Involvement of extracellular signal-related kinase signaling in esculetin induced G1 arrest of human leukemia U937 cells.
This study was conducted to further elucidate the possible mechanisms by which esculetin, a coumarin compound, exerts its anti-proliferative action on cultured human monocytic leukemia U937 cells. The inhibitory effects of esculetin on cell viability were found to be associated with a G1 arrest in cell cycle progression that was concomitant with an inhibition of cyclin E and an induction of cyclin-dependent kinase (Cdk) inhibitor p21/WAF1/CIP1 in a p53-independent manner. Cells that were treated with esculetin showed increased binding of p21 with Cdk2 and Cdk4 that was paralleled by a marked decrease in the Cdk2 and Cdk4 kinase activities with no change in their expression. We also observed that down-regulation of the phosphorylation of retinoblastoma protein (pRB) by this compound was associated with enhanced binding of pRB and the transcription factor E2F-1. Further investigation showed that inhibition of the extracellular-regulated kinase (ERK) signaling pathway reduced the induction of p21 and the inhibition of pRB phosphorylation and cyclin E expression by esculetin, which in turn overcame the G1 arrest and growth inhibition that was induced by esculetin. These data demonstrate that the ERK pathway participates in p21 induction and subsequently leads to a decrease in the kinase activity of Cdks and inhibition of pRB phosphorylation in esculetin-mediated G1 arrest of U937 cells.
Lee
Shin Hwa
SH
Korea Science Academy, Busan 614-822, South Korea.
Park
Cheol
C
Jin
Cheng-Yun
CY
Kim
Gi-Young
GY
Moon
Sung-Kwon
SK
Hyun
Jin Won
JW
Lee
Won Ho
WH
Choi
Byung Tae
BT
Kwon
Taeg Kyu
TK
Yoo
Young Hyun
YH
Choi
Yung Hyun
YH
D000970:Antineoplastic Agents / Q000494:pharmacology*; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D019927:Cyclin E / Q000096:biosynthesis; D051357:Cyclin-Dependent Kinase 2 / Q000378:metabolism; D051358:Cyclin-Dependent Kinase 4 / Q000378:metabolism; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000096:biosynthesis; D050687:E2F1 Transcription Factor / Q000378:metabolism; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors / Q000502:physiology*; D016193:G1 Phase; D006801:Humans; D010766:Phosphorylation; D011485:Protein Binding; D016160:Retinoblastoma Protein / Q000096:biosynthesis; D015398:Signal Transduction; D020298:U937 Cells; D014468:Umbelliferones / Q000494:pharmacology*
D000970:Antineoplastic Agents; D019927:Cyclin E; D050687:E2F1 Transcription Factor; D016160:Retinoblastoma Protein; D014468:Umbelliferones; D050760:Cyclin-Dependent Kinase Inhibitor p27; D051357:Cyclin-Dependent Kinase 2; D051358:Cyclin-Dependent Kinase 4; D048049:Extracellular Signal-Regulated MAP Kinases; C007628:esculetin