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Human papillomavirus oncoproteins: pathways to transformation

Nature Reviews Cancer volume 10, pages 550–560 (2010)Cite this article

Subjects

Key Points

  • Human papillomaviruses (HPVs) are the causative agents of over 99% of cervical cancers. Cervical cancer is the second largest cause of cancer deaths in women worldwide.

  • Infection by high-risk HPV types is necessary but not sufficient for progression to cancer. Mutations in cellular genes and chromosomal rearrangements induced by genomic instabilities are important contributing events.

  • HPV E6 and E7 are the primary transforming viral proteins and E5 enhances proliferation and may contribute to cancer progression.

  • A primary target of E7 is the retinoblastoma (Rb) family of proteins that control the activity of E2F transcription factors, which are key regulators of S phase genes. Inactivation of Rb is important for the differentiation-dependent productive viral lifecycle and for tumour progression.

  • The efficient abrogation of Rb function by E7 leads to increased levels of p53 and, consequently, the E6 proteins have evolved to target p53 for degradation. E6 also activates telomerase expression and modulates the activities of PDZ domain-containing proteins and tumour necrosis factor receptors.

  • E7 proteins also alter cell cycle control through interactions with histone deacetylases, cyclins and cyclin-dependent kinase inhibitors.

  • E6 and E7 induce genomic instability through multiple mechanisms, including aberrant centrosome duplication.

  • E6 and E7 also target cytokine expression to modulate cell proliferation and interferon responses, contributing to immune evasion.

  • E5 binds to B cell receptor-associated protein 31 in the endoplasmic reticulum to control trafficking of proteins and to the vacuolar ATPase in endosomes to modulate epidermal growth factor receptor turnover and maintain constitutive signalling.

Abstract

An association between human papillomavirus (HPV) infection and the development of cervical cancer was initially reported over 30 years ago, and today there is overwhelming evidence that certain subtypes of HPV are the causative agents of these malignancies. The p53 and retinoblastoma proteins are well-characterized targets of the HPV E6 and E7 oncoproteins, but recent studies have shown that the alteration of additional pathways are equally important for transformation. These additional factors are crucial regulators of cell cycle progression, telomere maintenance, apoptosis and chromosomal stability. Understanding how HPV oncoproteins modify these activities provides novel insights into the basic mechanisms of oncogenesis.

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Figure 1: The life cycle of human papillomaviruses.
Figure 2: Molecular mechanisms by which the human papillomavirus oncoproteins cooperate to induce cervical carcinogenesis.
Figure 3: The human papillomavirus E7 oncoprotein affects numerous cellular processes through interactions with multiple host cell proteins.
Figure 4: Cellular proteins and signalling pathways affected by the human papillomavirus E6 oncoprotein.
Figure 5: High-risk E5 interactions with cellular pathways and factors.

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Acknowledgements

L.A.L. is supported by grants from the National Cancer Institute and the National Institute for Allergy and Infectious Diseases. C.A.M. is supported by a K99 Pathway to Independence Award from the National Cancer Institute. We thank K. Simanis for assistance with the figures.

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  1. Department of MicrobiologyImmunology, Feinberg School of Medicine, Northwestern University, Chicago, 60611, Illinois, USA

    Cary A. Moody & Laimonis A. Laimins

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Glossary

Papanicolau smear

A method used to screen for the cellular changes that accompany HPV infection and used as a diagnostic for HPV-induced disease.

Episome

An extrachromosomal DNA element such as a plasmid that can replicate independently from host chromosomal DNA.

Organotypic raft culture

An in vitro method for growing keratinocytes at an air–liquid interphase that faithfully duplicates in vivo epithelial differentiation.

HECT family

A group of related E3 ubiquitin protein ligases that contain a conserved C-terminal 350 amino acid long homologous to the E6 C-terminus (HECT) domain that is involved in ubiquitylation of bound substrates.

Telomere

A double-stranded short tandem repeat found at the ends of chromosomes that consists of the sequence TTAGGG and is approximately 10–15 kb in length. Telomeres provide a cap for linear chromosomes and are important in maintaining genomic stability.

Telomerase reverse transcriptase

The catalytic protein subunit of telomerase, an RNA-dependent DNA polymerase that synthesizes telomere repeats at chromosomal ends.

Centrosome

The primary microtubule-organizing centre of human cells, which consists of a pair of centrioles. Centrosomes are duplicated only once before mitosis and are responsible for proper chromosome segregation during cell division.

ATM–ATR pathway

This involves phosphoinositide 3-like kinases important in sensing and repairing DNA damage. ATM is activated in response to double-stranded breaks and ATR is induced on the appearance of single-stranded lesions.

Fanconi anaemia

A rare disease characterized by chromosomal instability and a high incidence of squamous cell carcinomas of the head, neck and anogenital regions.

Anoikis

A form of programmed cell death that is activated when normal cells attempt to divide in the absence of attachment to the extracellular matrix.

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Moody, C., Laimins, L. Human papillomavirus oncoproteins: pathways to transformation. Nat Rev Cancer 10, 550–560 (2010). https://doi.org/10.1038/nrc2886

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