Activating transcription factor-2 mediates transcriptional regulation of gluconeogenic gene PEPCK by retinoic acid.

All-trans-retinoic acid (RA) is known to increase the rate of transcription of the PEPCK gene upon engagement of the RA receptor (RAR). RA also mediates induction of specific gene transcription via several signaling pathways as a nongenomic effect. Here we show that RA upregulation of PEPCK promoter activity requires the cAMP response element (CRE)-1 in addition to the RA-response element and that activating transcription factor-2 (ATF-2) binds the CRE element to mediate this effect. Furthermore, we show that RA treatment potentiates ATF-2-dependent transactivation by inducing specific phosphorylation of ATF-2 by p38beta kinase. ATF-2 activation by RA blocked the inhibitory intramolecular interaction of ATF-2 amino and carboxyl terminal domains in a p38beta kinase-dependent manner. Consistent with these results, RA treatment increased the DNA binding activity of ATF-2 on the PEPCK CRE-1 sequence. Taken together, the data suggest that RA activates the p38beta kinase pathway leading to phosphorylation and activation of ATF-2, thereby enhancing PEPCK gene transcription and glucose production.

[1]  Xuening Wang,et al.  Inhibition of p38MAP kinase potentiates the JNK/SAPK pathway and AP‐1 activity in monocytic but not in macrophage or granulocytic differentiation of HL60 cells , 2001, Journal of cellular biochemistry.

[2]  S. Minucci,et al.  Activation of Rac1 and the p38 Mitogen-activated Protein Kinase Pathway in Response to All-trans-retinoic Acid* , 2001, The Journal of Biological Chemistry.

[3]  J. Sambrook,et al.  Molecular Cloning: A Laboratory Manual , 2001 .

[4]  J. Cheong,et al.  Direct binding of hepatitis B virus X protein and retinoid X receptor contributes to phosphoenolpyruvate carboxykinase gene transactivation , 2000, FEBS letters.

[5]  L. Platanias,et al.  The Rac1/p38 mitogen-activated protein kinase pathway is required for interferon alpha-dependent transcriptional activation but not serine phosphorylation of Stat proteins. , 2000, The Journal of biological chemistry.

[6]  H. Schaeffer,et al.  Mitogen-Activated Protein Kinases: Specific Messages from Ubiquitous Messengers , 1999, Molecular and Cellular Biology.

[7]  R. Hanson,et al.  C/EBP and the Control of Phosphoenolpyruvate Carboxykinase Gene Transcription in the Liver* , 1998, The Journal of Biological Chemistry.

[8]  J. Coligan,et al.  Activating Transcription Factor-2 Regulates Phosphoenolpyruvate Carboxykinase Transcription through a Stress-inducible Mitogen-activated Protein Kinase Pathway* , 1998, The Journal of Biological Chemistry.

[9]  A. Yen,et al.  Retinoic acid induced mitogen-activated protein (MAP)/extracellular signal-regulated kinase (ERK) kinase-dependent MAP kinase activation needed to elicit HL-60 cell differentiation and growth arrest. , 1998, Cancer research.

[10]  W. Hong,et al.  All-trans-Retinoic Acid Inhibits Jun N-terminal Kinase-dependent Signaling Pathways* , 1998, The Journal of Biological Chemistry.

[11]  C. Sutherland,et al.  Activation of the Ras Mitogen-activated Protein Kinase-Ribosomal Protein Kinase Pathway Is Not Required for the Repression of Phosphoenolpyruvate Carboxykinase Gene Transcription by Insulin* , 1998, The Journal of Biological Chemistry.

[12]  W. Hong,et al.  All-trans-retinoic Acid Increases Transforming Growth Factor-β2 and Insulin-like Growth Factor Binding Protein-3 Expression through a Retinoic Acid Receptor-α-dependent Signaling Pathway* , 1997, The Journal of Biological Chemistry.

[13]  J. Coligan,et al.  ATF-2 and C/EBPalpha can form a heterodimeric DNA binding complex in vitro. Functional implications for transcriptional regulation. , 1997, The Journal of biological chemistry.

[14]  S. Schreiber,et al.  Nuclear Receptor Repression Mediated by a Complex Containing SMRT, mSin3A, and Histone Deacetylase , 1997, Cell.

[15]  R. O’Brien,et al.  Regulation of gene expression by insulin. , 1996, The Biochemical journal.

[16]  Wei Guo,et al.  Characterization of the Structure and Function of a New Mitogen-activated Protein Kinase (p38β)* , 1996, The Journal of Biological Chemistry.

[17]  Thorsten Heinzel,et al.  A CBP Integrator Complex Mediates Transcriptional Activation and AP-1 Inhibition by Nuclear Receptors , 1996, Cell.

[18]  John A. Mitchell,et al.  Identification and Characterization of a Second Retinoic Acid Response Element in the Phosphoenolpyruvate Carboxykinase Gene Promoter (*) , 1996, The Journal of Biological Chemistry.

[19]  R. Davis,et al.  MKK3- and MKK6-regulated gene expression is mediated by the p38 mitogen-activated protein kinase signal transduction pathway , 1996, Molecular and cellular biology.

[20]  X. Y. Li,et al.  Intramolecular inhibition of activating transcription factor-2 function by its DNA-binding domain. , 1996, Genes & development.

[21]  J. Flier,et al.  Insulin Regulation of Phosphoenolpyruvate Carboxykinase Gene Expression Does Not Require Activation of the Ras/Mitogen-activated Protein Kinase Signaling Pathway (*) , 1996, The Journal of Biological Chemistry.

[22]  Philippe Kastner,et al.  Nonsteroid nuclear receptors: What Are genetic studies telling us about their role in real life? , 1995, Cell.

[23]  J. Proietto,et al.  Impaired glucose tolerance and increased weight gain in transgenic rats overexpressing a non-insulin-responsive phosphoenolpyruvate carboxykinase gene. , 1995, Molecular endocrinology.

[24]  R. O’Brien,et al.  Phosphatidylinositol 3-Kinase, but Not p70/p85 Ribosomal S6 Protein Kinase, Is Required for the Regulation of Phosphoenolpyruvate Carboxykinase (PEPCK) Gene Expression by Insulin , 1995, The Journal of Biological Chemistry.

[25]  I. Herr,et al.  ATF‐2 is preferentially activated by stress‐activated protein kinases to mediate c‐jun induction in response to genotoxic agents. , 1995, The EMBO journal.

[26]  P. Chambon,et al.  RAR‐specific agonist/antagonists which dissociate transactivation and AP1 transrepression inhibit anchorage‐independent cell proliferation. , 1995, The EMBO journal.

[27]  F. Bosch,et al.  Transgenic mice overexpressing phosphoenolpyruvate carboxykinase develop non-insulin-dependent diabetes mellitus. , 1994, Proceedings of the National Academy of Sciences of the United States of America.

[28]  N. Jones,et al.  Different binding specificities and transactivation of variant CRE's by CREB complexes. , 1994, Nucleic acids research.

[29]  Tom Maniatis,et al.  Transcriptional activation: A complex puzzle with few easy pieces , 1994, Cell.

[30]  P Chambon,et al.  The retinoid signaling pathway: molecular and genetic analyses. , 1994, Seminars in cell biology.

[31]  T. Curran,et al.  Fos and Jun repress transcription activation by NF-IL6 through association at the basic zipper region , 1994, Molecular and cellular biology.

[32]  A. Moorman,et al.  Relative roles of CCAAT/enhancer-binding protein beta and cAMP regulatory element-binding protein in controlling transcription of the gene for phosphoenolpyruvate carboxykinase (GTP). , 1993, The Journal of biological chemistry.

[33]  W. Roesler,et al.  The liver-enriched transcription factor D-site-binding protein activates the promoter of the phosphoenolpyruvate carboxykinase gene in hepatoma cells. , 1992, The Journal of biological chemistry.

[34]  J. Liu,et al.  Opposing actions of Fos and Jun on transcription of the phosphoenolpyruvate carboxykinase (GTP) gene. Dominant negative regulation by Fos. , 1992, The Journal of biological chemistry.

[35]  R. Hammer,et al.  Tissue-specific, developmental, hormonal, and dietary regulation of rat phosphoenolpyruvate carboxykinase-human growth hormone fusion genes in transgenic mice , 1992, Molecular and cellular biology.

[36]  H. Samuels,et al.  Specificity of a retinoic acid response element in the phosphoenolpyruvate carboxykinase gene promoter: consequences of both retinoic acid and thyroid hormone receptor binding. , 1991, Molecular and cellular biology.

[37]  R. O’Brien,et al.  Regulation of gene expression by insulin. , 1991, Physiological reviews.

[38]  K.,et al.  Metabolic effects of developmental, tissue-, and cell-specific expression of a chimeric phosphoenolpyruvate carboxykinase (GTP)/bovine growth hormone gene in transgenic mice. , 1990, The Journal of biological chemistry.

[39]  W. Hoeppner,et al.  Induction of phosphoenolpyruvate carboxykinase gene expression by retinoic acid in an adult rat hepatocyte line. , 1990, Biochemistry.

[40]  J. Liu,et al.  The role of the CCAAT/enhancer-binding protein in the transcriptional regulation of the gene for phosphoenolpyruvate carboxykinase (GTP) , 1990, Molecular and cellular biology.

[41]  R. Blomhoff,et al.  Transport and storage of vitamin A , 1990, Science.

[42]  S. McKnight,et al.  Identification of two polypeptide segments of CCAAT/enhancer-binding protein required for transcriptional activation of the serum albumin gene. , 1990, Genes & development.

[43]  M. Magnuson,et al.  Identification of basal and cyclic AMP regulatory elements in the promoter of the phosphoenolpyruvate carboxykinase gene , 1988, Molecular and cellular biology.

[44]  R. Hanson,et al.  Thyroid hormone regulates transcription of the gene for cytosolic phosphoenolpyruvate carboxykinase (GTP) in rat liver. , 1985, Biochemistry.

[45]  D. Kioussis,et al.  Alterations in translatable messenger RNA coding for phosphoenolpyruvate carboxykinase (GTP) in rat liver cytosol during deinduction. , 1978, The Journal of biological chemistry.

[46]  R. Hanson,et al.  Regulation of phosphoenolpyruvate carboxykinase (GTP) gene expression. , 1997, Annual review of biochemistry.

[47]  W. Hong,et al.  All-trans-retinoic acid increases transforming growth factor-beta2 and insulin-like growth factor binding protein-3 expression through a retinoic acid receptor-alpha-dependent signaling pathway. , 1997, The Journal of biological chemistry.