Human immunodeficiency virus type 1 vpr gene induces phenotypic effects similar to those of the DNA alkylating agent, nitrogen mustard.
The product of the human immunodeficiency virus type 1 (HIV-1) vpr gene induces cell cycle arrest in the G2 phase of the cell cycle and is characterized by an accumulation of the hyperphosphorylated form of cdc2 kinase. This phenotype is similar to the effect of DNA-damaging agents, which can also cause cells to arrest at G2. We previously reported that Vpr mimicked some of the effects of a DNA alkylating agent known as nitrogen mustard (HN2). Here we extend these earlier observations by further comparing the activation state of cdc2 kinase, the kinetics of G2 arrest, and the ability to reverse the arrest with chemical compounds known as methylxanthines. Infection of cells synchronized in the G1 phase of the cell cycle with a pseudotyped HIV-1 resulted in arrest at G2 within 12 h postinfection, before the first mitosis. Similar to that induced by HN2, Vpr-induced arrest led to a decrease in cdc2 kinase activity. Vpr-mediated G2 arrest was alleviated by methylxanthines at concentrations similar to those needed to reverse the G2 arrest induced by HN2, and cells proceeded apparently normally through at least one complete cell cycle. These results are consistent with the hypothesis that Vpr induces G2 arrest through pathways that are similar to those utilized by DNA-damaging agents.
Poon
B
B
Department of Microbiology and Immunology, UCLA School of Medicine, Los Angeles, California 90095, USA.
Jowett
J B
JB
Stewart
S A
SA
Armstrong
R W
RW
Rishton
G M
GM
Chen
I S
IS
D000477:Alkylating Agents / Q000494:pharmacology*; D016203:CDC2 Protein Kinase / Q000378:metabolism; D016195:G2 Phase / Q000187:drug effects*; D016334:Genes, vpr / Q000502:physiology*; D015497:HIV-1 / Q000235:genetics*; D006367:HeLa Cells; D006801:Humans; D008466:Mechlorethamine / Q000494:pharmacology*; D008938:Mitosis; D010431:Pentoxifylline / Q000494:pharmacology; D010641:Phenotype; D016196:S Phase; D014970:Xanthines / Q000494:pharmacology
D000477:Alkylating Agents; D014970:Xanthines; C008514:methylxanthine; D008466:Mechlorethamine; D016203:CDC2 Protein Kinase; D010431:Pentoxifylline