The antiapoptotic gene mcl-1 is up-regulated by the phosphatidylinositol 3-kinase/Akt signaling pathway through a transcription factor complex containing CREB

J. U.Ming Wang, Jyh Rong Chao, Wannhsin Chen, Min Liang Kuo, Jeffrey J.Y. Yen, Hsin Fang Yang-Yen

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307 Citations (Scopus)

Abstract

mcl-1 is an immediate-early gene activated by the granulocyte-macrophage colony-stimulating factor (GMCSF) and interleukin 3 (IL-3) signaling pathways and plays an important role in the viability response of these cytokines. In this study, we demonstrated that cytokine stimulation of mcl-1 mRNA and protein expression were attenuated by pretreatment of cells with phosphatidylinositol 3-kinase (PI3-K) inhibitors. Reporter gene assays further showed that the PI3-K/Akt signaling pathway was involved in IL-3 activation of mcl-1 gene transcription. Analysis of the mcl-1 promoter revealed that both promoter elements, SIE at position -87 and CRE-2 at -70, contribute to IL-3 stimulation of mcl-1 gene expression. Although either the SIE site or the CRE-2 site alone was sufficient to confer IL-3 inducibility on a heterologous promoter, only IL-3 activation of the CRE-2 reporter was mediated via the PI3-K/Akt pathway. The SIE binding activity was constitutively high in cells deprived of or stimulated by IL-3. In contrast, the CRE-2 binding activity was low in cytokine-starved cells and was strongly induced within 1 h following cytokine treatment of cells. In addition, cytokine induction of the CRE-2 but not of the SIE binding activity was dependent on activation of the PI3-K/Akt signaling pathway. Lastly, we showed that CREB was one component of the CRE-2 binding complex and played a role in IL-3 activation of the mcl-1 reporter gene. Taken together, our results suggest that both PI3-K/Akt-dependent and -independent pathways contribute to the IL-3 activation of mcl-1 gene expression. Activation of mcl-1 by the PI3- K/Akt-dependent pathway is through a transcription factor complex containing CREB.

Original languageEnglish
Pages (from-to)6195-6206
Number of pages12
JournalMolecular and Cellular Biology
Volume19
Issue number9
DOIs
Publication statusPublished - 1999 Sep

All Science Journal Classification (ASJC) codes

  • Molecular Biology
  • Cell Biology

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