Papillomaviruses are small nonenveloped viruses with 55-nm-diameter icosahedral capsids that contain double-stranded DNA genomes of approximately 8,000 bp They are widely distributed throughout the animal kingdom, specifically infect squamous epithelia, and cause the generation of warts An

Mechanisms of Human Papillomavirus-Induced Oncogenesis

TFIID is a multisubunit protein complex comprised of the TATA-binding protein (TBP) and multiple TBP-associated factors (TAFs). The TAFs in TFIID are essential for activator-dependent transcription. The cloning of a complementary DNA encoding a human TFIID TAF, TAFII55, that has no known homolog in Drosophila TFIID is now described. TAFII55 is shown to interact with the largest subunit (TAFII230) of human TFIID through its central region and with multiple activators--including Sp1, YY1, USF, CTF, adenoviral E1A, and human immunodeficiency virus-type 1 Tat proteins--through a distinct amino-terminal domain. The TAFII55-interacting region of Sp1 was localized to its DNA-binding domain, which is distinct from the glutamine-rich activation domains previously shown to interact with Drosophila TAFII110. Thus, this human TFIID TAF may be a co-activator that mediates a response to multiple activators through a distinct mechanism.

https://science.sciencemag.org/content/sci/267/5197/531.full.pdf

Cloning of an intrinsic human TFIID subunit that interacts with multiple transcriptional activators

Human papillomaviruses (HPVs) are small double-stranded DNA viruses that infect the cutaneous and mucosal epithelium. Infection by specific HPV types has been linked to the development of cervical carcinoma. HPV infects epithelial cells that undergo terminal differentiation and so encode multiple mechanisms to override the normal regulation of differentiation to produce progeny virions. Two viral proteins, E6 and E7, alter cell cycle control and are the main arbitrators of HPV-induced oncogenesis. Recent data suggest that E6 and E7 also play a major role in the inhibition of the host cell innate immune response to HPV. The E1 and E2 proteins, in combination with various cellular factors, mediate viral replication. In addition, E2 has been implicated in both viral and cellular transcriptional control. Despite decades of research, the function of other viral proteins still remains unclear. While prophylactic vaccines to block genital HPV infection will soon be available, the widespread nature of HPV infection requires greater understanding of both the HPV life cycle as well as the mechanisms underlying HPV-induced carcinogenesis.

Human papillomaviruses: basic mechanisms of pathogenesis and oncogenicity

Human papillomavirus (HPV) infections play a crucial role in the pathogenesis of cervical neoplasia. Insights into the mechanisms by which HPV infection can, in a small numbers of cases, result in malignancy, comes from the observation that three proteins encoded by high-risk genital HPVs, E6, E7 and to a lesser extent E5, target factors that control the cell cycle and proliferation. These interactions result in abrogation of cell cycle control, chromosomal alterations, telomerase activation, and eventual cell immortalization. In this review, we discuss the functions of E6, E7, and E5 proteins that are most relevant to the malignant progression of HPV-transformed cells.

Human papillomaviruses: targeting differentiating epithelial cells for malignant transformation.

The papillomavirus E2 protein plays a central role in the viral life cycle as it regulates both transcription and replication of the viral genome. In this study, we showed that transient expression of bovine papillomavirus type 1 or human papillomavirus type 18 (HPV18) E2 proteins in HeLa cells activated the transcriptional activity of p53 through at least two pathways. The first one involved the binding of E2 to its recognition elements located in the integrated viral P105 promoter. E2 binding consequently repressed transcription of the endogenous HPV18 E6 oncogene, whose product has been shown previously to promote p53 degradation. The second pathway did not require specific DNA binding by E2. Expression of E2 induced drastic physiological changes, as evidenced by a high level of cell death by apoptosis and G1 arrest. Overexpression of a p53 trans-dominant-negative mutant abolished both E2-induced p53 transcriptional activation and E2-mediated G1 growth arrest, but showed no effect on E2-triggered apoptosis. These results suggest that the effects of E2 on cell cycle progression and cell death follow distinct pathways involving two different functions of p53.

/pdf/expression-of-the-papillomavirus-e2-protein-in-hela-cells-15d8g0rlp6.pdf

Expression of the papillomavirus E2 protein in HeLa cells leads to apoptosis.

We have shown that E1 and E2 proteins of human papillomavirus type 11 (HPV-11) were essential to support the replication of the homologous viral origin (ori) in a transient replication assay, similar to reports on bovine papillomavirus type 1 (BPV-1). Unexpectedly, matched or even mixed combinations of E1 and E2 proteins from HPV-11 or BPV-1 replicated either ori in human, monkey, and rodent cell lines of epithelial or fibroblastic lineage, albeit with varied efficiencies. Either set of viral proteins was also able to initiate replication of ori-containing plasmids from many other human and animal papillomaviruses. Thus the interactions among the cis elements and trans factors of papillomaviruses are more conserved than expected from the other members of the papovavirus family, simian virus 40 and polyomavirus, for which large tumor antigen does not replicate a heterologous ori in either permissive or nonpermissive cells. We infer that the stringent species and tissue specificities observed for papillomaviruses in vivo are not entirely due to direct restrictions on viral DNA replication. Rather, transcriptional control of viral gene expression must play a dominant role.

https://www.pnas.org/content/pnas/89/13/5799.full.pdf

Thau F. Ho

Papers

Viral E1 and E2 proteins support replication of homologous and heterologous papillomaviral origins.