Inhibitory action of phospholipid-interacting drugs on transcription initiation in a nuclear extract of Ehrlich ascites tumor cells.
Drugs with affinity for phospholipids, such as chlorpromazine, verapamil, tetracaine and imipramine, were found to inhibit accurate transcription from adenovirus 2 major late promoter in a nuclear extract of Ehrlich ascites tumor cells. The transcription activity of the nuclear extract inhibited by chlorpromazine was restored by addition of acidic phospholipids. The nuclear extract was also shown to lose transcription activity when treated with phospholipase A2. Chlorpromazine was found to inhibit transcription at the step of initiation, not elongation. Moreover, it did not affect the activity of purified RNA polymerase II, suggesting the interaction of phospholipids with transcription factors in the nuclear extract. Some transcription factors in the nuclear extract were found to have affinity for cardiolipin, and were precipitated with excess cardiolipin. The transcription factors precipitated with cardiolipin could be solubilized with guanidine hydrochloride, and restored the transcription activity of the cardiolipin-treated nuclear extract.
Hirai
H
H
Faculty of Pharmaceutical Sciences, University of Tokyo, Japan.
Natori
S
S
Sekimizu
K
K
D000260:Adenoviruses, Human / Q000235:genetics*; D000818:Animals; D002286:Carcinoma, Ehrlich Tumor / Q000378:metabolism*; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism*; D002746:Chlorpromazine / Q000494:pharmacology*; D006367:HeLa Cells / Q000378:metabolism; D006801:Humans; D007099:Imipramine / Q000494:pharmacology*; D007700:Kinetics; D051379:Mice; D010741:Phospholipases A / Q000494:pharmacology; D054467:Phospholipases A2; D010743:Phospholipids / Q000502:physiology*; D011401:Promoter Regions, Genetic / Q000187:drug effects*; D012319:RNA Polymerase II / Q000378:metabolism; D013748:Tetracaine / Q000494:pharmacology*; D014157:Transcription Factors / Q000378:metabolism; D014158:Transcription, Genetic / Q000187:drug effects*; D014700:Verapamil / Q000494:pharmacology*
D010743:Phospholipids; D014157:Transcription Factors; D013748:Tetracaine; D014700:Verapamil; D012319:RNA Polymerase II; D010741:Phospholipases A; D054467:Phospholipases A2; D007099:Imipramine; D002746:Chlorpromazine