Transcriptional Induction of MKP-1 in Response to Stress Is Associated with Histone H3 Phosphorylation-Acetylation

Abstract

Mitogen-activated protein (MAP) kinase phosphatase 1 (MKP-1) has been shown to play a critical role in mediating the feedback control of MAP kinase cascades in a variety of cellular processes, including proliferation and stress responsiveness. Although MKP-1 expression is induced by a broad array of extracellular stimuli, the mechanisms mediating its induction remain poorly understood. Here we show that MKP-1 mRNA was potently induced by arsenite and ultraviolet light and modestly increased by heat shock and hydrogen peroxide. Interestingly, arsenite also dramatically induces phosphorylation-acetylation of histone H3 at a global level which precedes the induction of MKP-1 mRNA. The transcriptional induction of MKP-1, histone H3 modification, and elevation in MKP-1 mRNA in response to arsenite are all partially prevented by the p38 MAP kinase inhibitor SB203580, suggesting that the p38 pathway is involved in these processes. Finally, analysis of the DNA brought down by chromatin immunoprecipitation (ChIP) reveals that arsenite induces phosphorylation-acetylation of histone H3 associated with the MKP-1 gene and enhances binding of RNA polymerase II to MKP-1 chromatin. ChIP assays following exposure to other stress agents reveal various degrees of histone H3 modification at the MKP-1 chromatin. The differential contribution of p38 and ERK MAP kinases in mediating MKP-1 induction by different stress agents further illustrates the complexity and versatility of stress-induced MKP-1 expression. Our results strongly suggest that chromatin remodeling after stress contributes to the transcriptional induction of MKP-1.The mitogen-activated protein (MAP) kinases play a central role in orchestrating many short-and long-term changes in the cell in response to extracellular stimuli (50). To date, three major MAP kinase subfamilies have been well characterized in mammalian cells: the extracellular signal-regulated kinase (ERK), the c-Jun N-terminal kinases/stress-activated protein kinase (JNK/SAPK), and p38 (11,40,50). Thus far, numerous proteins with a wide spectrum of biological functions have been identified as the targets of MAP kinase cascades, including protein kinases, cytoskeletal components, phospholipase A2, stalhmin, and the Na ϩ /H ϩ antipump NHE1 (6,23,42). In addition to the proteins that function on the membrane or in the cytoplasm, MAP kinases also play a crucial role in regulating gene transcription. Upon activation, MAP kinases translocate from the cytoplasm to the nucleus, where they phosphorylate and activate a multitude of transcription factors, including c-Myc, c-Jun, c-Fos, Elk-1, and ATF-2, ultimately resulting in enhanced gene transcription (8,24,58). The fact that a broad variety of extracellular signals conscript MAP kinase cascades to convey their specific messages suggests that MAP kinase cascades serve a myriad of purposes and the cascades need to be tightly controlled.The activities of all MAP kinases are regulated through reversible phosphorylation of two different amino acid residues (threonine ...

Immediate-early gene induction by the stresses anisomycin and arsenite in human osteosarcoma cells involves MAPK cascade signaling to Elk-1, CREB and SRF

“…Nor was it addressed by Lim et al (1998) in NIH3T3 cells, where SB only partially blocked egr-1 induction by anisomycin. Interestingly, As 3+ -driven induction of mkp-1 in C3H 10 1 2 cells is strongly sensitive to SB and weakly affected by ERK inhibition, implicating both the p38 and ERK cascades (Li et al, 2001). Thus, stress-induced signaling in C3H 10 1 2 cells resembles that of HOS cells in certain respects.…”

CREB and AP‐1 activation regulates MKP‐1 induction by LPS or M‐CSF and their kinetics correlate with macrophage activation versus proliferation

“…Like many other immediate-early genes, MKP-1 expression is regulated mainly at the transcriptional level. The chromatin on the MKP-1 locus is altered following treatment with arsenite [33] and several transcription factors (including Sp1, Sp3, AP-1 and USF) influence the MKP-1 gene transcription in response to growth factors and stress stimuli [34][35][36]. MKP-1 is silenced transcriptionally by the FBI1-14-3-3b complex [37].…”

MKP1/CL100 controls tumor growth and sensitivity to cisplatin in non-small-cell lung cancer

“…MKP1/CL100 is an immediate-early gene whose expression is regulated by mitogenic, inflammatory and DNA-damage stimuli (Beltman et al, 1996;Sa´nchez-Pe´rez et al, 1998;Li et al, 2001). Although MKP1 levels in normal cells are low, increased levels of MKP1 have been found in human ovarian carcinoma, breast and prostate cancer (Srikanth et al, 1999;Denkert et al, 2002;Wang et al, 2003).…”