Obstetrics and Gynecology Clinics of North America
THE GENETIC PROGRAM OF GENITAL HUMAN PAPILLOMAVIRUSES IN INFECTION AND CANCER
Section snippets
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.
References (151)
Transforming activity of bovine and human papillomaviruses in cultured cells
Adv Cancer Res
(1991)- et al.
WAF1, a potential mediator of p53 tumor suppression
Cell
(1993) - et al.
Contacts in context: Promoter specificity and macromolecular interactions in transcription
Cell
(1996) - et al.
Transcriptional activity of human papillomavirus type 31b enhancer is regulated through synergistic interaction of AP1 with two novel cellular factors
Virology
(1995) - et al.
Methylation sensitivity of the enhancer from the human papillomavirus type 16
J Biol Chem
(1994) - et al.
The bovine papillomavirus E5 transforming protein can stimulate the transforming activity of EGF and CSF-1 receptors
Cell
(1989) - et al.
Both episomal and integrated forms of human papillomavirus type 16 are involved in invasive cervical cancers
Virology
(1989) - et al.
A single element mediates glucocorticoid hormone response of HPV18 with no functional interactions with AP1 or hbrm
Virology
(1996) - et al.
Oct-1 activates the epithelial-specific enhancer of human papillomavirus type 16 via a synergistic interaction with NFI at a conserved composite regulatory element
Virology
(1995) - et al.
Oncogenic transformation by human papillomavirus type 16 deoxyribonucleic acid in the presence of progesterone or progestins from oral contraceptives
Am J Obstet Gynecol
(1990)
The noncoding region of HPV-6vc contains two distinct transcriptional enhancing elements
Virology
The human papillomavirus type 16 E7 gene product interacts with and trans-activates the AP1 family of transcription factors
EMBO J
Differentiation-specific alternative splicing of bovine papillomavirus late mRNAs
J Virol
Retinoic acid-mediated repression of human papillomavirus 18 transcription and different ligand regulation of the retinoic acid receptor β gene in non-tumorigenic and tumorigenic HeLa hybrid cells
EMBO J
Identification of a negative regulatory domain in the human papillomavirus type 18 promoter: Interaction with the transcriptional repressor YY1
EMBO J
A switch region determines the cell type-specific positive or negative action of YY1 on the activity of the human papillomavirus type 18 promoter
J Virol
Characterization of the human papillomavirus E2 protein: evidence of trans-activation and trans-repression in cervical keratinocytes
EMBO J
The putative E5 open reading frame of cottontail rabbit papillomavirus is dispensable for papilloma formation in domestic rabbits
J Virol
Characterization of human papillomavirus type 11 E1 and E2 proteins expressed in insect cells
J Virol
Genetic and biochemical definition of the bovine papillomavirus E5 transforming protein
EMBO J
Transcriptional control of human papillomavirus (HPV) oncogene expression: Composition of the HPV type 18 upstream regulatory region
J Virol
Modulation of enhancer-promoter interactions by insulators in the Drosophila embryo
Nature
Progesterone and glucocorticoid response elements occur in the long control regions of several human papillomaviruses involved in anogenital neoplasia
J Virol
Interaction of papillomavirus E6 oncoproteins with a putative calcium-binding protein
Science
Viral E1 and E2 proteins support replication of homologous and heterologous papillomaviral origins
Proc Natl Acad Sci USA
Identification of a novel constitutive enhancer element and an associated binding protein: implications for human papillomavirus type 11 enhancer regulation
J Virol
The enhancer of human papillomavirus type 16; binding sites for the ubiquitous transcription factors oct-1, NFA, TEF-2, NF1, and AP-1 participate in epithelial cell-specific transcription
J Virol
Transcriptional activation of human papillomavirus 16 by nuclear factor I, AP1, steroid receptors and a possibly novel transcription factor, PVF: a model for the composition of genital papillomavirus enhancers
Nucleic Acids Res
A common function for polyoma virus large-T and papillomavirus E1 proteins?
Nature
The conserved C-terminal domain of the bovine papillomavirus E5 oncoprotein can associate with an α-adaptin-like molecule: A possible link between growth factor receptors and viral transformation
Mol Cell Biol
The human papillomavirus type 6 and 16 E5 proteins are membrane-associated proteins which associate with the 16-kilodalton pore-forming protein
J Virol
Transcriptional activation of the human papillomavirus-16 P97 promoter by an 88-nucleotide enhancer containing distinct cell-dependent and AP-1-responsive modules
New Biol
Transcriptional regulation of the human papillomavirus-16 E6-E7 promoter by a keratinocyte-dependent enhancer, and by viral E2 trans-activator and repressor gene products: implications for cervical carcinogenesis
EMBO J
Human papillomavirus type 16 and early cervical neoplasia
N Engl J Med
Analysis of the physical state of different human papillomavirus DNAs in intraepithelial and invasive cervical neoplasm
J Virol
Characterization of a nuclear factor, papilloma enhancer binding factor-1, that binds the long control region of human papillomavirus type 16 and contributes to enhancer activity
Mol Carcinog
Jak-STAT pathways and transcriptional activation in response to IFNs and other extracellular signaling proteins
Science
Transient replication of human papillomavirus DNAs
J Virol
The E2 transcriptional repressor can compensate for Sp1 activation of the human papillomavirus type 18 early promoter
J Virol
Production of human papillomavirus and modulation of the infectious program in epithelial raft cultures
Genes Dev
Human papillomavirus type 11 E2 proteins repress the homologous E6 promoter by interfering with the binding of host transcription factors to adjacent elements
J Virol
Specific interaction between HPV-16 E1-E4 and cytokeratins results in collapse of the epithelial cell intermediate filament network
Nature
The functional BPV-1 E2 trans-activating protein can act as a repressor by preventing formation of the initiation complex
Genes Dev
Suppression of cellular proliferation by the papillomavirus E2 protein
J Virol
The physical state of human papillomavirus type 16 DNA in benign and malignant genital tumours
J Gen Virol
Latent papillomavirus and recurring genital warts
N Engl J Med
Cloning of a negative transcription factor that binds to the upstream conserved region of Moloney murine leukemia virus
Mol Cell Biol
Binding of the human papillomavirus E1 origin-recognition protein is regulated through complex formation with the E2 enhancer-binding protein
Proc Natl Acad Sci USA
In vitro synthesis of oncogenic human papillomaviruses requires episomal genomes for differentiation-dependent late expression
Proc Natl Acad Sci USA
An element in the bovine papillomavirus late 3′ untranslated region reduces polyadenylated cytoplasmic RNA levels
J Virol
Cited by (0)
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