期刊
JOURNAL OF BIOLOGICAL CHEMISTRY
卷 285, 期 34, 页码 26417-26430出版社
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.M110.121830
关键词
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资金
- Ministerio de Educacion y Ciencia [SAF2006-08319]
- Ministerio de Ciencia e Innovacion [SAF2009-10226]
- (Spain and Fondo Europeo de Desarrollo Regional, FEDER) Generalitat Valenciana [AP-117/08, AP-040/10, ACOMP/2009/363, ACOMP/2010/222]
- Instituto de Salud Carlos III [ISCIII-RETICS RD06/0020/0049]
- European Union [MRTN-CT-2006-035830]
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.
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