Functional link between tyrosine phosphorylation and human serotonin transporter gene expression.
Treatment of the JAR human placental choriocarcinoma cells with herbimycin A, an inhibitor of tyrosine kinases, led to an increase in the activity of the serotonin transporter. This effect was accompanied by an increase in the serotonin transporter density and in the steady-state levels of the serotonin transporter mRNA. A treatment time of > 4 h was necessary for herbimycin A to elicit its effect. Actinomycin D and cycloheximide blocked the effect. There was no increase in the steady-state levels of the serotonin transporter mRNA when cells were treated with herbimycin A in the presence of actinomycin D. The herbimycin A-induced increase in the transporter activity was abolished by genistein, another inhibitor of tyrosine kinases. But the increase in the transporter mRNA levels caused by herbimycin A was not affected by genistein. Treatment of cells with herbimycin A resulted in an increase in the tyrosine phosphorylation of specific cellular proteins, suggesting that herbimycin A directly or indirectly activates specific tyrosine kinases. It is concluded that tyrosine phosphorylation is an essential component in the signaling pathways participating in the regulation of the human serotonin transporter gene expression.
Prasad
P D
PD
Department of Biochemistry and Molecular Biology, Medical College of Georgia, Augusta 30912, USA.
Torres-Zamorano
V
V
Kekuda
R
R
Leibach
F H
FH
Ganapathy
V
V
D016227:Benzoquinones; D002352:Carrier Proteins / Q000096:biosynthesis* / Q000187:drug effects / Q000235:genetics; D002822:Choriocarcinoma / Q000378:metabolism; D004347:Drug Interactions; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D015870:Gene Expression; D019833:Genistein; D006801:Humans; D007529:Isoflavones / Q000494:pharmacology; D047029:Lactams, Macrocyclic; D008562:Membrane Glycoproteins / Q000096:biosynthesis* / Q000187:drug effects / Q000235:genetics; D026901:Membrane Transport Proteins; D009363:Neoplasm Proteins / Q000378:metabolism; D009419:Nerve Tissue Proteins; D010766:Phosphorylation; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors; D011809:Quinones / Q000037:antagonists & inhibitors / Q000494:pharmacology; D012333:RNA, Messenger / Q000187:drug effects / Q000378:metabolism; D017828:Rifabutin / Q000031:analogs & derivatives; D050486:Serotonin Plasma Membrane Transport Proteins; D014407:Tumor Cells, Cultured; D014443:Tyrosine / Q000378:metabolism*; D014594:Uterine Neoplasms / Q000378:metabolism
D016227:Benzoquinones; D002352:Carrier Proteins; D004791:Enzyme Inhibitors; D007529:Isoflavones; D047029:Lactams, Macrocyclic; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; D009363:Neoplasm Proteins; D009419:Nerve Tissue Proteins; D011809:Quinones; D012333:RNA, Messenger; C493230:SLC6A4 protein, human; D050486:Serotonin Plasma Membrane Transport Proteins; D017828:Rifabutin; D014443:Tyrosine; C020754:herbimycin; D019833:Genistein; D011505:Protein-Tyrosine Kinases