TY - JOUR
T1 - The p38 MAPK-MK2 axis regulates E2F1 and FOXM1 expression after epirubicin treatment
AU - De Olano, Natalia
AU - Koo, Chuay Yeng
AU - Monteiro, Lara J.
AU - Pinto, Paola H.
AU - Gomes, Ana R.
AU - Aligue, Rosa
AU - Lam, Eric W.F.
PY - 2012/9
Y1 - 2012/9
N2 - E2F1 is responsible for the regulation of FOXM1 expression, which plays a key role in epirubicin resistance. Here, weexamined the role andregulation of E2F1 in response to epirubicin in cancer cells. We first showed that E2F1 plays a key role in promoting FOXM1 expression, cell survival, and epirubicin resistance as its depletion by siRNAattenuated FOXM1 induction and cell viability in response to epirubicin.Wealso found that the p38-MAPK activity mirrors the expression patterns of E2F1 and FOXM1 in both epirubicin-sensitive and -resistant MCF-7 breast cancer cells, suggesting that p38 has a role in regulating E2F1 expression and epirubicin resistance. Consistently, studies using pharmacologic inhibitors, siRNA knockdown, and knockout mouse embryonic fibroblasts (MEF) revealed that p38 mediates the E2F1 induction by epirubicin and that the induction of E2F1 by p38 is, in turn, mediated through its downstream kinase MK2 [mitogen-activated protein kinase (MAPK)-activated protein kinase 2; MAPKAPK2]. In agreement, in vitro phosphorylation assays showed that MK2 can directly phosphorylate E2F1 at Ser-364. Transfection assays also showed that E2F1 phosphorylation at Ser-364 participates in its induction by epirubicin but also suggests that other phosphorylation events are also involved. In addition, the p38-MK2 axis can also limit cjun-NH2-kinase (JNK) induction by epirubicin and, notably, JNK represses FOXM1 expression. Collectively, these findings underscore the importance of p38-MK2 signaling in the control of E2F1 and FOXM1 expression as well as epirubicin sensitivity.
AB - E2F1 is responsible for the regulation of FOXM1 expression, which plays a key role in epirubicin resistance. Here, weexamined the role andregulation of E2F1 in response to epirubicin in cancer cells. We first showed that E2F1 plays a key role in promoting FOXM1 expression, cell survival, and epirubicin resistance as its depletion by siRNAattenuated FOXM1 induction and cell viability in response to epirubicin.Wealso found that the p38-MAPK activity mirrors the expression patterns of E2F1 and FOXM1 in both epirubicin-sensitive and -resistant MCF-7 breast cancer cells, suggesting that p38 has a role in regulating E2F1 expression and epirubicin resistance. Consistently, studies using pharmacologic inhibitors, siRNA knockdown, and knockout mouse embryonic fibroblasts (MEF) revealed that p38 mediates the E2F1 induction by epirubicin and that the induction of E2F1 by p38 is, in turn, mediated through its downstream kinase MK2 [mitogen-activated protein kinase (MAPK)-activated protein kinase 2; MAPKAPK2]. In agreement, in vitro phosphorylation assays showed that MK2 can directly phosphorylate E2F1 at Ser-364. Transfection assays also showed that E2F1 phosphorylation at Ser-364 participates in its induction by epirubicin but also suggests that other phosphorylation events are also involved. In addition, the p38-MK2 axis can also limit cjun-NH2-kinase (JNK) induction by epirubicin and, notably, JNK represses FOXM1 expression. Collectively, these findings underscore the importance of p38-MK2 signaling in the control of E2F1 and FOXM1 expression as well as epirubicin sensitivity.
UR - http://www.scopus.com/inward/record.url?scp=84866497672&partnerID=8YFLogxK
U2 - 10.1158/1541-7786.MCR-11-0559
DO - 10.1158/1541-7786.MCR-11-0559
M3 - Article
C2 - 22802261
AN - SCOPUS:84866497672
SN - 1541-7786
VL - 10
SP - 1189
EP - 1202
JO - Molecular Cancer Research
JF - Molecular Cancer Research
IS - 9
ER -