Human cytomegalovirus and human herpesvirus 6 genes that transform and transactivate.
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.
Doniger
J
J
Department of Microbiology and Immunology, Georgetown University Medical Center, Washington, D.C. 20007, USA.
Muralidhar
S
S
Rosenthal
L J
LJ
D002472:Cell Transformation, Viral / Q000235:genetics; D003587:Cytomegalovirus / Q000235:genetics*; D005814:Genes, Viral / Q000235:genetics; D016679:Genome, Viral; D015497:HIV-1 / Q000235:genetics; D015809:HLA-DR7 Antigen / Q000235:genetics / Q000378:metabolism; D015654:Herpesvirus 6, Human / Q000235:genetics*; D006801:Humans; D017874:Immediate-Early Proteins / Q000378:metabolism; D008562:Membrane Glycoproteins; D009369:Neoplasms / Q000821:virology; D009857:Oncogenes / Q000235:genetics; D016366:Open Reading Frames; D016160:Retinoblastoma Protein / Q000378:metabolism; D013601:T-Lymphocytes / Q000821:virology; D015534:Trans-Activators; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D014759:Viral Envelope Proteins; D014764:Viral Proteins / Q000378:metabolism
D015809:HLA-DR7 Antigen; C069186:IE2 protein, Cytomegalovirus; D017874:Immediate-Early Proteins; D008562:Membrane Glycoproteins; D016160:Retinoblastoma Protein; D015534:Trans-Activators; D016159:Tumor Suppressor Protein p53; C077406:UL115 protein, Human herpesvirus 5; D014759:Viral Envelope Proteins; D014764:Viral Proteins; C071440:glycoprotein H, Cytomegalovirus; C499358:glycoprotein H, Human cytomegalovirus; C439068:glycoprotein O, cytomegalovirus