Chapter 7 : Activities of the Transforming Proteins of Human Papillomaviruses

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This chapter deals with viruses which infect the genital tract, although viruses that infect in this region can also infect the oral cavity. Human papillomaviruses (HPVs) are the etiological agents of various lower genital tract cancers, which are important globally. The chapter describes the properties of HPV-16 E5, E6, and E7 and suggests ways in which they might collectively induce S phase in epithelial cells that are being programmed for terminal differentiation. Reference will be made to other HPVs where appropriate, and some comparisons with bovine papillomaviruses (BPVs) are made, especially when discussing the properties of E5. The first section deals with the E6 proteins, its interaction with cellular proteins, and the possible consequences of these interactions with regard to HPV life cycle. The second and third sections deal with E7 proteins and E5 proteins, respectively. E6, a multifunctional HPV protein, has been shown to activate transcription from some promoters and inhibit from others and binds to at least two cellular proteins, E6-associated protein (E6AP) and E6 binding protein (E6BP). The HPV E7 protein plays a critical role in altering the cellular environment for the benefit of viral replication. The E5 gene of most HPVs is located just downstream of the E2 open reading frame. The E5 proteins from both HPV-16 and BPV-1 also bind to the 16-kDa subunit of the vacuolar ATPase. The chapter provides a summary of the action of E6, E7, and E5 on keratinocyte differentiation and cell cycle progression.

Citation: Nead M, McCance D. 1998. Activities of the Transforming Proteins of Human Papillomaviruses, p 225-251. In McCance D (ed), Human Tumor Viruses. ASM Press, Washington, DC. doi: 10.1128/9781555818289.ch7
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Figure 1

Diagram of HPV-16 E6 and some of the mutations used in two studies to determine the domains of E6 important for binding to p53. The mutations are shown on the top line, and the percentage binding is given in parentheses for each study as indicated. The data as indicated are from references (above the box) and (below the box). A more complete description of the E6 mutations and p53 binding can be found in reference .

Citation: Nead M, McCance D. 1998. Activities of the Transforming Proteins of Human Papillomaviruses, p 225-251. In McCance D (ed), Human Tumor Viruses. ASM Press, Washington, DC. doi: 10.1128/9781555818289.ch7
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Figure 2

Diagrammatic representation of the HPV-16 E7 protein and the three domains CR1, CR2, and CR3. The known functions of each domain are indicated, and the cellular proteins which bind to each domain are noted below the diagram.

Citation: Nead M, McCance D. 1998. Activities of the Transforming Proteins of Human Papillomaviruses, p 225-251. In McCance D (ed), Human Tumor Viruses. ASM Press, Washington, DC. doi: 10.1128/9781555818289.ch7
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Figure 3

The retinoblastoma protein (Rb) represses the transactivation of E2F (panels A and C), and this repression is removed during normal cell cycling at the latter part of the G1 phase of the cell cycle when Rb is phosphorylated (B). Rb binds to the histone deacetylase 1 protein (HDAC-1), which may help in the repression of transcription from an E2F promoter. E7 is known to depress Rb, and it is thought to disrupt the Rb/E2F complex (D). In addition, E7 can bind HDAC-1 and so may derepress by competing away from Rb the inhibitory activity of HDAC-1 (D).

Citation: Nead M, McCance D. 1998. Activities of the Transforming Proteins of Human Papillomaviruses, p 225-251. In McCance D (ed), Human Tumor Viruses. ASM Press, Washington, DC. doi: 10.1128/9781555818289.ch7
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Figure 4

(A) Diagram of the binding of the EGF ligand to its receptor, EGFR, and the subsequent pathway of the down-regulation and destruction of receptor and ligand through the lysosomal pathway. In human keratinocytes in culture, about 5% of receptors recycle to the surface of the cell.

Citation: Nead M, McCance D. 1998. Activities of the Transforming Proteins of Human Papillomaviruses, p 225-251. In McCance D (ed), Human Tumor Viruses. ASM Press, Washington, DC. doi: 10.1128/9781555818289.ch7
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Figure 4

(B) The same pathway but this time in the presence of HPV-16 E5. The effects of E5 are indicated by the direction of the arrows inside the E5 boxes. Thus, for example, acidification of the endosomal compartment is inhibited in the present of E5 as indicated by the arrow, while recycling of the receptor is increased to 40% in the presence of E5.

Citation: Nead M, McCance D. 1998. Activities of the Transforming Proteins of Human Papillomaviruses, p 225-251. In McCance D (ed), Human Tumor Viruses. ASM Press, Washington, DC. doi: 10.1128/9781555818289.ch7
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