Activating Transcription Factor-2 Mediates Transcriptional Regulation of Gluconeogenic Gene PEPCK by Retinoic Acid

  1. Min Young Lee1,
  2. Che-Hun Jung2,
  3. Keesook Lee1,
  4. Yung Hyun Choi3,
  5. SunHwa Hong4 and
  6. JaeHun Cheong4
  1. 1Hormone Research Center, Chonnam National University, Kwangju, Korea
  2. 2Department of Chemistry, Chonnam National University, Kwangju, Korea
  3. 3Department of Biochemistry, College of Oriental Medicine, Dong-Eui University, Busan, Korea
  4. 4Department of Molecular Biology, Pusan National University, Busan, Korea

    Abstract

    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 p38β kinase. ATF-2 activation by RA blocked the inhibitory intramolecular interaction of ATF-2 amino and carboxyl terminal domains in a p38β 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 p38β kinase pathway leading to phosphorylation and activation of ATF-2, thereby enhancing PEPCK gene transcription and glucose production.

    Footnotes

    • Address correspondence and reprint requests to JaeHun Cheong, Department of Molecular Biology, Pusan National University, Pusan 609-735, Korea. E-mail: molecule85{at}pusan.ac.kr.

      Received for publication 12 June 2002 and accepted in revised form 7 August 2002.

      ATF, activating transcription factor; bZIP, basic-leucine zipper; C/EBP, CCAAT/enhancer-binding protein; CRE, cAMP response element; CREB, cAMP response element-binding protein; ERK, extracellular signal-regulated kinase; GR, glucocorticoid receptor; HNF, hepatocyte nuclear factor; JNK, c-Jun NH2-terminal kinase; MAP, mitogen-activated protein; NF-1, nuclear factor-1; RA, all-trans-retinoic acid; RAR, RA receptor; RARE, RA-response element; RXR, retinoid X receptor; TR, thyroid hormone receptor.

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