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Role of extracellular signal–regulated kinase pathway in RRR‐α‐tocopheryl succinate–induced differentiation of human MDA‐MB‐435 breast cancer cells
Author(s) -
You Huihong,
Yu Weiping,
MunozMedellin Debbie,
Brown Powel H.,
Sanders Bob G.,
Kline Kimberly
Publication year - 2002
Publication title -
molecular carcinogenesis
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.254
H-Index - 97
eISSN - 1098-2744
pISSN - 0899-1987
DOI - 10.1002/mc.10040
Subject(s) - biology , kinase , cellular differentiation , microbiology and biotechnology , protein kinase a , signal transduction , cancer research , biochemistry , gene
RRR‐α‐tocopheryl succinate (vitamin E succinate, VES) induces differentiation of human breast cancer cells. Previous studies ruled out transforming growth factor‐β and c‐jun N‐terminal kinase involvement in VES‐induced differentiation but implicated extracellular signal–regulated kinases (ERKs). Here we show that dominant‐negative mutants of either mitogen‐activated protein kinase kinase (MEK) 1 or ERK1 blocked VES‐induced differentiation of MDA‐MB‐435 cells, as measured by induction of cytokeratin 18 and p21 (Waf1/Cip1) proteins. Blockage of c‐jun protein expression using c‐ jun antisense oligonucleotides or expression of an inducible dominant‐negative c‐jun mutant protein inhibited VES‐induced differentiation. Elevated expression of wild‐type c‐jun alone was sufficient to induce cellular differentiation. A role for p21 (Waf1/Cip1) is implicated, in that p21 antisense oligomers blocked VES‐induced differentiation. In summary, MEK1, ERK1, the transcription factor c‐jun, and the cyclin‐dependent kinase inhibitor p21 (Waf1/Cip1) play a part in VES‐induced differentiation of human MDA‐MB‐435 breast cancer cells. © 2002 Wiley‐Liss, Inc.