KSHV encoded LANA upregulates Pim-1 and is a substrate for its kinase activity.

Abstract

Pim kinases are proto-oncogenes that are upregulated in a number of B cell cancers, including Epstein-Barr Virus (EBV) associated Burkitt's lymphoma. They have also been shown to be upregulated in Kaposi sarcoma-associated herpes virus (KSHV) infected primary B cells. Most cells in KSHV-associated tumors are latently infected and express only a small subset of viral genes, with KSHV latency associated nuclear antigen (LANA) being constitutively expressed. LANA regulates the transcription of a large number of cellular and viral genes. Here, we show that LANA upregulates transcription from the Pim-1 promoter (pPim-1) and map this activation to a region in the promoter located within the sequence (-681 to +37). We show that LANA expressing cells can proliferate faster and are better protected from drug induced apoptosis. Since transition through cell cycle check points and anti-apoptosis are functions associated with Pim-1, it is likely that higher Pim-1 expression in cells expressing LANA is responsible, at least in part, for this effect. A Pim-1 phosphorylation site was also identified within the amino-terminal domain of LANA. Using in vitro kinase assays, we confirmed that LANA was indeed a Pim-1 substrate, and the failure of Pim-1 to phosphorylate LANA mutated at SS205/6RR identified this site as the specific serine residues phosphorylated by Pim-1. This report provides valuable insight into yet another cellular signaling pathway subverted by KSHV LANA and suggests a contribution to KSHV related oncogenesis.

• Authors: Bharat G Bajaj, Subhash C Verma, Ke Lan, Murray A Cotter, Zenda L Woodman, Erle S Robertson
• Journal: Virology (Virology) Vol. 351 Issue 1 Pg. 18-28 (Jul 20 2006) ISSN: 0042-6822 [Print] United States
• PMID: 16647097 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• Antigens, Viral
• Nuclear Proteins
• latency-associated nuclear antigen
• PIM1 protein, human
• Proto-Oncogene Proteins c-pim-1

Topics

• Antigens, Viral (genetics, metabolism)
• Apoptosis
• B-Lymphocytes (metabolism)
• Cell Line
• Cell Proliferation
• Epithelial Cells (metabolism)
• Herpesvirus 8, Human (genetics, metabolism)
• Humans
• Nuclear Proteins (genetics, metabolism)
• Phosphorylation
• Promoter Regions, Genetic
• Proto-Oncogene Proteins c-pim-1 (genetics, metabolism)
• Signal Transduction
• Substrate Specificity
• Transcription, Genetic
• Up-Regulation