ReviewHuman papillomavirus immortalization and transformation functions
Introduction
Certain HPV types are causally associated with human cervical cancer. In addition to the many epidemiologic studies which have established that infection by specific HPV types is a risk factor for cervical preneoplastic disease and cancer, molecular studies have provided strong support for a mechanistic role for these viruses in the initiation of a process that can result in squamous cancer. Support for a role for the HPV E6 and E7 genes in cervical carcinogenesis comes from studies that have established that the transforming properties of these two proteins mirror their clinical associations. The cloned DNAs of the ‘high-risk’ HPVs are efficient at being able to extend the life span and contribute to the immortalization of squamous epithelial cells (Durst et al., 1987, Schlegel et al., 1988). This immortalization property is not shared by the DNAs of the ‘low-risk’ HPVs. The E6 and E7 genes of the ‘high-risk’ HPV types together are necessary and sufficient for the efficient immortalization of primary squamous epithelial cells (Hawley-Nelson et al., 1989, Münger et al., 1989a), whereas the E6 and E7 proteins encoded by the ‘low-risk’ viruses are either inactive or only weakly active in the same assays. The HPV E6 and E7 genes are invariably expressed in HPV positive cervical cancers. Shutting off the expression of E6 and E7 in cervical cancern lines either by antisense RNA or by E2 repression of the E6/E7 viral promoter, results in a growth arrest of the cancer cells that can lead to cellular senescence or apoptosis (Desaintes et al., 1997, Dowhanick et al., 1995, Francis et al., 2000, Hwang et al., 1993, Thierry and Yaniv, 1987, von Knebel-Doeberitz et al., 1988, Wells et al., 2000.
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Transformation and immortalization assays for human papillomaviruses
Human papillomaviruses (HPVs) have transforming properties in a number of established rodent cell lines. In contrast to the more potent transforming papillomavirus, bovine papillomavirus type I (BPV-1), the HPVs do not induce focus formation unless they are cotransfected with a selectable marker such as a neomycin resistance gene (Yasumoto et al., 1986). This procedure yields transformed colonies that are not density arrested, grow in soft agar containing growth medium, and cause the formation
The HPV E5 protein
In BPV-1 and other papillomaviruses that induce fibropapillomas, the E5 open reading frame encodes a major transforming function (DiMaio et al., 1986, Groff and Lancaster, 1986, Rabson et al., 1986, Schiller et al., 1986). The BPV-1 E5 gene encodes a small, 44 amino acid membrane associated protein (Schlegel et al., 1986) that is localized mostly to the Golgi apparatus and the endoplasmic reticulum (Burkhardt et al., 1989, Burnett et al., 1992). It forms a disulfide-linked dimer (Burkhardt et
The HPV E6 oncoprotein
The transforming properties of E6 were first revealed when it was shown that efficient immortalization of primary human fibroblasts or keratinocytes requires the combination of E6 and E7 (Hawley-Nelson et al., 1989, Münger et al., 1989a, Watanabe et al., 1989). Immortalization is dependent upon the full length E6 gene; mutational analysis has shown that major splice variant of E6 expressed in cervical cancer lines, the HPV-16 E6* gene does not provide this function (Münger et al., 1989a). There
The HPV E7 oncoprotein
The high-risk HPV E7 proteins are small predominantly nuclear polypeptides of approximately 100 amino acids. They bind zinc through their carboxyl terminal domain, which contains two copies of a Cys–X–X–Cys domain that is related to those that make up the E6 proteins (Münger et al., 2001). The E7 proteins are phosphorylated by casein kinase II (CK II) at an amino terminal domain and by an unidentified protein kinase in the carboxyl terminus. The HPV E7 protein has a short half-life and is
Functions of Eb and E7 oncoproteins in the viral life cycle
The major cell cycle pathways perturbed by the papillomavirus E6 and E7 oncoproteins are shown in Fig. 5. Since malignant progression of a high-risk HPV-associated lesion is frequently accompanied by integration of the viral DNA into a host chromosome, HPV-mediated cellular transformation represents an accidental and terminal event that is not part of the normal viral life cycle. What then are the roles of the high-risk HPV E6 and E7 oncoproteins in the normal viral life cycle? It is
Acknowledgements
The work from our own laboratories that is described in this review has been supported by grants from the National Institutes of Health.
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