Abstract
RRR-alpha-tocopheryl succinate (vitamin E succinate, VES) induces differentiation of human breast cancer cells. Previous studies ruled out transforming growth factor-beta 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.
Copyright 2002 Wiley-Liss, Inc.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Breast Neoplasms / pathology*
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Cell Differentiation / drug effects*
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Cyclin-Dependent Kinase Inhibitor p21
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Cyclins / genetics
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Doxycycline / pharmacology*
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Female
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Genes, jun
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Humans
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JNK Mitogen-Activated Protein Kinases
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Keratins / genetics
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MAP Kinase Kinase 1
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MAP Kinase Signaling System / physiology*
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Mitogen-Activated Protein Kinase 1 / genetics
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Mitogen-Activated Protein Kinase 3
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Mitogen-Activated Protein Kinase Kinases / genetics
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Mitogen-Activated Protein Kinases / genetics*
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Mitogen-Activated Protein Kinases / metabolism
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Oligodeoxyribonucleotides, Antisense / pharmacology
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Protein Serine-Threonine Kinases / genetics
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Proto-Oncogene Proteins c-jun / genetics
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Recombinant Proteins / metabolism
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Tocopherols
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Transfection
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Tumor Cells, Cultured
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Vitamin E / analogs & derivatives*
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Vitamin E / pharmacology*
Substances
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CDKN1A protein, human
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Cyclin-Dependent Kinase Inhibitor p21
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Cyclins
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Oligodeoxyribonucleotides, Antisense
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Proto-Oncogene Proteins c-jun
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Recombinant Proteins
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Vitamin E
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Keratins
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Protein Serine-Threonine Kinases
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JNK Mitogen-Activated Protein Kinases
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Mitogen-Activated Protein Kinase 1
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Mitogen-Activated Protein Kinase 3
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Mitogen-Activated Protein Kinases
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MAP Kinase Kinase 1
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MAP2K1 protein, human
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Mitogen-Activated Protein Kinase Kinases
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Doxycycline
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Tocopherols