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PMID: 16150942 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

KSHV G protein-coupled receptor inhibits lytic gene transcription in primary-effusion lymphoma cells via p21-mediated inhibition of Cdk2.

Blood ·Vol. 107 ·No. 1 ·2006-01-01 ·Pages 277-84

Cannon M, Cesarman E, Boshoff C

Abstract

Kaposi sarcoma (KS) remains the most common AIDS-associated malignancy worldwide. In sub-Saharan Africa especially, this aggressive endothelial-cell tumor is a cause of widespread morbidity and mortality. Infection with Kaposi sarcoma-associated herpesvirus (KSHV) is now known to be an etiologic force behind KS and primary-effusion lymphoma (PEL). Over time, KSHV has pirated many human genes whose products regulate angiogenesis, inflammation, and the cell cycle. One of these, the KSHV vGPCR, is a lytic product that is a constitutively active homolog of the IL-8 receptor. Although it is considered a viral oncogene and causes KS-like lesions in mice, vGPCR expression results in cell-cycle arrest of KSHV-infected PEL cells. In the present study, we show that this arrest is mediated by p21 in a p53-independent manner; the resulting Cdk2 inhibition decreases the efficiency of chemical induction of KSHV lytic transcripts ORF 50 and 26. Importantly, Cdk2 activity is also essential for replication in other human herpesviruses. The ability of vGPCR to delay or abort KSHV replication may explain how despite being a lytic product, this potent signaling molecule has a vital role in tumor formation via its induction of various KS-associated cytokines.

MeSH Terms
Cell Cycle Cell Line, Tumor Cyclin-Dependent Kinase 2/antagonists & inhibitors Cyclin-Dependent Kinase Inhibitor p21/physiology Herpesvirus 8, Human/chemistry,pathogenicity Humans Immediate-Early Proteins/genetics Lymphoma, Non-Hodgkin/pathology,virology Pleural Effusion, Malignant/pathology,virology Receptors, Chemokine/physiology Trans-Activators/genetics Transcription, Genetic Viral Proteins/genetics,physiology Virus Replication
Chemicals
Cyclin-Dependent Kinase Inhibitor p21 G protein-coupled receptor, Human herpesvirus 8 Immediate-Early Proteins Receptors, Chemokine Rta protein, Human herpesvirus 8 Trans-Activators Viral Proteins CDK2 protein, human Cyclin-Dependent Kinase 2
Authors & Affiliations
3 authors, click to expand affiliations / ORCID
Cannon Mark
Division of International Medicine and Infectious Diseases, Department of Medicine, Weill Medical College of Cornell University, New York, NY, USA. m.cannon@ucl.ac.uk
Cesarman Ethel
Boshoff Chris
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Article Info
Journal
Blood
Abbr.
Blood
ISSN
0006-4971
DOI
10.1182/blood-2005-06-2350
Email
m.cannon@ucl.ac.uk
Published
2006-01-01
Epub
2005-00-08
Pages
277-84
Language
English
Region
United States
NLM ID
7603509
PMCID
PMC1895347
Subset
IM
Grants
NCI NIH HHS · CA068 939 · United States
NIAID NIH HHS · K08-AI53 971 · United States
External Links
PubMed source DOI: 10.1182/blood-2005-06-2350 PMC Full Text View journal details
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