The PGC-1-related Protein PERC Is a Selective Coactivator of Estrogen Receptor α*

Peroxisome proliferator-activated receptor γ coactivator-1 (PGC-1) is a tissue-specific coactivator that enhances the activity of many nuclear receptors and coordinates transcriptional programs important for energy metabolism. We describe here a novel PGC-1-related coactivator that is expressed in a similar tissue-specific manner as PGC-1, with the highest levels in heart and skeletal muscle. In contrast to PGC-1, the new coactivator shows high receptor specificity. It enhances potently the activity of estrogen receptor (ER) α, while having only small effects on other receptors. Because of its nuclear receptor selectivity, we have termed the new protein PERC (PGC-1 related EstrogenReceptor Coactivator). We show here that the coactivation function of PERC relies on a bipartite transcriptional activation domain and two LXXLL motifs that interact with the AF2 domain of ERα in an estrogen-dependent manner. PERC and PGC-1 are likely to have different functions in ER signaling. Whereas PERC acts selectively on ERα and not on the second estrogen receptor ERβ, PGC-1 coactivates strongly both ERs. Moreover, PERC and PGC-1 show distinct preferences for enhancing ERα in different promoter contexts. Finally, PERC enhances the ERα-mediated response to the partial agonist tamoxifen, while PGC-1 modestly represses it. The two coactivators are likely to mediate distinct, tissue-specific responses to estrogens.

[1]  Jiandie D. Lin,et al.  Peroxisome Proliferator-activated Receptor γ Coactivator 1β (PGC-1β), A Novel PGC-1-related Transcription Coactivator Associated with Host Cell Factor* , 2002, The Journal of Biological Chemistry.

[2]  D. Na,et al.  Molecular Cloning and Characterization of CAPER, a Novel Coactivator of Activating Protein-1 and Estrogen Receptors* , 2002, The Journal of Biological Chemistry.

[3]  M. Mendelsohn,et al.  Protective effects of estrogen on the cardiovascular system. , 1999, The American journal of cardiology.

[4]  A. Nardulli,et al.  Estrogen Response Elements Alter Coactivator Recruitment through Allosteric Modulation of Estrogen Receptor β Conformation* , 2001, The Journal of Biological Chemistry.

[5]  A. Sahin,et al.  Molecular Cloning and Characterization of PELP1, a Novel Human Coregulator of Estrogen Receptor α , 2001 .

[6]  C. Glass,et al.  Coregulator Codes of Transcriptional Regulation by Nuclear Receptors* , 2001, The Journal of Biological Chemistry.

[7]  K. Korach,et al.  The Multifaceted Mechanisms of Estradiol and Estrogen Receptor Signaling* , 2001, The Journal of Biological Chemistry.

[8]  A. Kralli,et al.  PGC-1, a versatile coactivator , 2001, Trends in Endocrinology & Metabolism.

[9]  J. Hur,et al.  Selective coactivation of estrogen-dependent transcription by CITED1 CBP/p300-binding protein. , 2001, Genes & development.

[10]  Marc Montminy,et al.  CREB regulates hepatic gluconeogenesis through the coactivator PGC-1 , 2001, Nature.

[11]  Guillaume Adelmant,et al.  Control of hepatic gluconeogenesis through the transcriptional coactivator PGC-1 , 2001, Nature.

[12]  D. Kressler,et al.  Regulation of the transcriptional coactivator PGC-1 via MAPK-sensitive interaction with a repressor , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[13]  B. Komm,et al.  Structure-function evaluation of ER alpha and beta interplay with SRC family coactivators. ER selective ligands. , 2001, Biochemistry.

[14]  P. Heine,et al.  The role of estrogen and estrogen receptor-α in male adipose tissue , 2001, Molecular and Cellular Endocrinology.

[15]  R. Scarpulla,et al.  PGC-1-Related Coactivator, a Novel, Serum-Inducible Coactivator of Nuclear Respiratory Factor 1-Dependent Transcription in Mammalian Cells , 2001, Molecular and Cellular Biology.

[16]  B. Viollet,et al.  Transcription factor‐dependent regulation of CBP and P/CAF histone acetyltransferase activity , 2001, The EMBO journal.

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

[18]  D. Picard,et al.  Estradiol Decreases IGF-1 and IGF-1 Receptor Expression in Rat Aortic Smooth Muscle Cells , 2000, The Journal of Biological Chemistry.

[19]  O. Hermanson,et al.  Regulation of somatic growth by the p160 coactivator p/CIP. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[20]  G. Iwamoto,et al.  Increased adipose tissue in male and female estrogen receptor-α knockout mice , 2000 .

[21]  J. Saffitz,et al.  Peroxisome proliferator-activated receptor gamma coactivator-1 promotes cardiac mitochondrial biogenesis. , 2000, The Journal of clinical investigation.

[22]  P. Puigserver,et al.  Direct coupling of transcription and mRNA processing through the thermogenic coactivator PGC-1. , 2000, Molecular cell.

[23]  C. Deng,et al.  The steroid receptor coactivator SRC-3 (p/CIP/RAC3/AIB1/ACTR/TRAM-1) is required for normal growth, puberty, female reproductive function, and mammary gland development. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[24]  P. Puigserver,et al.  Modulation of Estrogen Receptor-α Transcriptional Activity by the Coactivator PGC-1* , 2000, The Journal of Biological Chemistry.

[25]  A. Kralli,et al.  A Tissue-Specific Coactivator of Steroid Receptors, Identified in a Functional Genetic Screen , 2000, Molecular and Cellular Biology.

[26]  Rick B. Vega,et al.  The Coactivator PGC-1 Cooperates with Peroxisome Proliferator-Activated Receptor α in Transcriptional Control of Nuclear Genes Encoding Mitochondrial Fatty Acid Oxidation Enzymes , 2000, Molecular and Cellular Biology.

[27]  C. Glass,et al.  The coregulator exchange in transcriptional functions of nuclear receptors. , 2000, Genes & development.

[28]  H. Esterbauer,et al.  Human peroxisome proliferator activated receptor gamma coactivator 1 (PPARGC1) gene: cDNA sequence, genomic organization, chromosomal localization, and tissue expression. , 1999, Genomics.

[29]  Guillaume Adelmant,et al.  Activation of PPARγ coactivator-1 through transcription factor docking , 1999 .

[30]  D. McDonnell,et al.  The Molecular Pharmacology of SERMs , 1999, Trends in Endocrinology & Metabolism.

[31]  Ruben Abagyan,et al.  NRIF3 Is a Novel Coactivator Mediating Functional Specificity of Nuclear Hormone Receptors , 1999, Molecular and Cellular Biology.

[32]  V. Mootha,et al.  Mechanisms Controlling Mitochondrial Biogenesis and Respiration through the Thermogenic Coactivator PGC-1 , 1999, Cell.

[33]  L. Freedman.  Strategies for transcriptional activation by steroid/nuclear receptors , 1999, Journal of cellular biochemistry.

[34]  G. Sathya,et al.  Sequence Requirements for Estrogen Receptor Binding to Estrogen Response Elements* , 1998, The Journal of Biological Chemistry.

[35]  R J Fletterick,et al.  Structure and specificity of nuclear receptor-coactivator interactions. , 1998, Genes & development.

[36]  C. Lyttle,et al.  A Transcriptional Coactivator, Steroid Receptor Coactivator-3, Selectively Augments Steroid Receptor Transcriptional Activity* , 1998, The Journal of Biological Chemistry.

[37]  T. Willson,et al.  Ligand binding and co-activator assembly of the peroxisome proliferator-activated receptor-γ , 1998, Nature.

[38]  Y. Liu,et al.  Thyroid Hormone Response Elements Differentially Modulate the Interactions of Thyroid Hormone Receptors with Two Receptor Binding Domains in the Steroid Receptor Coactivator-1* , 1998, The Journal of Biological Chemistry.

[39]  R J Fletterick,et al.  Hormone-dependent coactivator binding to a hydrophobic cleft on nuclear receptors. , 1998, Science.

[40]  B. O’Malley,et al.  Partial hormone resistance in mice with disruption of the steroid receptor coactivator-1 (SRC-1) gene. , 1998, Science.

[41]  M. Stallcup,et al.  Enhancement of Estrogen Receptor Transcriptional Activity by the Coactivator GRIP-1 Highlights the Role of Activation Function 2 in Determining Estrogen Receptor Pharmacology* , 1998, The Journal of Biological Chemistry.

[42]  P. Puigserver,et al.  A Cold-Inducible Coactivator of Nuclear Receptors Linked to Adaptive Thermogenesis , 1998, Cell.

[43]  K.,et al.  Diverse signaling pathways modulate nuclear receptor recruitment of N-CoR and SMRT complexes. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[44]  Christopher K. Glass,et al.  The transcriptional co-activator p/CIP binds CBP and mediates nuclear-receptor function , 1997, Nature.

[45]  David M. Heery,et al.  A signature motif in transcriptional co-activators mediates binding to nuclear receptors , 1997, Nature.

[46]  K. Yamamoto,et al.  Three Amino Acid Substitutions Selectively Disrupt the Activation but Not the Repression Function of the Glucocorticoid Receptor N Terminus* , 1997, The Journal of Biological Chemistry.

[47]  D. McDonnell,et al.  Identification of the sequences within the human complement 3 promoter required for estrogen responsiveness provides insight into the mechanism of tamoxifen mixed agonist activity. , 1996, Molecular endocrinology.

[48]  K. Umesono,et al.  The nuclear receptor superfamily: The second decade , 1995, Cell.

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

[50]  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.

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

[52]  S. Fawell,et al.  Identification of two transactivation domains in the mouse oestrogen receptor. , 1989, Nucleic acids research.