Differential up-regulation of MAP kinase phosphatases MKP3/DUSP6 and DUSP5 by Ets2 and c-Jun converge in the control of the growth arrest versus proliferation response of MCF-7 breast cancer cells to phorbol ester.
Different levels of regulation account for the inactivation of MAP kinases by MAPK phosphatases (MKPs), in a cell type- and stimuli-dependent manner. MCF-7 human breast carcinoma cells treated with the phorbol 12-myristate 13-acetate (PMA) suffer growth arrest and show morphological alterations, which depend on the activation of the ERK1/2 MAP kinases. MKP3/DUSP6 and DUSP5 MAP kinase phosphatases, two negative regulators of ERK1/2, were specifically up-regulated in MCF-7 and SKBR3 cells in response to PMA. MKP3 and DUSP5 up-regulation required the prolonged activation of the ERK1/2 pathway, and correlated with the shutdown of this route. MKP3 induction relied on the activation of the Ets2 transcription factor, whereas DUSP5 induction depended on the activation of c-Jun. Diminishing the expression of MKP3 and DUSP5 raised the activation of ERK1/2, and accelerated growth arrest of PMA-treated MCF-7 cells. Conversely, MCF-7 cell lines expressing high levels of MKP3 or DUSP5 did not undergo PMA-triggered growth arrest, displayed a migratory phenotype, and formed colonies in soft agar. We propose that the differential up-regulation of MKP3 by Ets2 and of DUSP5 by c-Jun may converge in similar functional roles for these MAP kinase phosphatases in the growth arrest versus proliferation decisions of breast cancer cells.
Nunes-Xavier
Caroline E
CE
Centro de Investigación Príncipe Felipe, Valencia 46012, Spain.
Tárrega
Céline
C
Cejudo-Marín
Rocío
R
Frijhoff
Jeroen
J
Sandin
Asa
A
Ostman
Arne
A
Pulido
Rafael
R
D001943:Breast Neoplasms / Q000473:pathology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D054642:Dual Specificity Phosphatase 6 / Q000235:genetics*; D054637:Dual-Specificity Phosphatases / Q000235:genetics*; D005260:Female; D006801:Humans; D010703:Phorbol Esters / Q000494:pharmacology; D050787:Proto-Oncogene Protein c-ets-2 / Q000502:physiology*; D016755:Proto-Oncogene Proteins c-jun / Q000502:physiology*; D015854:Up-Regulation / Q000235:genetics*
C494069:ETS2 protein, human; D010703:Phorbol Esters; D050787:Proto-Oncogene Protein c-ets-2; D016755:Proto-Oncogene Proteins c-jun; C442320:DUSP5 protein, human; D054642:Dual Specificity Phosphatase 6; D054637:Dual-Specificity Phosphatases