TY - JOUR
T1 - Activation of estrogen receptor α by raloxifene through an activating protein-1-dependent tethering mechanism in human cervical epithelial cancer cells
T2 - A role for c-Jun N-terminal kinase
AU - Fogarty, Elizabeth A.
AU - Matulis, Christina K.
AU - Kraus, W. Lee
N1 - Funding Information:
The authors would like to thank the following: (1) Dr. Gary Isaacs and Dr. Nina Heldring for technical advice and helpful discussions about the directions of this work, (2) Shrikanth Gadad, Miao Sun, and Jane Bowman for critical reading of this manuscript, (3) Dr. Steve Nordeen for the MMP1 reporter plasmid, (4) Dr. Miltos Kininis for the PRUNE-Luc reporter plasmid, (5) Dr. David Shapiro for the HeLa–ERα cells, (6) Dr. Charles Vinson for the dominant negative A-Fos construct, and (7) Dr. Benita Katzenellenbogen for the RSV-hERα expression plasmid. This work was supported by a Grant from the NIH/NIDDK ( DK058110 ) to W.L.K. and the Cecil H. and Ida Green Reproductive Biology Sciences endowments.
PY - 2012/1/2
Y1 - 2012/1/2
N2 - Nuclear estrogen receptor α (ERα) regulates target gene expression in response to ligands through two distinct mechanisms: direct binding to DNA and indirect tethering through other DNA-bound transcription factors, such as AP-1. In the studies described herein, we examined the molecular mechanisms underlying the activation of ERα in the AP-1 tethering pathway by the selective estrogen receptor modulator (SERM) raloxifene (Ral). Our results with the MMP1 and PRUNE genes indicate that the c-Fos component of the AP-1 tethering factor and the c-Jun N-terminal kinase 1 (JNK1) are constitutively bound at the promoter regions prior to Ral exposure. Ral then promotes the binding of ERα at the promoter in a c-Fos-dependent manner. Interestingly, we found that JNK1 enzymatic activity is required for Ral-dependent gene activation through ERα. Our results suggest that one role for Ral-dependent recruitment of ERα to the AP-1 binding site is to stimulate JNK1 enzymatic activity. Alternatively, Ral-occupied ERα might recruit protein substrates to promoter-bound JNK1 without any change in JNK1 activity. Collectively, our studies have revealed a new role for JNK1 in determining gene regulatory outcomes by ERα.
AB - Nuclear estrogen receptor α (ERα) regulates target gene expression in response to ligands through two distinct mechanisms: direct binding to DNA and indirect tethering through other DNA-bound transcription factors, such as AP-1. In the studies described herein, we examined the molecular mechanisms underlying the activation of ERα in the AP-1 tethering pathway by the selective estrogen receptor modulator (SERM) raloxifene (Ral). Our results with the MMP1 and PRUNE genes indicate that the c-Fos component of the AP-1 tethering factor and the c-Jun N-terminal kinase 1 (JNK1) are constitutively bound at the promoter regions prior to Ral exposure. Ral then promotes the binding of ERα at the promoter in a c-Fos-dependent manner. Interestingly, we found that JNK1 enzymatic activity is required for Ral-dependent gene activation through ERα. Our results suggest that one role for Ral-dependent recruitment of ERα to the AP-1 binding site is to stimulate JNK1 enzymatic activity. Alternatively, Ral-occupied ERα might recruit protein substrates to promoter-bound JNK1 without any change in JNK1 activity. Collectively, our studies have revealed a new role for JNK1 in determining gene regulatory outcomes by ERα.
KW - Activating protein-1 (AP-1)
KW - C-Fos
KW - C-Jun N-terminal kinase (JNK1)
KW - Estrogen receptor
KW - Raloxifene
KW - Transcriptional activation
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U2 - 10.1016/j.mce.2011.09.032
DO - 10.1016/j.mce.2011.09.032
M3 - Article
C2 - 21964465
AN - SCOPUS:80755133263
SN - 0303-7207
VL - 348
SP - 331
EP - 338
JO - Molecular and Cellular Endocrinology
JF - Molecular and Cellular Endocrinology
IS - 1
ER -