The E6 oncoprotein derived from tumour-associated human papillomaviruses (HPVs) binds to and induces the degradation of the cellular tumour-suppressor protein p53. A common polymorphism that occurs in the p53 amino-acid sequence results in the presence of either a proline or an arginine at position 72. The effect of this polymorphism on the susceptibility of p53 to E6-mediated degradation has been investigated and the arginine form of p53 was found to be significantly more susceptible than the proline form. Moreover, allelic analysis of patients with HPV-associated tumours revealed a striking overrepresentation of homozygous arginine-72 p53 compared with the normal population, which indicated that individuals homozygous for arginine 72 are about seven times more susceptible to HPV-associated tumorigenesis than heterozygotes. The arginine-encoding allele therefore represents a significant risk factor in the development of HPV-associated cancers.

The wild-type p53 protein exhibits a common polymorphism at amino acid 72, resulting in either a proline residue (p53Pro) or an arginine residue (p53Arg) at this position. Despite the difference that this change makes in the primary structure of the protein resulting in a difference in migration during sodium dodecyl sulfate-polyacrylamide gel electrophoresis, no differences in the biochemical or biological characteristics of these wild-type p53 variants have been reported. We have recently shown that p53Arg is significantly more susceptible than p53Pro to the degradation induced by human papillomavirus (HPV) E6 protein. Moreover, this may result in an increased susceptibility to HPV-induced tumors in homozygous p53Arg individuals. In further investigating the characteristics of these p53 variants, we now show that both forms are morphologically wild type and do not differ in their ability to bind to DNA in a sequence-specific manner. However, there are a number of differences between the p53 variants in their abilities to bind components of the transcriptional machinery, to activate transcription, to induce apoptosis, and to repress the transformation of primary cells. These observations may have implications for the development of cancers which harbor wild-type p53 sequences and possibly for the ability of such tumors to respond to therapy, depending on their p53 genotype.

Human papillomaviruses (HPVs) are associated with a number of clinical conditions, of which the most serious is cervical carcinoma. The E6 protein of the oncogenic, mucosal-speci®c HPV types has been shown to complex with p53 and, as a result, target it for rapid proteasomemediated degradation. As a consequence, p53's growtharrest and apoptosis-inducing activities are abrogated. Since p53 is frequently wild type in cervical cancers, unlike other cancers in which it is often mutated, the notion has arisen that E6's activity with respect to p53 is equivalent to an inactivating mutation of p53. In addition, several studies have shown that the pathways both upstream and downstream of p53 are intact in cervical cancers; this suggests the potential importance of the E6 ± p53 interaction for therapeutic intervention. However, like all viral oncoproteins, E6 is a multifunctional protein and a plethora of other cellular targets has been identi®ed. Indeed, E6's interactions with some of these additional targets appear to be equally important in the pathogenesis of HPV, and may also represent valid targets for therapeutic intervention.

The oncoproteins of small DNA tumor viruses promote tumorigenesis by complexing with cellular factors intimately involved in the control of cell proliferation. The major oncogenic determinants for human adenovirus type 9 (Ad9) and high-risk human papillomaviruses (HPV) are the E4-ORF1 and E6 proteins, respectively. These seemingly unrelated viral oncoproteins are similar in that their transforming activities in cells depend, in part, on a carboxyl-terminal PDZ domain-binding motif which mediates interactions with the cellular PDZprotein DLG. Here we demonstrated that both Ad9 E4-ORF1 and high-risk HPV E6 proteins also bind to the DLG-related PDZ-protein MAGI-1. These interactions resulted in MAGI-1 being aberrantly sequestered in the cytoplasm by the Ad9 E4-ORF1 protein or being targeted for degradation by high-risk HPV E6 proteins. Transformation-defective mutant viral proteins, however, were de®cient for these activities. Our ®ndings indicate that MAGI-1 is a member of a select group of cellular PDZ proteins targeted by both adenovirus E4-ORF1 and high-risk HPV E6 proteins and, in addition, suggest that the tumorigenic potentials of these viral oncoproteins depend, in part, on an ability to inhibit the function of MAGI-1 in cells.

Ultraviolet B (UVB) damage is recognized as the most important etiological factor in the development of skin cancer. Human papillomaviruses (HPV) have also been implicated in the disease, although the mechanism of action of these viruses remains unknown. We present evidence here that Bak protein is involved in signaling apoptosis in the skin in response to UVB damage, and that cutaneous HPV E6 proteins target and abrogate Bak function by promoting its proteolytic degradation both in vitro and in regenerated epithelium. Additionally, HPV positive skin cancers had undetectable levels of Bak in contrast to HPV negative cancers, which expressed Bak. This study supports a link between the virus and UVB in the induction of HPV-associated skin cancer and reveals a survival mechanism of virally infected cells.

Human papillomavirus (HPV) E6 proteins inhibit apoptosis in both p53-dependent and p53-independent manners. A key point in apoptosis is the regulation provided by the Bcl-2 family; and in dierentiating keratinocytes, in which HPV replicates, the Bak protein is highly expressed. We show that HPV-18 E6 will inhibit Bak-induced apoptosis and this is mediated by an interaction between the E6 and Bak proteins resulting in degradation of the Bak protein in vivo. We also show that Bak protein interacts with the ubiquitin ligase, E6AP, and that a mutant of Bak defective in E6AP binding is overexpressed in comparison with wild type. These studies suggest that Bak is probably the ®rst naturally occurring target of E6AP to be identi®ed.

The E6 proteins from the high-risk human papillomavirus (HPV) types have previously been shown to target a number of PDZ domain-containing proteins for proteasome-mediated degradation. These include the hDlg tumour suppressor and the MAGI-1 protein. In this study we show that high-risk HPV E6 proteins also target the related MAGI-2 and MAGI-3 proteins for degradation. Moreover, we show that the interaction is specific to one PDZ domain, and that co-expression of this domain can protect each of the full-length MAGI proteins from E6-mediated degradation. These data provide clear indicators for the potential design of compounds that could specifically inhibit the interaction of oncogenic HPV E6 proteins with an important class of target proteins.

Human papillomaviruses (HPVs) are the causative agents of a number of human cancers, of which cervical cancer is the most important. This occurs following persistent infection with a limited number of viral subtypes and is characterized by continued expression of the viral E6 and E7 oncoproteins. A unique characteristic of the cancercausing HPV types is the presence of a PDZ recognition motif on the carboxy terminus of the E6 oncoprotein. Through this motif, E6 directs the proteasome-mediated degradation of cellular proteins involved in the regulation of cell polarity and in cell proliferation control. These include components of the Scrib and Par polarity complexes, as well as a number of other PDZ domaincontaining substrates. Thus, PVs are now providing novel insights into the functioning of many of these cellular proteins, and into which of these functions, in particular, are relevant for maintaining normal cellular homeostasis. In this review, we discuss the biological consequences of papillomaviral targeting of these cell polarity regulators, both with respect to the viral life cycle and, most importantly, to the development of HPV-induced malignancy.