Androgen Receptor-Ets Protein Interaction Is a Novel Mechanism for Steroid Hormone-mediated Down-modulation of Matrix Metalloproteinase Expression*

Matrix metalloproteinases belong to a family of structurally related enzymes that plays important role in tissue morphogenesis, differentiation, and wound healing. Their expression is negatively regulated by several members of the steroid hormone receptor family. This is thought to occur through interaction of the steroid receptors with the transcription factor AP-1 that is otherwise required for positive regulation. Here, we demonstrate that AP-1 is not always a target for down-regulation of expression of matrix metalloproteinases by steroid receptors. Androgen receptor negatively regulates matrix metalloproteinase-1 expression not through AP-1 but through a family of Ets-related transcription factors that are also required for positive regulation. This negative regulation is specific for the androgen receptor. It does not require the DNA binding activity but needs amino-terminal sequences of the receptor. These results identify a novel regulatory pathway for negative regulation utilized by a member of the steroid hormone receptor family for down-regulating the expression of matrix metalloproteinases.

[1]  P. Defossez,et al.  Two functionally distinct domains responsible for transactivation by the Ets family member ERM. , 1996, Oncogene.

[2]  R. Nagle,et al.  Matrilysin expression in human prostate carcinoma , 1996, Molecular carcinogenesis.

[3]  U. Gehring,et al.  A protein that interacts with members of the nuclear hormone receptor family: identification and cDNA cloning. , 1995, Proceedings of the National Academy of Sciences of the United States of America.

[4]  J. Inazawa,et al.  ERM, a PEA3 Subfamily of Ets Transcription Factors, Can Cooperate with c-Jun (*) , 1995, The Journal of Biological Chemistry.

[5]  K. Osteen,et al.  Transforming growth factor beta mediates the progesterone suppression of an epithelial metalloproteinase by adjacent stroma in the human endometrium. , 1995, Proceedings of the National Academy of Sciences of the United States of America.

[6]  H. Broxmeyer,et al.  Regulation of interleukin-6, osteoclastogenesis, and bone mass by androgens. The role of the androgen receptor. , 1995, The Journal of clinical investigation.

[7]  H. Klocker,et al.  A single amino acid exchange abolishes dimerization of the androgen receptor and causes Reifenstein syndrome , 1995, Molecular and Cellular Endocrinology.

[8]  F. Moreau-Gachelin.  Spi-1/PU.1: an oncogene of the Ets family. , 1994, Biochimica et biophysica acta.

[9]  K. Osteen,et al.  Stromal-epithelial interaction mediates steroidal regulation of metalloproteinase expression in human endometrium. , 1994, Proceedings of the National Academy of Sciences of the United States of America.

[10]  P. Herrlich,et al.  A distinct modulating domain in glucocorticoid receptor monomers in the repression of activity of the transcription factor AP‐1. , 1994, The EMBO journal.

[11]  B. Wasylyk,et al.  The oncoprotein v-Ets is less selective in DNA binding than c-Ets-1 due to the C-terminal sequence change. , 1994, Oncogene.

[12]  P. Defossez,et al.  Molecular cloning and characterization of human ERM, a new member of the Ets family closely related to mouse PEA3 and ER81 transcription factors. , 1994, Oncogene.

[13]  P. Angel,et al.  Phenotypic alterations in fos-transgenic mice correlate with changes in Fos/Jun-dependent collagenase type I expression. Regulation of mouse metalloproteinases by carcinogens, tumor promoters, cAMP, and Fos oncoprotein. , 1994, The Journal of biological chemistry.

[14]  N. Mermod,et al.  Post-transcriptional down-regulation of expression of transcription factor NF1 by Ha-ras oncogene. , 1994, The Journal of biological chemistry.

[15]  L. Matrisian,et al.  Expression and regulation of stromelysin and matrilysin by growth factors and oncogenes. , 1994, Biochemical Society transactions.

[16]  A. Nordheim,et al.  Gene regulation by Ets proteins. , 1993, Biochimica et biophysica acta.

[17]  J. Gauthier,et al.  Functional interference between the Spi‐1/PU.1 oncoprotein and steroid hormone or vitamin receptors. , 1993, The EMBO journal.

[18]  H. Klocker,et al.  A mutant androgen receptor from patients with Reifenstein syndrome: identification of the function of a conserved alanine residue in the D box of steroid receptors , 1993, Molecular and cellular biology.

[19]  T. Salo,et al.  Demonstration of 72-kDa and 92-kDa forms of type IV collagenase in human skin: variable expression in various blistering diseases, induction during re-epithelialization, and decrease by topical glucocorticoids. , 1993, The Journal of investigative dermatology.

[20]  Leo M. Lee,et al.  Characterization of the DNA binding and transcriptional activation domains of the erg protein. , 1993, Oncogene.

[21]  F. S. French,et al.  Transcriptional repression of the glycoprotein hormone alpha subunit gene by androgen may involve direct binding of androgen receptor to the proximal promoter. , 1993, The Journal of biological chemistry.

[22]  P. Courtoy,et al.  Progesterone regulates the activity of collagenase and related gelatinases A and B in human endometrial explants. , 1992, Proceedings of the National Academy of Sciences of the United States of America.

[23]  P. Verde,et al.  A regulatory element that mediates co‐operation between a PEA3‐AP‐1 element and an AP‐1 site is required for phorbol ester induction of urokinase enhancer activity in HepG2 hepatoma cells. , 1992, The EMBO journal.

[24]  M. Saarma,et al.  Regulatory elements and transcriptional regulation by testosterone and retinoic acid of the rat nerve growth factor receptor promoter. , 1992, Gene.

[25]  M. Wilson,et al.  Metalloproteinase activities expressed during development and maturation of the rat prostatic complex and seminal vesicles. , 1992, Biology of reproduction.

[26]  L. Matrisian.  The matrix‐degrading metalloproteinases , 1992, Journal of neuro-oncology.

[27]  P. Herrlich,et al.  Interference between pathway‐specific transcription factors: glucocorticoids antagonize phorbol ester‐induced AP‐1 activity without altering AP‐1 site occupation in vivo. , 1992, The EMBO journal.

[28]  J. Hassell,et al.  Molecular cloning and characterization of PEA3, a new member of the Ets oncogene family that is differentially expressed in mouse embryonic cells. , 1992, Genes & development.

[29]  M. Jalkanen,et al.  Syndecan expression regulates cell morphology and growth of mouse mammary epithelial tumor cells. , 1992, Proceedings of the National Academy of Sciences of the United States of America.

[30]  H. Gronemeyer,et al.  Cell‐specific inhibitory and stimulatory effects of Fos and Jun on transcription activation by nuclear receptors. , 1991, The EMBO journal.

[31]  M. Wilson,et al.  Calcium-dependent and calcium-independent gelatinolytic proteinase activities of the rat ventral prostate and its secretion: characterization and effect of castration and testosterone treatment. , 1991, Biology of reproduction.

[32]  J. Woessner,et al.  Matrix metalloproteinases and their inhibitors in connective tissue remodeling , 1991, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[33]  B. Wasylyk,et al.  The c‐Ets oncoprotein activates the stromelysin promoter through the same elements as several non‐nuclear oncoproteins. , 1991, The EMBO journal.

[34]  J. Wilson,et al.  A mutation in the DNA-binding domain of the androgen receptor gene causes complete testicular feminization in a patient with receptor-positive androgen resistance. , 1991, The Journal of clinical investigation.

[35]  M. Karin,et al.  Transcriptional interference between c-Jun and the glucocorticoid receptor: Mutual inhibition of DNA binding due to direct protein-protein interaction , 1990, Cell.

[36]  Stephan Gebel,et al.  Antitumor promotion and antiinflammation: Down-modulation of AP-1 (Fos/Jun) activity by glucocorticoid hormone , 1990, Cell.

[37]  M. Klemsz,et al.  The ETS-domain: a new DNA-binding motif that recognizes a purine-rich core DNA sequence. , 1990, Genes & development.

[38]  B. Wasylyk,et al.  The c-ets proto-oncogenes encode transcription factors that cooperate with c-Fos and c-Jun for transcriptional activation , 1990, Nature.

[39]  B. Wasylyk,et al.  The collagenase gene promoter contains a TPA and oncogene‐responsive unit encompassing the PEA3 and AP‐1 binding sites. , 1990, The EMBO journal.

[40]  T. Hökfelt,et al.  Expression of beta-nerve growth factor receptor mRNA in Sertoli cells downregulated by testosterone. , 1990, Science.

[41]  S. Ho,et al.  Site-directed mutagenesis by overlap extension using the polymerase chain reaction. , 1989, Gene.

[42]  M. Kozak.  The scanning model for translation: an update , 1989, The Journal of cell biology.

[43]  J D Baxter,et al.  Negative regulation by glucocorticoids through interference with a cAMP responsive enhancer. , 1988, Science.

[44]  J. Abecassis,et al.  The collagenase gene family in humans consists of at least four members. , 1988, The Biochemical journal.

[45]  H. Ruley,et al.  Transcription from the stromelysin promoter is induced by interleukin-1 and repressed by dexamethasone. , 1987, The Journal of biological chemistry.

[46]  D. Housman,et al.  Cloning of human mineralocorticoid receptor complementary DNA: structural and functional kinship with the glucocorticoid receptor. , 1987, Science.

[47]  P. Herrlich,et al.  12-O-tetradecanoyl-phorbol-13-acetate induction of the human collagenase gene is mediated by an inducible enhancer element located in the 5'-flanking region , 1987, Molecular and cellular biology.

[48]  B. Chatterjee,et al.  Molecular cloning and characterization of cDNA for androgen-repressible rat liver protein, SMP-2. , 1987, The Journal of biological chemistry.

[49]  R. Evans,et al.  Functional domains of the human glucocorticoid receptor , 1986, Cell.

[50]  C. Dani,et al.  Various rat adult tissues express only one major mRNA species from the glyceraldehyde-3-phosphate-dehydrogenase multigenic family. , 1985, Nucleic acids research.

[51]  A. Mariotti,et al.  Actions of androgen and estrogen on collagen levels in male accessory sex organs. , 1981, Endocrinology.

[52]  M. Kaufman,et al.  Complete androgen insensitivity due to mutations in the probable alpha-helical segments of the DNA-binding domain in the human androgen receptor. , 1994, Human molecular genetics.

[53]  R. Nagle,et al.  Adhesion molecules, extracellular matrix, and proteases in prostate carcinoma. , 1994, Journal of cellular biochemistry. Supplement.

[54]  J. Müntzing.  Androgen and collagen as growth regulators of the rat ventral prostate , 1980, The Prostate.