Involvement of p38 mitogen-activated protein kinase in the cell growth inhibition by sodium arsenite.
It is well-known that p38 mitogen-activated protein kinase (p38MAPK) participates in cellular responses to mitogenic stimuli, environmental and genotoxic stresses, and apoptotic agents. Although there are several reports on p38MAPK in relation to cell growth and apoptosis, the exact mechanism of p38MAPK-mediated cell growth regulation remains obscure. Here, we examined possible roles of p38MAPK in the sodium arsenite-induced cell growth inhibition in NIH3T3 cells. Sodium arsenite induced transient cell growth delay with marked activation of p38MAPK. In addition, arsenite induced CDK inhibitor p21(CIP1/WAF1) and enhanced its binding to the CDK2, which resulted in inhibition of CDK2 activity. The levels of cyclin D1 expression and the CDK4 kinase activity were also significantly reduced. pRB was hypophosphorylated by sodium arsenite. SB203580, a specific inhibitor of p38MAPK, blocked arsenite-induced growth inhibition as well as the arsenite-induced p21(CIP1/WAF1) expression. Expression of dominant negative p38MAPK also blocked arsenite-induced p21(CIP1/WAF1) expression. Inhibited-CDK2 activity was also completely reversed by SB203580 or expression of dominant negative p38MAPK, while the decreased-cyclin D1 protein by the compound was not restored. These data demonstrate a possible link between the activation of p38MAPK and induction of p21(CIP1/WAF1), suggesting that the activation of p38MAPK is, at least in part, related to the cell growth inhibition by sodium arsenite.
Kim
Ja-Young
JY
Laboratory of Radiation Effect, Korea Cancer Center Hospital, Gongneung-Dong, Nowon-Ku, Seoul 139-706, Korea.
Choi
Jung-A
JA
Kim
Tae-Hwan
TH
Yoo
Young-Do
YD
Kim
Jong-Il
JI
Lee
Yong J
YJ
Yoo
Seong-Yul
SY
Cho
Chul-Koo
CK
Lee
Yun-Sil
YS
Lee
Su-Jae
SJ
D016475:3T3 Cells / Q000166:cytology / Q000187:drug effects* / Q000201:enzymology*; D000818:Animals; D018053:Arsenites / Q000494:pharmacology*; D042846:CDC2-CDC28 Kinases; D002455:Cell Division / Q000187:drug effects; D019925:Cyclin A / Q000378:metabolism; D019938:Cyclin D1 / Q000378:metabolism; D019927:Cyclin E / Q000378:metabolism; D051357:Cyclin-Dependent Kinase 2; D051358:Cyclin-Dependent Kinase 4; D050759:Cyclin-Dependent Kinase Inhibitor p21; D018844:Cyclin-Dependent Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D016213:Cyclins / Q000235:genetics / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects; D007093:Imidazoles / Q000494:pharmacology; D051379:Mice; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D011518:Proto-Oncogene Proteins; D011725:Pyridines / Q000494:pharmacology; D016160:Retinoblastoma Protein / Q000378:metabolism; D017670:Sodium Compounds / Q000494:pharmacology*; D014162:Transfection; D048051:p38 Mitogen-Activated Protein Kinases
D018053:Arsenites; C493957:Cdkn1a protein, mouse; D019925:Cyclin A; D019927:Cyclin E; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D004791:Enzyme Inhibitors; D007093:Imidazoles; D011518:Proto-Oncogene Proteins; D011725:Pyridines; D016160:Retinoblastoma Protein; D017670:Sodium Compounds; D019938:Cyclin D1; C017947:sodium arsenite; D017346:Protein Serine-Threonine Kinases; D042846:CDC2-CDC28 Kinases; C495893:Cdk2 protein, mouse; C495902:Cdk4 protein, mouse; D051357:Cyclin-Dependent Kinase 2; D051358:Cyclin-Dependent Kinase 4; D018844:Cyclin-Dependent Kinases; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; C093642:SB 203580