CID755673 enhances mitogenic signaling by phorbol esters, bombesin and EGF through a protein kinase D-independent pathway.
Recently, CID755673 was reported to act as a highly selective inhibitor of protein kinase D (PKD). In the course of experiments using CID755673, we noticed that it exerted unexpected stimulatory effects on [(3)H]thymidine incorporation and cell cycle progression in Swiss 3T3 cells stimulated by bombesin, a Gq-coupled receptor agonist, phorbol 12,13-dibutyrate (PDBu), a biologically active tumor promoting phorbol ester and epidermal growth factor (EGF). These stimulatory effects could be dissociated from the inhibitory effect of CID755673 on PKD activity, since enhancement of DNA synthesis was still evident in cells with severely down-regulated PKD1 after transfection of siRNA targeting PKD1. A major point raised by our study is that CID755673 can not be considered a specific inhibitor of PKD and it should be used with great caution in experiments attempting to elucidate the role of PKD family members in cellular regulation, particularly cell cycle progression from G(1)/G(o) to S phase.
Torres-Marquez
Eugenia
E
Division of Digestive Diseases, Department of Medicine, David Geffen School of Medicine, CURE, Digestive Diseases Research Center and Molecular Biology Institute, University of California, Los Angeles, CA 90095-1786, USA.
Sinnett-Smith
James
J
Guha
Sushovan
S
Kui
Robert
R
Waldron
Richard T
RT
Rey
Osvaldo
O
Rozengurt
Enrique
E
D016475:3T3 Cells; D000818:Animals; D001381:Azepines / Q000494:pharmacology*; D001572:Benzofurans / Q000494:pharmacology*; D001839:Bombesin / Q000494:pharmacology*; D002453:Cell Cycle / Q000187:drug effects*; D004247:DNA / Q000096:biosynthesis; D004261:DNA Replication / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D004815:Epidermal Growth Factor / Q000494:pharmacology*; D051379:Mice; D015240:Phorbol 12,13-Dibutyrate / Q000494:pharmacology*; D010982:Platelet-Derived Growth Factor / Q000494:pharmacology; D011493:Protein Kinase C / Q000037:antagonists & inhibitors* / Q000378:metabolism; D016211:Transforming Growth Factor alpha / Q000494:pharmacology
D001381:Azepines; D001572:Benzofurans; C534615:CID755673; D004791:Enzyme Inhibitors; D010982:Platelet-Derived Growth Factor; D016211:Transforming Growth Factor alpha; D015240:Phorbol 12,13-Dibutyrate; D004815:Epidermal Growth Factor; D004247:DNA; C089212:protein kinase D; D011493:Protein Kinase C; D001839:Bombesin