Chapter 2 : Introduction to DNA Tumor Viruses: Adenovirus, Simian Virus 40, and Polyomavirus

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Human adenovirus, simian virus 40 (SV40), and murine polyomavirus are small DNA viruses, classified as tumor viruses because they can induce tumors in rodents and immortalize primary cells in vitro. This chapter reviews the historical role of adenovirus and SV40 in illuminating the molecular basis of retinoblastoma gene product (pRb) and p53 function. More recently recognized interactions between the transforming proteins of adenovirus, SV40, and polyomavirus and cell growth control products are considered in this chapter. Human papillomaviruses (HPVs) have small circular genomes like SV40 and polyomavirus, but they express a series of early genes more like adenovirus. The contribution of E1A and large-T-antigen studies to the current understanding of the molecular roles of p53 and the pRb family in the control of cell growth is discussed in this chapter. Interactions of the adenovirus, SV40, and polyomavirus transforming proteins are described in this chapter. The human adenoviruses, SV40, and murine polyomavirus have each contributed importantly to the understanding of the molecular events that underlie carcinogenesis. Adenovirus interactions with its human hosts are of considerable importance for at least two reasons. One is that adenovirus targets the major tumor suppressors pRb and p53 very effectively, yet, in contrast to viruses such as HPV, has never been associated with human cancer. The second reason for interest in adenovirus/human interactions is that the biological properties of adenovirus have made it an attractive gene therapy vector. These viruses provided the first clear view of the functional links between disparate families of cell cycle-regulating molecules.

Citation: Beck, Jr. G, Zerler B, Moran E. 1998. Introduction to DNA Tumor Viruses: Adenovirus, Simian Virus 40, and Polyomavirus, p 51-86. In McCance D (ed), Human Tumor Viruses. ASM Press, Washington, DC. doi: 10.1128/9781555818289.ch2
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Figure 1

Schematic representation of adenovirus genome transcription products and the translation products of the E1A and E1B transforming genes. (A) The Ad2 or Ad5 genome consists of approximately 36,000 bp of linear double-stranded DNA. Adenovirus transcribes from both strands (the direction is indicated by the arrows). The early (E) and major late transcription units are represented as bars. Each transcription unit is further processed to produce a variety of products. The early transcription units produce the transforming proteins and proteins involved in virus replication, gene expression, and host interactions. The late proteins are mostly virus structural proteins. (B) The E1A and E1B genes produce a series of mRNAs through alternate splicing. The splice junctions are represented by dashed lines. The most prominent E1A splice products early in infection are the 13S and 12S mRNAs, named for their sedimentation coefficients. The corresponding 13S and 12S proteins are translated in the same reading frame and differ only by an internal region of 46 amino acids unique to the 13S product. The 13S unique region is required for efficient transcription of the remaining viral transcription units. However, all of the functions required for transformation of rodent cells in culture are contained within the common sequence represented by the 12S product. E1B produces two distinct proteins which initiate from different reading frames and have no sequence in common. As indicated in the text, the E1B 55K product targets p53. The 19K product is a homolog of the cellular protein Bcl-2, which restricts the apoptosis response. AA, amino acids.

Citation: Beck, Jr. G, Zerler B, Moran E. 1998. Introduction to DNA Tumor Viruses: Adenovirus, Simian Virus 40, and Polyomavirus, p 51-86. In McCance D (ed), Human Tumor Viruses. ASM Press, Washington, DC. doi: 10.1128/9781555818289.ch2
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Figure 2

Linear representation of the SV40 genome and transcription products. The SV40 genome consists of 5,243 bp of circular double-stranded DNA. SV40 transcribes from sequences near the single origin of replication in the clockwise direction to produce the early mRNAs (direction of transcription represented by the rightward arrow), and in the counterclockwise direction to produce the late mRNAs (direction of transcription represented by the leftward arrow). The late transcription unit encodes the virus structural proteins (VP-1, VP-2, and VP-3). The early transcription unit is differentially spliced (the splice site is represented by the dashed line) to produce mRNAs encoding the two SV40 transforming proteins, large T and small t antigens. Large T and small t antigens share an amino-terminal region of 82 residues, followed by areas of sequence unique to each.

Citation: Beck, Jr. G, Zerler B, Moran E. 1998. Introduction to DNA Tumor Viruses: Adenovirus, Simian Virus 40, and Polyomavirus, p 51-86. In McCance D (ed), Human Tumor Viruses. ASM Press, Washington, DC. doi: 10.1128/9781555818289.ch2
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Figure 3

Linear representation of the murine polyomavirus genome and transcription products. The polyomavirus genome consists of 5,295 bp of circular double-stranded DNA with a genetic organization similar to that of SV40. Polyomavirus transcribes from sequences near the single origin of replication in the clockwise direction to produce the early mRNAs (direction of transcription represented by the rightward arrow), and in the counterclockwise direction to produce the late mRNAs (direction of transcription represented by the leftward arrow). The late transcription unit encodes the virus structural proteins (VP-1, VP-2, and VP-3). The early transcription unit is differentially spliced (the splice site junctions are represented by the dashed lines) to produce four messages encoding the early proteins: large T, middle T, small t, and tiny t antigens. All of the polyomavirus T antigens share amino-terminal protein sequence, and the carboxy-terminal sequence of small t antigen is contained within large T antigen. Small t antigen has an internal region that is not present in large T or tiny t antigens, but is common to middle T antigen. The carboxy-terminal regions of middle T antigen and tiny t antigen are unique. Despite the overall similarity of the polyomavirus and SV40 genome structures, the T antigens differ significantly between the two viruses. The large T antigens of both contain J domains and functional pRb family binding motifs. However, polyomavirus large T antigen does not show p53 binding activity and does not transform efficiently in the absence of middle T antigen. Middle T antigen is the major transforming agent of the polyomavirus genome. Its transforming activity is largely localized to its unique sequence, which encodes binding sites for a number of cytoplasmic cell proteins involved in growth factor signaling (see also Fig. 9 ).

Citation: Beck, Jr. G, Zerler B, Moran E. 1998. Introduction to DNA Tumor Viruses: Adenovirus, Simian Virus 40, and Polyomavirus, p 51-86. In McCance D (ed), Human Tumor Viruses. ASM Press, Washington, DC. doi: 10.1128/9781555818289.ch2
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Figure 4

Schematic of the 708-residue SV40 large T antigen gene product and major protein binding sites linked with transforming activities. (A) SV40 large T antigen contains an amino-terminal J domain of approximately 80 residues which mediates interaction with cellular hsc70. This interaction promotes the degradation of pl30 and posttranslational modifications of pl07, effects that correlate with increased cell cycle activity. This interaction may have consequences for other targets of large T function as well, including components of replication complexes. The J domain is present in both the large T and small t antigens. Sequences downstream of the J domain are not common to small t antigen. These include the pRb family binding site, which is specified by the conserved Leu-X-Cys-X-Glu (LXCXE) motif. p53 is bound via two noncontiguous regions near the C terminus of the protein. The potential Bcl-2 homology domain falls between the p53 binding regions. SV40 large T antigen has a variety of other functions not indicated here. It participates directly in transcription of the SV40 late genes and interacts with the basal transcription machinery. It also participates directly in replication complexes and encodes ATPase and helicase active regions which are required for its role in replication. The murine polyomavirus large T antigen has regions of both homology and dissimilarity with SV40 large T antigen. Polyomavirus large T antigen contains an amino-terminal J domain that binds hsc70 and an LXCXE motif that mediates binding to the pRb family. However, polyomavirus large T antigen does not include a recognizable p53 binding function, nor does it transform well in the absence of middle T antigen, which has no direct homolog in SV40. The properties of middle T antigen are illustrated in Fig. 9 . (B) p53 is present in immune complexes isolated from infected cells using a monoclonal antibody reactive with large T antigen. In the autoradiogram shown, isotopically labeled cells were lysed and the lysate was immunoprecipitated with an antibody that reacts with the N-terminal region common to large T and small t antigens. Visualization of immune complexes such as this one first called attention to p53 and were the impetus for the cloning and characterization of this important cell growth regulatory molecule. Not all important associations are readily detectable in this manner. Detection of pRb association with large T antigen requires more sensitive assays, although this binding activity is readily apparent with the E1A proteins (shown in Fig. 5 ).

Citation: Beck, Jr. G, Zerler B, Moran E. 1998. Introduction to DNA Tumor Viruses: Adenovirus, Simian Virus 40, and Polyomavirus, p 51-86. In McCance D (ed), Human Tumor Viruses. ASM Press, Washington, DC. doi: 10.1128/9781555818289.ch2
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Figure 5

Representation of the 243-residue E1 A12S product and protein binding activities. (A) The 12S protein is represented by the bar. The break in the bar indicates the splice site, where the first and second exons are joined. Shaded regions are those that have been linked with binding activities and transforming functions. Conserved regions 1 and 2 are areas that are extensively conserved among adenoviruses of different serotypes. Conserved region 1 contributes to the nonoverlapping binding sites of both the p300 and pRb families and so is represented as a loop. The key residues required for pRb family binding are the Leu-X-Cys-X-Glu (LXCXE) motif in conserved region 2. The same motif mediates pRb binding activity in SV40 and polyomavirus large T antigens. A key residue required for p300 binding is a conserved Arg (R) at position 2 in the amino-terminal region (N). The E1A second exon contains an activity that restricts the tumorigenic potential of cells immortalized by El A. This function is linked with binding of a C-terminal binding protein (CtBP) through a conserved five-residue motif, PLDLS ( ). (B) Immune complexes isolated from infected cells using a monoclonal antibody with specificity for the carboxy-terminal region of the El A proteins show stable association with p300, CBP, and the pRb family (p105-Rb, pl07, and pl30). This autoradiogram shows an electrophoretic separation of the proteins associated with the wild-type 12S El A product. (p300 and CBP do not resolve distinguishably in the conditions of this gel.) Various E1A mutants have been generated that abrogate binding to either p300/CBP or the pRb family. Such mutants have been very useful in distinguishing the respective roles of the p300 and pRb families in pathways regulating cell growth and differentiation. Closer examination of the E1A complexes revealed that they also contain cyclin A and cyclin E, with their associated cyclin-dependent kinases, products which are not as prominent in the conditions of this gel. The presence of the cyclins in the E1A complexes is dependent on the presence of the pRb-related proteins, which led to the understanding that they do not contact E1A directly, but are associated through pl30 and pl07.

Citation: Beck, Jr. G, Zerler B, Moran E. 1998. Introduction to DNA Tumor Viruses: Adenovirus, Simian Virus 40, and Polyomavirus, p 51-86. In McCance D (ed), Human Tumor Viruses. ASM Press, Washington, DC. doi: 10.1128/9781555818289.ch2
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Figure 6

Cellular targets of the DNA tumor virus transforming proteins. The tumor viruses have evolved similar strategies for targeting host cell pathways important for cellular proliferation and apoptosis. This diagram illustrates the roles of the major host proteins targeted by the viral protein products (gray boxes). A common target among tumor viruses is the pRb family of proteins. This protein family functions, in part, by regulating the E2F family of transcription factors. The E2F family of proteins is responsible for the transcription of many key cell cycle regulatory genes. The adenovirus E1A proteins, the SV40 and polyomavirus large T antigens (LT-ag), and the HPV E7 protein all bind directly to the pRb family of proteins. This, in turn, abrogates control of E2F transcription, allowing the cell to enter the cell cycle. Another key regulator of cell growth is p53. p53 can stop the cell cycle by upregulating, among other targets, the cyclin-dependent kinase inhibitor p21. Depending on other signals, p53 can also initiate the cell death machinery (apoptosis). Adenovirus E1B 55K, SV40 large T antigen, and the HPV E6 protein all target p53 directly. Adenovirus E1A targets p53 indirectly by binding p300, which normally serves as a transcriptional coactivator of p53. Still another way in which adenovirus targets apoptotic pathways is through its E1B19K protein product. This protein mimics the growth survival protein Bcl-2. Polyomavirus middle T antigen has evolved a different method for circumventing cell growth control. It is a plasma membrane-bound protein that targets the growth factor signal transduction cascade. Middle T antigen usurps this signal cascade by binding key components of the signaling pathway, including the Src family of tyrosine kinases (c-, c-, and c-), protein phosphatase 2A (PP2A), the Shc-Grb2 complex, 14-3-3 proteins, phosphatidylinositol 3-kinase (PI3-K), and phospholipase C (PLCγ-I).

Citation: Beck, Jr. G, Zerler B, Moran E. 1998. Introduction to DNA Tumor Viruses: Adenovirus, Simian Virus 40, and Polyomavirus, p 51-86. In McCance D (ed), Human Tumor Viruses. ASM Press, Washington, DC. doi: 10.1128/9781555818289.ch2
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Figure 7

Functional regions of human p53. The bar represents the 393-residue open reading frame of human p53. Major functional regions are indicated by shading. The binding sites for the Ad5 E1B 55K protein, SV40 large T antigen, and HPV E6 are indicated by lines below the bar. p300 and CBP interact with p53 in the amino-terminal activation domain, a region also involved in MDM2 (mouse double minute 2) binding. p300/CBP-mediated acetylation at a site near the carboxy terminus (represented by the asterisk) relieves the repressive effect that the carboxy-terminal regulatory domain exerts on p53 site-specific DNA binding. This permits p53 to bind to DNA target sequences with greater affinity and increases transcription of p53 targets such as the cyclin-dependent kinase inhibitor, p21, which inhibits cell cycle progression (see also Fig. 6 ).

Citation: Beck, Jr. G, Zerler B, Moran E. 1998. Introduction to DNA Tumor Viruses: Adenovirus, Simian Virus 40, and Polyomavirus, p 51-86. In McCance D (ed), Human Tumor Viruses. ASM Press, Washington, DC. doi: 10.1128/9781555818289.ch2
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Figure 8

Functions of p300. (A) The bar represents the 2,414-residue open reading frame of p300. At least four distinguishable protein binding sites have been identified in p300 and are indicated by shading. An amino-terminal region binds various nuclear hormone receptors including the retinoic acid receptor, the estrogen receptor, and the glucocorticoid receptor. p300 contains a binding site for the cyclic AMP-responsive element binding protein (CREB). The CREB binding region also serves as a binding site for various other transcription factors including c- and c-. p300 contains a bromodomain, but no specific function has yet been linked with this motif. p300 has both intrinsic and associated histone acetyltransferase (HAT) activities. Associated acetylases include P/CAF (p300/CBP-associated factor). p300 also contains an intrinsic HAT activity, which maps to the region indicated by the line below the bar. p300 has at least one other protein binding region, a region near the carboxy terminus which binds the nuclear hormone receptor cofactor SRC-1. Sequences in this region also mediate binding to other transcription factors including YY-1. The binding site for p53 association has not yet been localized definitively on p300. In addition to binding various upstream activators of transcription, p300 interacts with the basal transcription machinery. p300 and CBP are stably associated with TBP (TATA binding protein) complexes in vivo, and p300 binds directly in vitro to TFIIB (transcription factor IIB) at a region similar to that used by P/CAF. (B). The combination of properties, binding to upstream activators, association with the basal transcription machinery, and the presence of HAT activity suggests that p300 integrates signals from each of these sources. p300 can bind multiple upstream activators and/or cofactors simultaneously and thus has the potential to synergize the effects of these molecules. Similarly, p300 can connect upstream activation signals to the basal transcription machinery. The HAT activity may contribute to transcriptional activation through multiple channels. p300 can acetylate histones, suggesting that it contributes to chromatin remodeling. p300 can also mediate acetylation of at least one upstream activator, p53. This acetylation enhances p53 site-specific DNA binding activity and consequent transactivation function. Acetylation of components of the basal transcription machinery may also be an aspect of p300 function.

Citation: Beck, Jr. G, Zerler B, Moran E. 1998. Introduction to DNA Tumor Viruses: Adenovirus, Simian Virus 40, and Polyomavirus, p 51-86. In McCance D (ed), Human Tumor Viruses. ASM Press, Washington, DC. doi: 10.1128/9781555818289.ch2
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Figure 9

Binding activities of murine polyomavirus middle T antigen. The bar represents the 421-residue open reading frame of murine polyomavirus middle T antigen. Major functional regions are indicated by shading. The amino-terminal 79 residues comprise a J domain motif, which mediates interaction with the cellular hsc70 protein. The approximate binding sites for PP2A and various cell signaling molecules bound by middle T antigen are also indicated. Middle T antigen binds c- (and other family members including c- and c-). c- binding is mediated by two Cys-X-Cys-X-X-Cys motifs (2X-CXCXXC). Binding activates the tyrosine kinase activity of the src family members and promotes tyrosine phosphorylation at sites indicated by “Y.” Phosphorylation at these sites in turn promotes the binding of other signal transfer proteins, including the Shc-Grb2 complex, phosphatidylinositol 3-kinase (PI3-K), and PLC-γ-1. Middle T antigen also binds 14-3-3 proteins. Binding of these proteins promotes cell growth signals in a manner analogous to the binding of growth factors to plasma membrane receptors (see also Fig. 6 ). The polyomavirus small t antigen shares the J domain sequence with the other T antigens. Additional sequence shared with middle T antigen includes the PP2A binding region, but does not include functions downstream of PP2A binding (see also Fig. 3 ). The more recently discovered tiny t antigen also shares the J domain sequence and associated hsc70 binding function.

Citation: Beck, Jr. G, Zerler B, Moran E. 1998. Introduction to DNA Tumor Viruses: Adenovirus, Simian Virus 40, and Polyomavirus, p 51-86. In McCance D (ed), Human Tumor Viruses. ASM Press, Washington, DC. doi: 10.1128/9781555818289.ch2
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