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Hyperosmotic stress strongly potentiates serum response factor (SRF)‐dependent transcriptional activity in ehrlich lettré ascites cells through a mechanism involving p38 mitogen‐activated protein kinase
Author(s) -
Gorbatenko Andrej,
Wiwel Maria,
Klingberg Henrik,
Nielsen Anni Bech,
Kapus András,
Pedersen Stine Falsig
Publication year - 2011
Publication title -
journal of cellular physiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.529
H-Index - 174
eISSN - 1097-4652
pISSN - 0021-9541
DOI - 10.1002/jcp.22628
Subject(s) - creb , ribosomal s6 kinase , mapk/erk pathway , protein kinase a , kinase , p38 mitogen activated protein kinases , microbiology and biotechnology , phosphorylation , transcription factor , mitogen activated protein kinase , biology , chemistry , biochemistry , p70 s6 kinase 1 , protein kinase b , gene
Long‐term osmotic stress results in altered gene transcription, however, with the exception of the TonE/TonEBP system, the underlying mechanisms are poorly understood. We previously showed that upon osmotic shrinkage of Ehrlich Lettré Ascites (ELA) fibroblasts, the MEK1‐ERK1/2 pathway is transiently inhibited while p38 MAPK is activated, in turn impacting on cell survival (Pedersen et al., 2007, Cell Physiol Biochem 20: 735–750). Here, we show that downstream of these kinases, two transcription factors with major roles in control of cell proliferation and death, serum response factor (SRF) and cAMP response element‐binding protein (CREB) are differentially regulated in ELA cells. SRF Ser 103 phosphorylation and SRF‐dependent transcriptional activity were strongly augmented 5–30 min and 24 h, respectively, after hyperosmotic stress (50% increase in extracellular ionic strength), in a p38 MAPK‐dependent manner. In contrast, CREB Ser 133 was transiently dephosphorylated upon osmotic shrinkage. The ERK1/2 effector ribosomal S kinase (RSK) and the ERK1/2‐ and p38 MAPK effector mitogen‐ stress‐activated protein kinase 1 (MSK1) both phosphorylate CREB at Ser 133 . RSK and MSK1 were dephosphorylated within 5 min of shrinkage. MSK1 phosphorylation recovered within 30 min in a p38‐MAPK‐dependent manner. CREB was transiently dephosphorylated after shrinkage in a manner exacerbated by p38 MAPK inhibition or MSK1 knockdown, but unaffected by inhibition of RSK. In conclusion, in ELA cells, hyperosmotic stress activates SRF in a p38 MAPK‐dependent manner and transiently inactivates CREB, likely due to MSK1 inactivation. We suggest that these events contribute to shrinkage‐induced changes in gene transcription and death/survival balance. J. Cell. Physiol. 226: 2857–2868, 2011. © 2011 Wiley‐Liss, Inc.