Identification of homeodomain proteins, PBX1 and PREP1, involved in the transcription of murine leukemia virus.
Cyclin-dependent kinase inhibitors (CDKIs) have been shown to block human immunodeficiency virus and herpes simplex virus. It is hypothesized that CDKIs block viral replication by inhibiting transcription of specific cellular genes. Here we find that three CDKIs, flavopiridol, purvalanol A, and methoxy-roscovitine, block Moloney murine leukemia virus (MLV) transcription events. Using gene expression microarray technology to examine the inhibitory effects of CDKIs, we observed a cellular gene, the pre-B-cell leukemia transcription factor 1 (Pbx1) gene, down-regulated by CDKI treatment. The PBX consensus element (PCE), TGATTGAC, is conserved in the long terminal repeats of several murine retroviruses, including Moloney MLV. Mutations in the PCE completely inhibited viral transcription whereas overexpression of PBX1 and a PBX1-associated protein, PREP1, enhanced viral transcription. The interaction between the PCE and PBX1-PREP1 proteins was confirmed by gel shift experiments. Blocking PBX1 protein synthesis resulted in a significant decrease in viral transcription. Collectively, our results represent the first work demonstrating that the homeodomain proteins PBX1 and PREP1 are cellular factors involved in Moloney MLV transcription regulation.
Chao
Sheng-Hao
SH
Genomics Institute of the Novartis Research Foundation, San Diego, California 92121, USA.
Walker
John R
JR
Chanda
Sumit K
SK
Gray
Nathanael S
NS
Caldwell
Jeremy S
JS
D016475:3T3 Cells; D000818:Animals; D001483:Base Sequence; D002460:Cell Line; D016384:Consensus Sequence; D018844:Cyclin-Dependent Kinases / Q000037:antagonists & inhibitors; D004279:DNA, Viral / Q000235:genetics; D004268:DNA-Binding Proteins / Q000502:physiology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005419:Flavonoids / Q000494:pharmacology; D018398:Homeodomain Proteins / Q000502:physiology*; D006801:Humans; D051379:Mice; D008979:Moloney murine leukemia virus / Q000187:drug effects / Q000235:genetics* / Q000502:physiology; D010880:Piperidines / Q000494:pharmacology; D000075062:Pre-B-Cell Leukemia Transcription Factor 1; D011518:Proto-Oncogene Proteins / Q000502:physiology*; D014158:Transcription, Genetic / Q000187:drug effects; D014779:Virus Replication / Q000187:drug effects
D004279:DNA, Viral; D004268:DNA-Binding Proteins; D004791:Enzyme Inhibitors; D005419:Flavonoids; D018398:Homeodomain Proteins; C106682:PKNOX1 protein, human; D010880:Piperidines; C491412:Pknox1 protein, mouse; D000075062:Pre-B-Cell Leukemia Transcription Factor 1; D011518:Proto-Oncogene Proteins; C083400:PBX1 protein, human; C077990:alvocidib; D018844:Cyclin-Dependent Kinases