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Review
. 1999 Jul;12(3):367-82.
doi: 10.1128/CMR.12.3.367.

Human cytomegalovirus and human herpesvirus 6 genes that transform and transactivate

J Doniger  1 , S Muralidhar, L J Rosenthal
Affiliations
Review

Human cytomegalovirus and human herpesvirus 6 genes that transform and transactivate

J Doniger et al. Clin Microbiol Rev. 1999 Jul.

Abstract

This review is an update on the transforming genes of human cytomegalovirus (HCMV) and human herpesvirus 6 (HHV-6). Both viruses have been implicated in the etiology of several human cancers. In particular, HCMV has been associated with cervical carcinoma and adenocarcinomas of the prostate and colon. In vitro transformation studies have established three HCMV morphologic transforming regions (mtr), i.e., mtrI, mtrII, and mtrIII. Of these, only mtrII (UL111A) is retained and expressed in both transformed and tumor-derived cells. The transforming and tumorigenic activities of the mtrII oncogene were localized to an open reading frame (ORF) encoding a 79-amino-acid (aa) protein. Furthermore, mtrII protein bound to the tumor suppressor protein p53 and inhibited its ability to transactivate a p53-responsive promoter. In additional studies, the HCMV immediate-early protein IE86 (IE2; UL122) was found to interact with cell cycle-regulatory proteins such as p53 and Rb. However, IE86 exhibited transforming activity in vitro only in cooperation with adenovirus E1A. HHV-6 is a T-cell-tropic virus associated with AIDS-related and other lymphoid malignancies. In vitro studies identified three transforming fragments, i.e., SalI-L, ZVB70, and ZVH14. Of these, only SalI-L (DR7) was retained in transformed and tumor-derived cells. The transforming and tumorigenic activities of SalI-L have been localized to a 357-aa ORF-1 protein. The ORF-1 protein was expressed in transformed cells and, like HCMV mtrII, bound to p53 and inhibited its ability to transactivate a p53-responsive promoter. HHV-6 has also been proposed to be a cofactor in AIDS because both HHV-6 and human immunodeficiency virus type 1 (HIV-1) have been demonstrated to coinfect human CD4(+) T cells, causing accelerated cytopathic effects. Interestingly, like the transforming proteins of DNA tumor viruses such as simian virus 40 and adenovirus, ORF-1 was also a transactivator and specifically up-regulated the HIV-1 long terminal repeat when cotransfected into CD4(+) T cells. Finally, based on the interactions of HCMV and HHV-6 transforming proteins with tumor suppressor proteins, a scheme is proposed for their role in oncogenesis.

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Figures

FIG. 1
FIG. 1
(A) Restriction map of HCMV strain Towne showing the location of the morphological transforming regions, mtrI, mtrII, and mtrIII. mtrI has been identified in strain AD169. mtrII, also designated UL111A, contains an ORF encoding the 79-aa protein. Adapted from reference with permission of the publisher. (B) The XbaI-BamHI EM fragment of strain Towne showing the BanII-XhoI (mtrII 980) fragment with its encoded proteins. The solid open, and shaded rectangles represent the 79-, 83-, and 34-aa proteins, respectively. (C) ORFs of the mtrII 980 colinear regions of strains AD169 and Tanaka. The analogous amino acid sequences of strains AD169 and Tanaka are shown (the same rectangle symbols are used as those shown for the proteins of strain Towne). XXX, sequences not found in the proteins of strain Towne.
FIG. 2
FIG. 2
Hydropathy profile of mtrII. The hydropathy value was determined by the method of Kyte and Doolittle (95) with a window of 9 aa. Hydrophobic regions are indicated by positive values. Depicted above the hydropathy profile are wild-type and mutant peptides of mtrII and their tumorigenicity. Adapted from reference with permission of the publisher.
FIG. 3
FIG. 3
Map of the human wild-type p53 protein. Shown are the locations of the mtrII and ORF-1-binding domains, with the critical regions for binding indicated in black (86, 127). Also depicted are the DNA-binding domains (189), transcriptional activation and TATA-binding protein (TBP) binding domains (106), oligomerization domain (188), conserved regions (160), E6/E6-AP-binding and degradation domains (116), mdm-2- and adenovirus E1B (55-kDa)-binding domains (103), and SV40 T-antigen-binding domain (146). Adapted from reference with permission of the publisher.
FIG. 4
FIG. 4
HCMV IE locus showing alternate splicing patterns used for the synthesis of the two major IE proteins, IE72 and IE86. The primary transcript and exons 1 to 5 are shown by the thick lines, and the introns are shown by thin lines. The solid rectangles indicate the protein-coding sequences.
FIG. 5
FIG. 5
(A) SalI restriction map of the HHV-6 strain U1102 genome showing the locations of transforming regions (86, 140, 178) and genes that transactivate the HIV-1 LTR promoter (57, 87, 117, 181, 185, 196). Below each transactivating gene are indicated (i) the fragment in which the gene was originally identified, (ii) the common gene name, (iii) the HHV-6 systematic gene name (where known), (iv) the protein size, and (v) the HIV-1 promoter elements required for transactivation. Also shown are the unique segment and the left and right direct repeat regions (DRL and DRR, respectively). Adapted from reference with permission of the publisher. (B) Restriction map of HHV-6 strain U1102 SalI-L showing the locations and sizes of the ORFs (178). The hatched rectangle represents the junctional telomeric repeats ([TAACCC]43) which divide the left direct repeat (DRL) (heavy line) from the unique segment (light line). Depicted below the ORF-1 is the truncated peptide translated from the ORF-1–TTL172 mutant construct. Adapted from reference with permission of the publisher.
FIG. 6
FIG. 6
Features of the ORF-1 protein. (A) Hydropathy profile of ORF-1. The hydropathy value was determined by the method of Kyte and Doolittle (95) with a window of 9 aa. Hydrophobic regions are indicated by positive values. Depicted above the hydrophobicity profile are the wild-type ORF-1 and ORF-1-TTL172 mutant peptides and their tumorigenicity. Adapted from reference with permission of the publisher. (B) Alignment of ORF-1 protein amino acid sequences with domains 2 and 3 of members of the HCMV US22 family of proteins. The schematic shows regions of alignment (solid rectangles) that were detected as statistically significant (P ≤ 0.003) by the MACAW software (153).
FIG. 7
FIG. 7
Schematic diagram of the complete HIV-1 LTR promoter, indicating its regulatory sequences and showing deletion mutant CAT reporter constructs (CD52 and CD54) used to study sequences required for transactivation by ORF-1. The ability of SalI-L to transactivate each HIV-1 LTR construct is shown on the right. Adapted from reference with permission of the publisher.
FIG. 8
FIG. 8
Schematic showing the interactions of HCMV and HHV-6 proteins with the host tumor suppressors p53 and Rb. The HCMV mtrII and IE86 proteins and the HHV-6 ORF-1 protein bind to p53 and inhibit p53-activated transcription. HCMV IE86 also binds to Rb. Shown below p53 and Rb are the potential cellular pathways that may be deregulated by the above interactions, such as apoptosis, G1 and G2 growth arrest, and DNA repair for p53 and control of the G1-to-S-phase transition for Rb.
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