Immediate-early gene induction by the stresses anisomycin and arsenite in human osteosarcoma cells involves MAPK cascade signaling to Elk-1, CREB and SRF.
Cellular stress activates multiple mitogen-activated protein kinase (MAPK) cascades and immediate-early gene (IEG) transcription. To address how these events are linked, we investigated the endogenous signaling/transcription factor network driving IEG activation by arsenite and anisomycin in the human osteosarcoma cell line HOS/TE-85. Induction of IEG transcription by both stresses corresponded temporally with the phosphorylation of the regulatory factors Elk-1 and cAMP response element-binding protein (CREB), along with activation of the extracellular signal-regulated kinase (ERK), stress-activated protein kinase (SAPK) and p38 MAPK cascades. To assess the role of the different cascades, they were selectively inhibited with PD98059, SP600125 and SB203580, respectively. This implicated all three cascades in Elk-1 phosphorylation after arsenite treatment, whereas ERK and SAPK inhibition diminished this, and IEG mRNA levels, downstream of anisomycin. SB blocked phosphorylation of both serum response factor (SRF) and CREB, and strongly reduced IEG activation by both stresses. Combining PD with SB further reduced arsenite induction of IEG transcription. Thus, all three MAPK cascades mediate anisomycin- and arsenite-induced signaling to IEG promoters in HOS cells through the differential targeting of Elk-1, SRF and CREB.
Bébien
Magali
M
Institut de Génétique Moléculaire de Montpellier, CNRS, UMR 5535, IFR 24, France.
Salinas
Sara
S
Becamel
Carine
C
Richard
Véronique
V
Linares
Laetitia
L
Hipskind
Robert A
RA
D000841:Anisomycin / Q000494:pharmacology*; D018053:Arsenites / Q000494:pharmacology*; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism*; D004268:DNA-Binding Proteins; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects* / Q000502:physiology; D017781:Genes, Immediate-Early; D006801:Humans; D020935:MAP Kinase Signaling System; D010766:Phosphorylation; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D026362:Serum Response Factor / Q000378:metabolism*; D014157:Transcription Factors; D015533:Transcriptional Activation; D014407:Tumor Cells, Cultured; D050807:ets-Domain Protein Elk-1
D018053:Arsenites; D017362:Cyclic AMP Response Element-Binding Protein; D004268:DNA-Binding Proteins; C494112:ELK1 protein, human; D011518:Proto-Oncogene Proteins; D026362:Serum Response Factor; D014157:Transcription Factors; D050807:ets-Domain Protein Elk-1; D000841:Anisomycin; C015001:arsenite