Role of extracellular signal-regulated kinase pathway in RRR-alpha-tocopheryl succinate-induced differentiation of human MDA-MB-435 breast cancer cells.
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.
You
Huihong
H
Department of Molecular Genetics and Microbiology/C0900 School of Biological Sciences, The University of Texas at Austin, 78712-1097, USA.
Yu
Weiping
W
Munoz-Medellin
Debbie
D
Brown
Powel H
PH
Sanders
Bob G
BG
Kline
Kimberly
K
D001943:Breast Neoplasms / Q000473:pathology*; D002454:Cell Differentiation / Q000187:drug effects*; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins / Q000235:genetics; D004318:Doxycycline / Q000494:pharmacology*; D005260:Female; D016758:Genes, jun; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases; D007633:Keratins / Q000235:genetics; D048369:MAP Kinase Kinase 1; D020935:MAP Kinase Signaling System / Q000502:physiology*; D019950:Mitogen-Activated Protein Kinase 1 / Q000235:genetics; D048052:Mitogen-Activated Protein Kinase 3; D020929:Mitogen-Activated Protein Kinase Kinases / Q000235:genetics; D020928:Mitogen-Activated Protein Kinases / Q000235:genetics* / Q000378:metabolism; D020319:Oligodeoxyribonucleotides, Antisense / Q000494:pharmacology; D017346:Protein Serine-Threonine Kinases / Q000235:genetics; D016755:Proto-Oncogene Proteins c-jun / Q000235:genetics; D011994:Recombinant Proteins / Q000378:metabolism; D024505:Tocopherols; D014162:Transfection; D014407:Tumor Cells, Cultured; D014810:Vitamin E / Q000031:analogs & derivatives* / Q000494:pharmacology*
C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D020319:Oligodeoxyribonucleotides, Antisense; D016755:Proto-Oncogene Proteins c-jun; D011994:Recombinant Proteins; D014810:Vitamin E; D007633:Keratins; D017346:Protein Serine-Threonine Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases; D048369:MAP Kinase Kinase 1; C482125:MAP2K1 protein, human; D020929:Mitogen-Activated Protein Kinase Kinases; D004318:Doxycycline; D024505:Tocopherols