Immediate-early gene induction by the stresses anisomycin and
arsenite in human osteosarcoma cells involves MAPK cascade signaling to Elk-1,
CREB and SRF.
Bebien M, Salinas S, Becamel C, Richard V, Linares L, Hipskind RA.
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.Oncogene (2003) 22, 1836-1847.