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Induction of cyclin‐dependent kinase 5 and its activator p35 through the extracellular‐signal‐regulated kinase and protein kinase A pathways during retinoic‐acid mediated neuronal differentiation in human neuroblastoma SK‐N‐BE(2)C cells
Author(s) -
Lee JongHee,
Kim KyongTai
Publication year - 2004
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1111/j.1471-4159.2004.02770.x
Subject(s) - cyclin dependent kinase 5 , cyclin dependent kinase 2 , ask1 , cyclin dependent kinase 9 , map kinase kinase kinase , protein kinase a , map2k7 , mitogen activated protein kinase kinase , microbiology and biotechnology , cyclin dependent kinase 4 , biology , activator (genetics) , kinase , retinoic acid , signal transduction , neurite , creb , mitogen activated protein kinase 3 , cyclin dependent kinase , transcription factor , biochemistry , cell cycle , receptor , cell , gene , in vitro
Cyclin‐dependent kinase 5 (Cdk5), a neuronal Cdc2‐like kinase, exhibits a variety of functions in neuronal differentiation and neurocytoskeleton dynamics, as well as neuronal degeneration. However, its role and induction mechanisms in retinoic acid (RA)‐induced neuronal differentiation have not been well understood. In this study we newly found that RA treatment of SK‐N‐BE(2)C, human neuroblastoma cells, increased the expression of Cdk5 and its neuron specific activator p35 through the extracellular‐signal‐regulated kinase1/2 (ERK1/2) and cAMP‐dependent protein kinase A (PKA) pathway. Inhibition of Cdk5 activity either by an inhibitor, roscovitine, or by transfection with a dominant negative form of Cdk5 caused a dramatic decrease in RA‐induced differentiation, suggesting the requirement of Cdk5 kinase activity for the RA‐induced neurite outgrowth. Furthermore, Cdk5 and p35 expression was decreased by ERK1/2 inhibition with PD98059 and increased by overexpression of a constitutive active mitogen‐activated protein kinase kinase 1 (MEK1) mutant, suggesting the critical role of ERK1/2 in the induction of Cdk5 and p35. In addition, a transcription factor early growth response 1 (Egr‐1) was induced by RA through the ERK1/2 pathway, suggesting its possible involvement in the p35 induction. RA treatment also induced c‐ fos mediated AP‐1 binding, and cAMP‐responsive element binding protein (CREB) mediated CRE binding via ERK1/2 and PKA pathway, respectively, in the Cdk5 promoter region, resulting in the induction of Cdk5. Our results suggest that ERK1/2 and PKA‐induced regulation of Cdk5 activity possibly through Egr‐1, c‐ fos , and CREB plays a critical role in the RA‐induced neuronal differentiation.