Oncogenic activities of human papillomaviruses

Abstract

Infectious etiologies for certain human cancers have long been suggested by epidemiological studies and studies with experimental animals. Important support for this concept came from the discovery by Harald zur Hausen's group that human cervical carcinoma almost universally contains certain "high-risk" human papillomavirus (HPV) types. Over the years, much has been learned about the carcinogenic activities of high-risk HPVs. These studies have revealed that two viral proteins, E6 and E7, that are consistently expressed in HPV-associated carcinomas, are necessary for induction and maintenance of the transformed phenotype. Hence, HPV-associated tumors are unique amongst human solid tumors in that they are universally caused by exposure to the same, molecularly defined oncogenic agents, and the molecular signal transduction pathways subverted by these viral transforming agents are frequently disrupted in other, non-virus-associated human cancers.

Figure 1

Schematic representation of the HPV16 genome. The double stranded circular DNA genome is represented by the central circle. Early (E) and late (L) genes are encoded on a single DNA strand in all three possible open reading frames as indicated. The major early promoter in the non-coding region (NCR) (also referred to as Long Control Region, LCR or Upstream Regulatory Region, URR) is represented by an arrow. Early and late genes are transcribed unidirectionally. See text for details.

Figure 2

Major mechanisms (white boxes) utilized by the HPV E7 oncoprotein to induce specific hallmarks of human tumors (black boxes). See text for details.

Figure 3

Major mechanisms (white boxes) utilized by the HPV E6 oncoprotein to induce specific hallmarks of human tumors (black boxes). See text for details.

Figure 4

High-risk HPV E6 and E7 oncoproteins contribute to early and late steps of tumor development. The HPV E7 oncoprotein subverts G1/S restriction through degradation of the retinoblastoma tumor suppressor, pRB. This causes aberrant cell cycle entry, which would normally result in activation of the p53 tumor suppressor, causing cell death. High-risk HPV E6 oncoproteins target p53 for degradation thereby allowing cells to undergo persistent, aberrant proliferation. To avoid telomere erosion as a result of extensive cell division, HPV16 E6 activates hTERT transcription causing cellular immortalization. In addition high-risk HPV oncoproteins also contribute to malignant progression through induction of mitotic abnormalities, which result in genomic instability. See text for detail

Figure 5

Schematic representation of the HPV16 E6 (top) and E7 (bottom) oncoproteins. Sequences involved in cellular transformation are marked by gray bars, and some of the major cellular targets that associate with the viral oncoproteins through such sequences are indicated. See text for details

Figure 6

Reprogramming of cellular ubiquitin ligases by HPV16 oncoproteins. (A) HPV16 E7 retargets the cullin 2 ubiquitin ligase complex to ubiquitinate the retinoblastoma tumor suppressor and potentially other HPV16 E7 associated cellular protein. (B) High-risk HPV E6 oncoproteins associate with the ubiquitin ligase E6AP to ubiquitinate the p53 tumor suppressor protein. The E6/E6AP complex has also been implicated in mediating ubiquitination of high-risk HPV E6 associated cellular PDZ proteins. See text for details.