Epstein-Barr virus nuclear antigens 3C and 3A maintain lymphoblastoid cell growth by repressing p16INK4A and p14ARF expression.
Epstein-Barr virus (EBV) nuclear antigen 3C (EBNA3C) and EBNA3A are each essential for EBV conversion of primary human B lymphocytes into continuously proliferating lymphoblast cell lines (LCLs) and for maintaining LCL growth. We now find that EBNA3C and EBNA3A's essential roles are to repress p16(INK4A) and p14(ARF). In the absence of EBNA3C or EBNA3A, p16(INK4A) and p14(ARF) expression increased and cell growth ceased. EBNA3C inactivation did not alter p16(INK4A) promoter CpG methylation, but reduced already low H3K27me3, relative to resting B cells, and increased H3K4me3 and H3-acetylation, linking EBNA3C inactivation to histone modifications associated with increased transcription. Importantly, knockdown of p16(INK4A) or p14(ARF) partially rescued LCLs from EBNA3C or EBNA3A inactivation-induced growth arrest and knockdown of both rescued LCL growth, confirming central roles for p16(INK4A) and p14(ARF) in LCL growth arrest following EBNA3C or EBNA3A inactivation. Moreover, blockade of p16(INK4A) and p14(ARF) effects on pRb and p53 by human papilloma virus type 16 E7 and E6 expression, sustained LCL growth after EBNA3C or EBNA3A inactivation. These data indicate that EBNA3C and EBNA3A joint repression of CDKN2A p16(INK4A) and p14(ARF) is essential for LCL growth.
Department of Tumor Virology, Institute for Genetic Medicine, Hokkaido University, Sapporo 060-0815, Japan. smaruo@igm.hokudai.ac.jp
Seiji
S
Maruo
Bo
B
Zhao
Eric
E
Johannsen
Elliott
E
Kieff
James
J
Zou
Kenzo
K
Takada
D002455:Cell Division / Q000502:physiology*; D002460:Cell Line; D018899:CpG Islands; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics / Q000502:physiology*; D019175:DNA Methylation; D019309:Epstein-Barr Virus Nuclear Antigens / Q000502:physiology*; D055785:Gene Knockdown Techniques; D006801:Humans; D011401:Promoter Regions, Genetic; D025803:Tumor Suppressor Protein p14ARF / Q000235:genetics / Q000502:physiology*
D019941:Cyclin-Dependent Kinase Inhibitor p16; D019309:Epstein-Barr Virus Nuclear Antigens; D025803:Tumor Suppressor Protein p14ARF
J Virol. 2002 Jan;76(1):232-42
11739688
Proc Natl Acad Sci U S A. 2006 Dec 19;103(51):19500-5
17159137
Cancer Cell. 2003 Oct;4(4):301-10
14585357
BMC Cancer. 2007 Mar 14;7:47
17359536
J Virol. 2002 Dec;76(23):12055-68
12414947
Virology. 1991 Apr;181(2):595-608
1849678
J Virol. 2009 Dec;83(23):12368-77
19776126
Cancer Cell. 2002 Aug;2(2):103-12
12204530
Nature. 1967 Nov 25;216(5117):810-1
6074953
Proc Natl Acad Sci U S A. 2005 Dec 20;102(51):18562-6
16352731
J Virol. 2002 Sep;76(17):8702-9
12163590
J Virol. 2001 Aug;75(16):7749-55
11462050
J Virol. 2004 Feb;78(4):1981-91
14747563
Nature. 1998 Nov 5;396(6706):84-8
9817205
J Virol. 2003 Apr;77(7):4261-72
12634383
Oncogene. 2008 Jan 17;27(4):421-33
17653091
J Virol. 1993 Apr;67(4):2014-25
8445720
Trends Genet. 2000 Apr;16(4):168-74
10729832
Proc Natl Acad Sci U S A. 1996 Sep 3;93(18):9821-6
8790415
Nat Rev Mol Cell Biol. 2009 Oct;10(10):697-708
19738629
J Virol. 2006 Mar;80(5):2548-65
16474161
PLoS Pathog. 2009 Jun;5(6):e1000492
19557159
J Virol. 2003 Jan;77(2):999-1010
12502816
Proc Natl Acad Sci U S A. 2009 Mar 17;106(11):4419-24
19237563
Cancer Res. 2000 Jan 1;60(1):129-33
10646864
J Virol. 1995 May;69(5):3108-16
7707539
Science. 1967 Sep 1;157(3792):1064-5
6036237
Mol Cell Biol. 2000 Aug;20(15):5722-35
10891508
J Exp Med. 2010 Dec 20;207(13):2817-30
21098095
Nat Rev Cancer. 2009 Nov;9(11):773-84
19851313
J Virol. 1996 May;70(5):3068-74
8627785
Genes Dev. 2009 May 15;23(10):1177-82
19451218
Science. 1989 Feb 17;243(4893):934-7
2537532
J Virol. 1996 Jun;70(6):4179-83
8648764
Nature. 2006 Mar 30;440(7084):702-6
16572177
Mol Cell Biol. 2005 Mar;25(5):1749-63
15713632
Proc Natl Acad Sci U S A. 2006 Feb 7;103(6):1900-5
16446431
J Virol. 1996 Sep;70(9):5909-15
8709211
PLoS Pathog. 2010 Jun 10;6(6):e1000951
20548956
Genes Dev. 2009 May 15;23(10):1171-6
19451217
J Virol. 2003 Oct;77(19):10437-47
12970429
Mol Cell Biol. 2008 May;28(10):3457-64
18332116
Nucleic Acids Res. 1995 May 25;23(10):1686-90
7784172
Cell. 2006 Oct 20;127(2):265-75
17055429
J Virol. 2006 Oct;80(20):10139-50
17005691
J Virol. 2001 May;75(10):4705-12
11312342
J Virol. 2002 May;76(10):4699-708
11967287
J Virol. 2005 Apr;79(7):4506-9
15767450
J Virol. 2004 Dec;78(23):12857-67
15542638
J Virol. 1999 Jun;73(6):4678-88
10233927
J Virol. 1992 May;66(5):2893-903
1313908
J Biol Chem. 2002 Dec 6;277(49):47197-204
12372828
Cell Host Microbe. 2010 Dec 16;8(6):510-22
21147465
J Virol. 2005 Aug;79(16):10171-9
16051810
J Virol. 1999 May;73(5):4481-4
10196351
Curr Mol Med. 2006 May;6(3):291-308
16712476
J Biol Chem. 1999 Jul 2;274(27):19136-44
10383418
Science. 1994 Jul 1;265(5168):92-5
8016657
Pathol Int. 2002 May-Jun;52(5-6):375-83
12100520
Nat Rev Mol Cell Biol. 2006 Sep;7(9):667-77
16921403
J Virol. 1997 Nov;71(11):8552-62
9343213
J Virol. 1999 Jul;73(7):5688-97
10364319
Science. 1990 Apr 6;248(4951):76-9
2157286
J Virol. 1996 Jul;70(7):4228-36
8676443
J Virol. 2000 Jun;74(11):5151-60
10799590
Proc Natl Acad Sci U S A. 1994 Aug 2;91(16):7568-72
8052621
PLoS Pathog. 2009 Jul;5(7):e1000506
19578441