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Smith ER , Cai KQ , Smedberg JL , Ribeiro MM , Rula ME , Slater C , Godwin AK , Xu XX
Nuclear Entry of Activated MAPK Is Restricted in Primary Ovarian and Mammary Epithelial Cells
Plos One. 2010 Feb;5(2)
PMID: ISI:000274654700022    PMCID: PMC2823791   
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Background: The MAPK/ERK1/2 serine kinases are primary mediators of the Ras mitogenic signaling pathway. Phosphorylation by MEK activates MAPK/ERK in the cytoplasm, and phospho-ERK is thought to enter the nucleus readily to modulate transcription. Principal Findings: Here, however, we observe that in primary cultures of breast and ovarian epithelial cells, phosphorylation and activation of ERK1/2 are disassociated from nuclear translocalization and transcription of downstream targets, such as c-Fos, suggesting that nuclear translocation is limited in primary cells. Accordingly, in import assays in vitro, primary cells showed a lower import activity for ERK1/2 than cancer cells, in which activated MAPK readily translocated into the nucleus and activated c-Fos expression. Primary cells express lower levels of nuclear pore complex proteins and the nuclear transport factors, importin B1 and importin 7, which may explain the limiting ERK1/2 import found in primary cells. Additionally, reduction in expression of nucleoporin 153 by siRNA targeting reduced ERK1/2 nuclear activity in cancer cells. Conclusion: ERK1/2 activation is dissociated from nuclear entry, which is a rate limiting step in primary cells and in vivo, and the restriction of nuclear entry is disrupted in transformed cells by the increased expression of nuclear pores and/or nuclear transport factors.
Smith, Elizabeth R. Cai, Kathy Qi Smedberg, Jennifer L. Ribeiro, Melina M. Rula, Malgorzata E. Slater, Carolyn Godwin, Andrew K. Xu, Xiang-Xi National Cancer Institute [R01CA099471, R01CA79716, R01CA75389]; Marsha Rivkin Ovarian Cancer Research Center and DOD Ovarian Concept [W81XWH-07-1-0303] This work was supported by National Cancer Institute grants R01CA099471, R01CA79716, and R01CA75389 (to X-XX). E. R. S. received support from the Marsha Rivkin Ovarian Cancer Research Center and DOD Ovarian Concept W81XWH-07-1-0303. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. 55 Public library science; 185 berry st, ste 1300, san francisco, ca 94107 usa 557fj