Viral cyclin promotes KSHV-induced cellular transformation and tumorigenesis by overriding contact inhibition.

Cell Cycle

Department of Molecular Medicine; University of Texas Health Science Center at San Antonio; San Antonio, TX USA; Department of Molecular Microbiology and Immunology; Keck School of Medicine; University of Southern California; Los Angeles, CA USA; Department of Pediatrics; University of Texas Health Science Center at San Antonio; San Antonio, TX USA.

Published: May 2015

Kaposi sarcoma-associated herpesvirus (KSHV) is a tumor virus encoding several proto-oncogenes. However, the roles of these viral genes in KSHV-induced tumorigenesis have not been defined. In this study, we used a recently developed model of KSHV-induced cellular transformation and tumorigenesis combining with a reverse genetic system to examine the role of a KSHV latent gene vCyclin (ORF72), a cellular Cyclin D2 homolog, in KSHV-induced oncogenesis. Deletion of vCyclin did not affect cell proliferation and cell cycle progression at a low-density condition, when cells were at an active proliferation state. However, vCyclin mutant cells were contact-inhibited and arrested at G 1 phase at a high-density condition. As a result, vCyclin mutant cells formed less and smaller colonies in soft agar assay. Nude mice inoculated with vCyclin mutant cells had reduced tumor incidence and extended tumor latency and survival compared with mice inoculated with wild-type (WT) virus-infected cells. WT but not mutant virus effectively induced Cyclin-dependent kinase inhibitor p27/Kip1 Ser10 phosphorylation and cytoplasmic relocalization. shRNA knockdown of p27 released the blockage of the mutant cells from cell cycle arrest at G 1 phase at a high-density condition. Together, these results indicate that vCyclin primarily functions to enhance cellular transformation and tumorigenesis by promoting cell cycle progression and cell proliferation at a contact-inhibited condition.

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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3979920PMC
http://dx.doi.org/10.4161/cc.27758DOI Listing

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