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.
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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)
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Chemical References |
- Antigens, Viral
- Nuclear Proteins
- latency-associated nuclear antigen
- PIM1 protein, human
- Proto-Oncogene Proteins c-pim-1
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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
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