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      PKC-dependent stimulation of the human MCT1 promoter involves transcription factor AP2.

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          Abstract

          Monocarboxylate transporter (MCT1) plays an important role in the absorption of short-chain fatty acids (SCFA) such as butyrate in the human colon. Previous studies from our laboratory have demonstrated that phorbol ester, PMA (1 microM, 24 h), upregulates butyrate transport and MCT1 protein expression in human intestinal Caco-2 cells. However, the molecular mechanisms involved in the transcriptional regulation of MCT1 gene expression by PMA in the intestine are not known. In the present study, we showed that PMA (0.1 microM, 24 h) increased the MCT1 promoter activity (-871/+91) by approximately fourfold. A corresponding increase in MCT1 mRNA abundance in response to PMA was also observed. PMA-induced stimulation of MCT1 promoter activity was observed as early as 1 h and persisted until 24 h, suggesting that the effects of PMA are attributable to initial PKC activation. Kinase inhibitor and phosphorylation studies indicated that these effects may be mediated through activation of the atypical PKC-zeta isoform. 5'-deletion studies demonstrated that the MCT1 core promoter region (-229/+91) is the PMA-responsive region. Site-directed mutagenesis studies showed the predominant involvement of potential activator protein 2 (AP2) binding site in the activation of MCT1 promoter activity by PMA. In addition, overexpression of AP2 in Caco-2 cells significantly increased MCT1 promoter activity in a dose-dependent manner. These findings showing the regulation of MCT1 promoter by PKC and AP2 are of significant importance for an understanding of the molecular regulation of SCFA absorption in the human intestine.

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          Author and article information

          Journal
          Am. J. Physiol. Gastrointest. Liver Physiol.
          American journal of physiology. Gastrointestinal and liver physiology
          American Physiological Society
          0193-1857
          0193-1857
          Feb 2009
          : 296
          : 2
          Affiliations
          [1 ] Department of Medicine, University of Illinois at Chicago, Chicago, IL 60612, USA. saksena@uic.edu
          Article
          90503.2008
          10.1152/ajpgi.90503.2008
          2643915
          19033536
          7bc55e75-e188-4032-905a-bb9c8db0f9cb
          History

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