Role of EB virus nuclear protein EBNA3C in B-cell growth transformation

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Epstein-Barr virus (EBV) infection converts primary human B cells into indefinitely proliferating lymphoblastoid cell lines (LCLs) in vitro. EBV nuclear protein EBNA3C is essential for this growth transformation. To investigate how EBNA3C contributes to LCL growth, we established LCLs that express a conditionally active EBNA3C. EBNA3C inactivation resulted in growth arrest of LCLs. We also found that EBNA3C inactivation caused the induction of pl6(INK4A) expression accompanied by the decrease of pRb phosphorylation. Thus, it is likely that EBNA3C contributes LCL growth maintenance through inhibiting p16(INK4A) expression.EBNA3C associates with the sequence-specific DNA binding protrein RBP-Jkappa and regulates RBP-Jkappa dependent transcription We examined whether EBNA3C association with RBP-Jkappa is critical for LCL growth maintenance. Analyses using a series of EBNA3C mutant revealed that the ability of EBNA3C mutant to regulate transcription through RBP-Jkappa was exactly correlated with its ability to sustain LCL growth maintenance. The data indicates that EBNA3C regulation of transcription through RBP-Jkappa is critical for maintaining LCL growth.We also evaluated a series of EBNA3C deletion mutant for the ability to support LCL growth to identify the critical or dispensable regions of EBNA3C. We found that the amino acid residues (aa) 1 to 506, and the as 733 to 909 of EBNA3C are critical for LCL growth maintenance. These regions were previously noted to have amino acid sequence homology and functional homology among EBV and nonhuman primate lymphocriptviruses, suggesting that the regions essential for LCL growth maintenance are evolutionally conserved.