A virus-encoded telomerase RNA promotes malignant T cell lymphomagenesis.
Telomerase is a ribonucleoprotein complex consisting of two essential core components: a reverse transcriptase and an RNA subunit (telomerase RNA [TR]). Dysregulation of telomerase has been associated with cell immortalization and oncogenesis. Marek's disease herpesvirus (MDV) induces a malignant T cell lymphoma in chickens and harbors in its genome two identical copies of a viral TR (vTR) with 88% sequence identity to chicken TR. MDV mutants lacking both copies of vTR were significantly impaired in their ability to induce T cell lymphomas, although lytic replication in vivo was unaffected. Tumor incidences were reduced by >60% in chickens infected with vTR- viruses compared with animals inoculated with MDV harboring at least one intact copy of vTR. Lymphomas in animals infected with the vTR- viruses were also significantly smaller in size and less disseminated. Constitutive expression of vTR in the chicken fibroblast cell line DF-1 resulted in a phenotype consistent with transformation as indicated by morphological alteration, enhanced anchorage-independent cell growth, cell growth beyond saturation density, and increased expression levels of integrin alpha v. We concluded that vTR plays a critical role in MDV-induced T cell lymphomagenesis. Furthermore, our results provide the first description of tumor-promoting effects of TR in a natural virus-host infection model.
Trapp
Sascha
S
Department of Microbiology and Immunology, Cornell University, Ithaca, NY 14853, USA.
Parcells
Mark S
MS
Kamil
Jeremy P
JP
Schumacher
Daniel
D
Tischer
B Karsten
BK
Kumar
Pankaj M
PM
Nair
Venugopal K
VK
Osterrieder
Nikolaus
N
D000818:Animals; D002460:Cell Line; D002472:Cell Transformation, Viral; D002645:Chickens; D005347:Fibroblasts / Q000378:metabolism / Q000473:pathology / Q000821:virology; D015973:Gene Expression Regulation, Leukemic / Q000502:physiology; D015967:Gene Expression Regulation, Viral / Q000502:physiology; D016678:Genome; D039001:Integrin alpha Chains / Q000096:biosynthesis; D039641:Integrin beta Chains / Q000096:biosynthesis; D016399:Lymphoma, T-Cell / Q000201:enzymology* / Q000235:genetics / Q000473:pathology / Q000821:virology; D025922:Mardivirus / Q000201:enzymology* / Q000235:genetics; D008380:Marek Disease / Q000201:enzymology / Q000235:genetics / Q000473:pathology / Q000821:virology; D009154:Mutation; D017386:Sequence Homology, Amino Acid; D019098:Telomerase / Q000235:genetics / Q000378:metabolism*; D014764:Viral Proteins / Q000235:genetics / Q000378:metabolism*
D039001:Integrin alpha Chains; D039641:Integrin beta Chains; D014764:Viral Proteins; D019098:Telomerase