Differential regulation of estrogen receptor alpha turnover and transactivation by Mdm2 and stress-inducing agents.

In mammalian cells, the level of estrogen receptor alpha (ERalpha) is rapidly decreased upon estrogen treatment, and this regulation involves proteasome degradation. Using different approaches, we showed that the Mdm2 oncogenic ubiquitin-ligase directly interacts with ERalpha in a ternary complex with p53 and is involved in the regulation of ERalpha turnover (both in the absence or presence of estrogens). Several lines of evidence indicated that this effect of Mdm2 required its ubiquitin-ligase activity and involved the ubiquitin/proteasome pathway. Moreover, in MCF-7 human breast cancer cells, various p53-inducing agents (such as UV irradiation) or treatment with RITA (which inhibits the interaction of p53 with Mdm2) stabilized ERalpha and abolished its 17beta-estradiol-dependent turnover. Interestingly, our data indicated that ligand-dependent receptor turnover was not required for efficient transactivation. Altogether, our results indicate that the Mdm2 oncoprotein and stress-inducing agents complexly and differentially regulate ERalpha stability and transcriptional activity in human cancer cells.

[1]  R. Métivier,et al.  Differential Regulation of Estrogen-Inducible Proteolysis and Transcription by the Estrogen Receptor α N Terminus , 2005, Molecular and Cellular Biology.

[2]  S. Kato,et al.  Ligand‐dependent switching of ubiquitin–proteasome pathways for estrogen receptor , 2004, The EMBO journal.

[3]  M. Protopopova,et al.  Small molecule RITA binds to p53, blocks p53–HDM-2 interaction and activates p53 function in tumors , 2004, Nature Medicine.

[4]  W. Shao,et al.  Coactivator AIB1 links estrogen receptor transcriptional activity and stability. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[5]  Bohdan Wasylyk,et al.  Physiological and Pathological Consequences of the Interactions of the p53 Tumor Suppressor with the Glucocorticoid, Androgen, and Estrogen Receptors , 2004, Annals of the New York Academy of Sciences.

[6]  C. Glass,et al.  A Corepressor/Coactivator Exchange Complex Required for Transcriptional Activation by Nuclear Receptors and Other Regulated Transcription Factors , 2004, Cell.

[7]  Timothy M. Errington,et al.  Extracellular Signal-Regulated Kinase 7, a Regulator of Hormone-Dependent Estrogen Receptor Destruction , 2003, Molecular and Cellular Biology.

[8]  E. Alarid,et al.  Thyroid hormone is an inhibitor of estrogen-induced degradation of estrogen receptor-alpha protein: estrogen-dependent proteolysis is not essential for receptor transactivation function in the pituitary. , 2003, Endocrinology.

[9]  H. Kinyamu,et al.  Estrogen Receptor-Dependent Proteasomal Degradation of the Glucocorticoid Receptor Is Coupled to an Increase in Mdm2 Protein Expression , 2003, Molecular and Cellular Biology.

[10]  Z. Nawaz,et al.  Specific ubiquitin-conjugating enzymes promote degradation of specific nuclear receptor coactivators. , 2003, Molecular endocrinology.

[11]  Kenneth P Nephew,et al.  The NEDD8 pathway is required for proteasome-mediated degradation of human estrogen receptor (ER)-alpha and essential for the antiproliferative activity of ICI 182,780 in ERalpha-positive breast cancer cells. , 2003, Molecular endocrinology.

[12]  M. Oren,et al.  The p53-Mdm2 module and the ubiquitin system. , 2003, Seminars in cancer biology.

[13]  K. Belguise,et al.  Receptor-interacting protein 140 binds c-Jun and inhibits estradiol-induced activator protein-1 activity by reversing glucocorticoid receptor-interacting protein 1 effect. , 2003, Molecular endocrinology.

[14]  Chawnshang Chang,et al.  Phosphorylation‐dependent ubiquitylation and degradation of androgen receptor by Akt require Mdm2 E3 ligase , 2002, The EMBO journal.

[15]  P. Chambon,et al.  Phosphorylation by p38MAPK and recruitment of SUG‐1 are required for RA‐induced RARγ degradation and transactivation , 2002, The EMBO journal.

[16]  D. Meek.  p53 Induction: Phosphorylation Sites Cooperate in Regulating Interatction , 2002, Cancer biology & therapy.

[17]  D. McDonnell,et al.  The Human Estrogen Receptor-α Is a Ubiquitinated Protein Whose Stability Is Affected Differentially by Agonists, Antagonists, and Selective Estrogen Receptor Modulators* , 2001, The Journal of Biological Chemistry.

[18]  B. Wasylyk,et al.  Ligand-dependent interaction of the glucocorticoid receptor with p53 enhances their degradation by Hdm2. , 2001, Genes & development.

[19]  T. Ishizuka,et al.  Human immunodeficiency virus type 1 Tat binding protein-1 is a transcriptional coactivator specific for TR. , 2001, Molecular endocrinology.

[20]  J. Nicolas,et al.  Reporter cell lines are useful tools for monitoring biological activity of nuclear receptor ligands. , 2001, Luminescence : the journal of biological and chemical luminescence.

[21]  J. Thomsen,et al.  Mechanisms of estrogen action. , 2001, Physiological reviews.

[22]  D. Chalbos,et al.  Unliganded and liganded estrogen receptors protect against cancer invasion via different mechanisms. , 2000, Molecular endocrinology.

[23]  Pierre Roux,et al.  Extinction of Rac1 and Cdc42Hs signalling defines a novel p53-dependent apoptotic pathway , 2000, Oncogene.

[24]  G. Liu,et al.  Estrogen receptor protects p53 from deactivation by human double minute-2. , 2000, Cancer research.

[25]  R. Honda,et al.  Activity of MDM2, a ubiquitin ligase, toward p53 or itself is dependent on the RING finger domain of the ligase , 2000, Oncogene.

[26]  C. Lange,et al.  Phosphorylation of human progesterone receptors at serine-294 by mitogen-activated protein kinase signals their degradation by the 26S proteasome. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[27]  Han-Jong Kim,et al.  Steroid receptor coactivator-1 and its family members differentially regulate transactivation by the tumor suppressor protein p53. , 1999, Molecular endocrinology.

[28]  E. Alarid,et al.  Proteasome-mediated proteolysis of estrogen receptor: a novel component in autologous down-regulation. , 1999, Molecular endocrinology.

[29]  J. Nicolas,et al.  Reporter cell lines to study the estrogenic effects of xenoestrogens. , 1999, The Science of the total environment.

[30]  G. Leclercq,et al.  Implication of proteasome in estrogen receptor degradation , 1999, FEBS letters.

[31]  B. O’Malley,et al.  Proteasome-dependent degradation of the human estrogen receptor. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[32]  M. Tsai,et al.  The Angelman Syndrome-Associated Protein, E6-AP, Is a Coactivator for the Nuclear Hormone Receptor Superfamily , 1999, Molecular and Cellular Biology.

[33]  P. Meltzer,et al.  In breast cancer, amplification of the steroid receptor coactivator gene AIB1 is correlated with estrogen and progesterone receptor positivity. , 1998, Clinical cancer research : an official journal of the American Association for Cancer Research.

[34]  J. Niland,et al.  The MDM2 gene amplification database. , 1998, Nucleic acids research.

[35]  Hirofumi Tanaka,et al.  Oncoprotein MDM2 is a ubiquitin ligase E3 for tumor suppressor p53 , 1997, FEBS letters.

[36]  M. Oren,et al.  Mdm2 promotes the rapid degradation of p53 , 1997, Nature.

[37]  K. McMasters,et al.  mdm2 deletion does not alter growth characteristics of p53-deficient embryo fibroblasts. , 1996, Oncogene.

[38]  M. Imhof,et al.  Yeast RSP5 and its human homolog hRPF1 potentiate hormone-dependent activation of transcription by human progesterone and glucocorticoid receptors , 1996, Molecular and cellular biology.

[39]  Guillermina Lozano,et al.  Rescue of early embryonic lethality in mdm2-deficient mice by deletion of p53 , 1995, Nature.

[40]  D. Moore,et al.  Interaction of thyroid-hormone receptor with a conserved transcriptional mediator , 1995, Nature.

[41]  M. Parker,et al.  Interaction of proteins with transcriptionally active estrogen receptors. , 1994, Proceedings of the National Academy of Sciences of the United States of America.

[42]  D. Weil,et al.  In vivo cooperation between introns during pre-mRNA processing. , 1993, Genes & development.

[43]  M. Parker,et al.  Antiestrogen ICI 164,384 reduces cellular estrogen receptor content by increasing its turnover. , 1992, Proceedings of the National Academy of Sciences of the United States of America.

[44]  M. Ptashne,et al.  A vector for expressing GAL4(1-147) fusions in mammalian cells. , 1989, Nucleic acids research.

[45]  E. Jensen,et al.  Oestrogen-receptor interaction in target tissues. , 1969, Biochemical Journal.

[46]  B. Katzenellenbogen,et al.  ERalpha and ERbeta expression and transcriptional activity are differentially regulated by HDAC inhibitors. , 2006, Oncogene.

[47]  H. Richard-Foy,et al.  CSN5/Jab1 is involved in ligand-dependent degradation of estrogen receptor {alpha} by the proteasome. , 2005, Molecular and cellular biology.

[48]  K. Nephew,et al.  Inhibiting proteasomal proteolysis sustains estrogen receptor-alpha activation. , 2004, Molecular endocrinology.

[49]  S. Khochbin,et al.  Multiple domains of the Receptor-Interacting Protein 140 contribute to transcription inhibition. , 2004, Nucleic acids research.

[50]  S. Angeloni,et al.  Regulation of estrogen receptor- expression by the tumor suppressor gene p53 in MCF-7 cells , 2004 .

[51]  Angélique Gougelet,et al.  Various phosphorylation pathways, depending on agonist and antagonist binding to endogenous estrogen receptor alpha (ERalpha), differentially affect ERalpha extractability, proteasome-mediated stability, and transcriptional activity in human breast cancer cells. , 2003, Molecular endocrinology.

[52]  B. O’Malley,et al.  FRAP reveals that mobility of oestrogen receptor-alpha is ligand- and proteasome-dependent. , 2001, Nature cell biology.

[53]  S. Saji,et al.  MDM2 enhances the function of estrogen receptor alpha in human breast cancer cells. , 2001, Biochemical and biophysical research communications.

[54]  B. O’Malley,et al.  The 26S proteasome is required for estrogen receptor-alpha and coactivator turnover and for efficient estrogen receptor-alpha transactivation. , 2000, Molecular cell.

[55]  J. Xu,et al.  Nuclear receptor coactivators: multiple enzymes, multiple complexes, multiple functions. , 1999, Journal of Steroid Biochemistry and Molecular Biology.