Activation of the Estrogen Receptor Through Phosphorylation by Mitogen-Activated Protein Kinase

The phosphorylation of the human estrogen receptor (ER) serine residue at position 118 is required for full activity of the ER activation function 1 (AF-1). This Ser118 is phosphorylated by mitogen-activated protein kinase (MAPK) in vitro and in cells treated with epidermal growth factor (EGF) and insulin-like growth factor (IGF) in vivo. Overexpression of MAPK kinase (MAPKK) or of the guanine nucleotide binding protein Ras, both of which activate MAPK, enhanced estrogen-induced and antiestrogen (tamoxifen)-induced transcriptional activity of wild-type ER, but not that of a mutant ER with an alanine in place of Ser118. Thus, the activity of the amino-terminal AF-1 of the ER is modulated by the phosphorylation of Ser118 through the Ras-MAPK cascade of the growth factor signaling pathways.

[1]  C. Marshall,et al.  Specificity of receptor tyrosine kinase signaling: Transient versus sustained extracellular signal-regulated kinase activation , 1995, Cell.

[2]  B. O’Malley,et al.  Molecular mechanisms of action of steroid/thyroid receptor superfamily members. , 1994, Annual review of biochemistry.

[3]  S. Fawell,et al.  Identification of constitutive and steroid-dependent transactivation domains in the mouse oestrogen receptor. , 1989, Journal of steroid biochemistry.

[4]  E. Nishida,et al.  Involvement of the MAP kinase cascade in Xenopus mesoderm induction. , 1995, The EMBO journal.

[5]  Gene regulation by steroid hormones , 1989, Cell.

[6]  P. Chambon,et al.  A far upstream estrogen response element of the ovalbumin gene contains several half-palindromic 5′-TGACC-3′ motifs acting synergistically , 1992, Cell.

[7]  R. Clarke,et al.  MCF7/LCC2: a 4-hydroxytamoxifen resistant human breast cancer variant that retains sensitivity to the steroidal antiestrogen ICI 182,780. , 1993, Cancer research.

[8]  N. Webster,et al.  The human estrogen receptor has two independent nonacidic transcriptional activation functions , 1989, Cell.

[9]  P. Chambon,et al.  Nuclear receptors enhance our understanding of transcription regulation. , 1988, Trends in genetics : TIG.

[10]  S. Pelech,et al.  MAP kinases: charting the regulatory pathways. , 1992, Science.

[11]  W. Gullick.  Growth factors and oncogenes in breast cancer. , 1990, Progress in growth factor research.

[12]  W. Gullick,et al.  Type 1 growth factor receptors: an overview of recent developments , 1995 .

[13]  Stimulation of estrogen receptor-mediated transcription and alteration in the phosphorylation state of the rat uterine estrogen receptor by estrogen, cyclic adenosine monophosphate, and insulin-like growth factor-I. , 1993, Molecular endocrinology.

[14]  S. F. Arnold,et al.  In vivo and in vitro phosphorylation of the human estrogen receptor , 1995, The Journal of Steroid Biochemistry and Molecular Biology.

[15]  G. McKnight,et al.  Regulation of transcription by cyclic AMP-dependent protein kinase. , 1989, Proceedings of the National Academy of Sciences of the United States of America.

[16]  K. Korach,et al.  Peptide growth factors elicit estrogen receptor-dependent transcriptional activation of an estrogen-responsive element. , 1993, Molecular endocrinology.

[17]  P. Chambon,et al.  Characterization of the Amino-terminal Transcriptional Activation Function of the Human Estrogen Receptor in Animal and Yeast Cells (*) , 1995, The Journal of Biological Chemistry.

[18]  E. Nishida,et al.  In vitro effects on microtubule dynamics of purified Xenopus M phase-activated MAP kinase , 1991, Nature.

[19]  E. Nishida,et al.  Characterization of recombinant Xenopus MAP kinase kinases mutated at potential phosphorylation sites. , 1994, Oncogene.

[20]  P. Chambon,et al.  Role of the two activating domains of the oestrogen receptor in the cell‐type and promoter‐context dependent agonistic activity of the anti‐oestrogen 4‐hydroxytamoxifen. , 1990, The EMBO journal.

[21]  C. Benz,et al.  Incidence of activating ras oncogene mutations associated with primary and metastatic human breast cancer. , 1989, Cancer research.

[22]  H. Gronemeyer,et al.  Transcription activation by estrogen and progesterone receptors. , 1991, Annual review of genetics.

[23]  P. Chambon,et al.  Effect of antagonists on DNA binding properties of the human estrogen receptor in vitro and in vivo. , 1995, Molecular endocrinology.

[24]  V. Jordan,et al.  Development of tamoxifen-stimulated growth of MCF-7 tumors in athymic mice after long-term antiestrogen administration. , 1988, Cancer research.

[25]  K. Korach,et al.  Uterine estrogen receptor in vivo: phosphorylation of nuclear specific forms on serine residues. , 1991, Molecular endocrinology.

[26]  R. Davis,et al.  Identification of substrate recognition determinants for human ERK1 and ERK2 protein kinases. , 1991, The Journal of biological chemistry.

[27]  P. Chambon,et al.  The hormone-binding domains of the estrogen and glucocorticoid receptors contain an inducible transcription activation function , 1988, Cell.

[28]  W Godolphin,et al.  Studies of the HER-2/neu proto-oncogene in human breast and ovarian cancer. , 1989, Science.

[29]  N. Koszewski,et al.  Estrogen receptor phosphorylation. Hormonal dependence and consequence on specific DNA binding. , 1992, The Journal of biological chemistry.

[30]  P. Chambon,et al.  Functional domains of the human estrogen receptor , 1987, Cell.

[31]  R. Evans,et al.  The steroid and thyroid hormone receptor superfamily. , 1988, Science.

[32]  J. Lees,et al.  Identification of a conserved region required for hormone dependent transcriptional activation by steroid hormone receptors. , 1992, The EMBO journal.

[33]  K. Kaibuchi,et al.  Transforming and c-fos promoter/enhancer-stimulating activities of a stimulatory GDP/GTP exchange protein for small GTP-binding proteins. , 1992, The Journal of biological chemistry.

[34]  Richard Treisman,et al.  Transcriptional Regulation by Extracellular signals: Mechanisms and Specificity , 1995, Cell.

[35]  A. deFazio,et al.  Activation of the Ras signalling pathway in human breast cancer cells overexpressing erbB-2. , 1994, Oncogene.

[36]  B. Katzenellenbogen,et al.  Phosphorylation of the human estrogen receptor. Identification of hormone-regulated sites and examination of their influence on transcriptional activity. , 1994, The Journal of biological chemistry.

[37]  L. Murphy,et al.  Epidermal growth factor: receptor and ligand expression in human breast cancer. , 1990, Seminars in cancer biology.

[38]  D. Lannigan,et al.  Estradiol and phorbol ester cause phosphorylation of serine 118 in the human estrogen receptor. , 1995, Molecular endocrinology.

[39]  P. Chambon,et al.  Modulation of transcriptional activation by ligand‐dependent phosphorylation of the human oestrogen receptor A/B region. , 1993, The EMBO journal.