The human immunodeficiency virus type 1 Vpr protein and its carboxy-terminally truncated form induce apoptosis in tumor cells.
The human immunodeficiency virus type 1 (HIV-1) accessory protein Vpr induces apoptosis after cell cycle arrest at the G2 phase in primate cells. We have reported previously that C81, a carboxy-terminally truncated form of Vpr, interferes with cell proliferation and results in apoptosis without G2 arrest. Here, we investigated whether this property of Vpr and C81 could be exploited for use as a potential anticancer agent. First, we demonstrated that C81 induced G1 arrest and apoptosis in all tumor cells tested. In contrast, Vpr resulted in G2 arrest and apoptosis in HeLa and 293 T cells. Vpr also suppressed the damaged-DNA-specific binding protein 1 (DDB1) in HepG2 cells, thereby inducing apoptosis without G2 arrest. G2 arrest was restored when DDB1 was overexpressed in cells that also expressed Vpr. Surprisingly, C81 induced G2 arrest when DDB1 was overexpressed in HepG2 cells, but not in HeLa or 293 T cells. Thus, the induction of Vpr- and C81-mediated cell cycle arrest appears to depend on the cell type, whereas apoptosis was observed in all tumor cells tested. Overall, Vpr and C81 have potential as novel therapeutic agents for treatment of cancer.
Nonaka
Mizuho
M
Viral Infectious Diseases Unit, RIKEN, 2-1 Hirosawa, Wako, Saitama 351-0198, Japan. mizuho-624.1128@s7.dion.ne.jp
Hashimoto
Yoshie
Y
Takeshima
Shin-Nosuke
SN
Aida
Yoko
Y
Mol Cell. 2006 Sep 1;23(5):709-21
16949367
Oncogene. 2002 Jul 11;21(30):4613-25
12096338
Ann N Y Acad Sci. 1960 Oct 5;89:474-83
13706673
Nat Med. 1998 Jan;4(1):65-71
9427608
Microbes Infect. 2006 Mar;8(3):670-9
16480911
Nature. 2006 Oct 5;443(7111):590-3
16964240
Curr HIV Res. 2009 Mar;7(2):163-8
19275585
Mol Ther. 2006 Nov;14(5):647-55
16950655
Curr Opin Cell Biol. 2004 Dec;16(6):629-33
15530773
J Mol Biol. 2003 Mar 14;327(1):215-27
12614620
Virology. 2000 Oct 10;276(1):16-26
11021990
Oncogene. 2008 Jan 3;27(1):32-43
17653096
Mol Cell Biol. 1987 Jan;7(1):379-87
3031469
J Virol. 2005 Mar;79(6):3557-64
15731250
J Virol. 2000 Jul;74(13):6058-67
10846089
Retrovirology. 2005 Feb 22;2:11
15725353
Biochem Biophys Res Commun. 1997 Mar 17;232(2):550-4
9125220
J Biol Chem. 1994 Jun 3;269(22):15577-82
8195203
J Biol Chem. 2007 Sep 14;282(37):27046-27057
17620334
Science. 1980 Jul 25;209(4455):497-9
6248960
Mol Cell Biol. 2004 Nov;24(21):9286-94
15485898
Nature. 1979 Dec 6;282(5739):615-6
233137
Virology. 1999 Oct 25;263(2):313-22
10544105
Proc Natl Acad Sci U S A. 1994 Jul 19;91(15):7311-5
8041786
Gene. 1996;173(1 Spec No):33-8
8707053
J Virol. 2008 Feb;82(3):1066-72
17855541
Nat Cell Biol. 2006 Nov;8(11):1277-83
17041588
Proc Natl Acad Sci U S A. 2007 Jul 10;104(28):11778-83
17609381
Curr HIV Res. 2009 Mar;7(2):136-43
19275582
Virol J. 2007 Jun 08;4:57
17559673
J Biol Chem. 2008 Aug 1;283(31):21686-92
18524771
Microbes Infect. 2007 Apr;9(4):490-7
17347016
Cancer Biol Ther. 2007 Aug;6(8):1269-75
17700061
Cell Cycle. 2007 Jan 15;6(2):182-8
17314515
Genes Dev. 2006 Nov 1;20(21):2949-54
17079684
J Virol. 2006 Nov;80(21):10407-18
16956949
Microbes Infect. 2005 Jul;7(9-10):1150-60
15908254
J Virol. 2002 Oct;76(19):9724-34
12208951
J Virol. 2007 May;81(10):5284-93
17344301
Proc Natl Acad Sci U S A. 2007 Mar 6;104(10):4130-5
17360488
J Virol. 1996 Apr;70(4):2516-24
8642681
J Virol. 1997 Jun;71(6):4331-8
9151821
Curr HIV Res. 2005 Jan;3(1):43-51
15638722
Proc Natl Acad Sci U S A. 1998 Apr 28;95(9):5281-6
9560267
Proc Natl Acad Sci U S A. 1999 Oct 12;96(21):12039-43
10518572
PLoS Pathog. 2007 Jul;3(7):e85
17630831