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Genistein‐induced neuronal differentiation is associated with activation of extracellular signal‐regulated kinases and upregulation of p21 and N‐cadherin
Author(s) -
Hung S.P.,
Hsu J.R.,
Lo C.P.,
Huang H.J.,
Wang J.P.,
Chen S.T.
Publication year - 2005
Publication title -
journal of cellular biochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.028
H-Index - 165
eISSN - 1097-4644
pISSN - 0730-2312
DOI - 10.1002/jcb.20626
Subject(s) - genistein , mapk/erk pathway , kinase , mitogen activated protein kinase 3 , microbiology and biotechnology , downregulation and upregulation , biology , cellular differentiation , tyrosine kinase , retinoic acid , signal transduction , chemistry , cancer research , endocrinology , biochemistry , gene
Neuronal differentiation in the mammalian CNS is driven by multiple events. When treated with retinoic acid (RA), hNTera‐2 (NT‐2) cells undergo postmitotic neuronal differentiation. Here, we show that a prolonged exposure of NT‐2 cells with non‐cytotoxic doses of genistein, a protein tyrosine kinase (PTK) inhibitor, induced differentiation of NT‐2 cells. Additionally, genistein enhanced RA‐induced neuronal differentiation by increasing the activation of extracellular signal‐related kinase 1/2 (ERK1/2) via phosphorylation at Thr183 and Tyr185 in 3–7 days. Meanwhile, genistein also upregulated N‐cadherin and p21 (a Cdk inhibitor), but downregulated proliferating cell nuclear antigen protein (PCNA). MEK1/2 inhibitors, such as PD98059 and U0126, reduced RA‐induced ERK1/2 activity, but could not block the genistein effects. Our observations indicate that genistein‐induced neuronal differentiation is not dependent of the MEK‐ERK signaling cascade. Instead, genistein‐upregulated ERK activation is likely due to this chemical's direct effect on chromosome and gene transcription, rather than its inhibition on tyrosine kinases. Failure of inhibition of ERK1/2 activation by the MEK1/2 inhibitors PD98059 and U0126 suggests presence of an unknown activator for ERK1/2 in neuronal cells. J. Cell. Biochem. © 2005 Wiley‐Liss, Inc.