Regulation of p21WAF1/CIP1 expression through mitogen-activated protein kinase signaling pathway.
p21WAF1/CIP1 is a cyclin-dependent kinase inhibitor whose expression in mammalian tissues is highly induced in response to stress as well as during normal development and differentiation. Induction of p21WAF1/CIP1 in response to DNA damage occurs through a transcriptional mechanism that is dependent on the activation of the tumor suppressor protein p53. Recent evidence indicates that p21WAF1/CIP1 can also be induced independently of p53, but the signal transduction mechanisms involved in regulating p21WAF1/CIP1 expression in these situations have not been elucidated. In this study, we have addressed the role of the mitogen-activated protein kinase signaling pathway in the induction of p21WAF1/CIP1 in response to growth factor treatment. Using an experimental approach involving cotransfection of a p21WAF1/CIP1 promoter-luciferase construct with a variety of plasmids expressing dominant positive or dominant negative mutant proteins involved in this signaling pathway, we provide evidence to support a role for mitogen-activated protein kinase in the transcriptional activation of p21WAF1/CIP1 by growth factor stimulation.
Laboratory of Cellular and Molecular Biology, Gerontology Research Center, National Institute on Aging, Baltimore, Maryland 21224, USA.
Y
Y
Liu
J L
JL
Martindale
M
M
Gorospe
N J
NJ
Holbrook
D000818:Animals; D001483:Base Sequence; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000235:genetics / Q000378:metabolism*; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins / Q000235:genetics / Q000378:metabolism*; D005786:Gene Expression Regulation; D018014:Gene Transfer Techniques; D005799:Genes, Dominant; D005808:Genes, Recessive; D006367:HeLa Cells; D006801:Humans; D008934:Mitogens / Q000494:pharmacology*; D008969:Molecular Sequence Data; D009154:Mutation; D016716:PC12 Cells; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D015398:Signal Transduction
C493956:CDKN1A protein, human; C493958:Cdkn1a protein, rat; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D008934:Mitogens; D012333:RNA, Messenger; D017871:Calcium-Calmodulin-Dependent Protein Kinases