor cell lines, but do not function well in fibroblasts (Cripe et al., 1990). Cell type-specific activation of viral transcription thus correlates with the host range of HPV infection restricted to mucosal and cutaneous keratinocytes and related cells (see Bernard and Apt, 1994; Turek and Smith, 1996 for reviews). In BPV-1, weak E2-independent enhancer activity was localized to a short segment in the distal part of the URR (Stenlund and Botchan, 1990; Stenlund et al., 1987; Vande Pol and Howley, 1990) and observed to activate the E2-TA-coding P2443 promoter (Spalholz et al., 1991; Szymanski and Stenlund, 1991).

    • Enhanced cell death by AdCMV-p53 after irradiation of HeLa cells with <sup>12</sup>C<sup>6+</sup> ions

      2008, European Journal of Obstetrics and Gynecology and Reproductive Biology
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      The present study indicated that at certain dose of AdCMV-p53 (such as, 80 MOI), the exogenous p53 gene were not only successfully delivered into HeLa cells, but also translated into p53 protein in the cells irradiated before gene transfer. The reason 40 MOI AdCMV-p53 transfer could not result in p53 levels above GFP in irradiated cells might be related to the presence of oncogenic protein E6, which might suppress expression of endogenous p53 and low levels of exogenous p53 [6–8]. At high levels of exogenous p53, E6 might be saturated thus producing a threshold for the effect of exogenous p53.

    • Interactions of the cellular CCAAT displacement protein and human papillomavirus E2 protein with the viral origin of replication can regulate DNA replication

      2006, Virology
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      The papillomaviruses are termed ‘high risk’ if they are associated with development of cancer (e.g., HPV 16, 18, and 31) or ‘low risk’ when seen in warts but not typically associated with cancer [e.g., HPV 6 and 11 (zur Hausen, 2002)]. All papillomaviruses have a similar genomic organization divided into three regions: the long control region (LCR) which contains the major cis regulatory sequences and the origin of replication, the early region that encodes six to eight proteins, and the late region that codes for 2 late structural proteins (Laimins, 1993; Turek and Smith, 1996). In the case of low-risk HPV, three promoters have been identified, the E6, E7, and E1 promoters (Karlen et al., 1996; Rapp et al., 1997; Smotkin et al., 1989).

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    Address reprint requests to Lubomir P. Turek, MD, Department of Pathology, University of Iowa College of Medicine, 200 Hawkins Drive–ML144, Iowa City, IA 52242

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