p38γ mitogen-activated protein kinase (MAPK) confers breast cancer hormone sensitivity by switching estrogen receptor (ER) signaling from classical to nonclassical pathway via stimulating ER phosphorylation and c-Jun transcription. J Biol Chem 2012 Apr 27;287(18):14681-91
Date
03/09/2012Pubmed ID
22399296Pubmed Central ID
PMC3340246DOI
10.1074/jbc.M112.349357Scopus ID
2-s2.0-84860370781 (requires institutional sign-in at Scopus site) 24 CitationsAbstract
Estrogen receptor (ER) α promotes breast cancer growth by regulating gene expression through classical estrogen response element (ERE) binding and nonclassical (interaction with c-Jun at AP-1 sites) pathways. ER is the target for anti-estrogens such as tamoxifen (TAM). However, the potential for classical versus nonclassical ER signaling to influence hormone sensitivity is not known. Moreover, anti-estrogens frequently activate several signaling cascades besides the target ER, and the implications of these "off-target" signaling events have not been explored. Here, we report that p38γ MAPK is selectively activated by treatment with TAM. This results in both phosphorylation of ER at Ser-118 and stimulation of c-Jun transcription, thus switching ER signaling from the classical to the nonclassical pathway leading to increased hormone sensitivity. Unexpectedly, phosphorylation at Ser-118 is required for ER to bind both p38γ and c-Jun, thereby promoting ER relocation from ERE to AP-1 promoter sites. Thus, ER/Ser-118 phosphorylation serves as a central mechanism by which p38γ regulates signaling transduction of ER with its inhibitor TAM.
Author List
Qi X, Zhi H, Lepp A, Wang P, Huang J, Basir Z, Chitambar CR, Myers CR, Chen GAuthors
Guan Chen MD, PhD Professor in the Pharmacology and Toxicology department at Medical College of WisconsinXiao-Mei Qi MD Associate Professor in the Pharmacology and Toxicology department at Medical College of Wisconsin
MESH terms used to index this publication - Major topics in bold
Antineoplastic Agents, HormonalBreast Neoplasms
Cell Line, Tumor
Enzyme Activation
Estrogen Receptor alpha
Female
Humans
MAP Kinase Signaling System
Mitogen-Activated Protein Kinase 12
Phosphorylation
Protein Binding
Proto-Oncogene Proteins c-jun
Response Elements
Tamoxifen
Transcription, Genetic