Ras-mediated Up-regulation of Survivin Expression in Cytokine-dependent Murine Pro-B Lymphocytic Cells

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  • Shinjyo Tetsuharu
    Department of Endocrinology and Metabolism, Department of Internal Medicine, University of the Ryukyus, School of Medicine
  • Kurosawa Hidemitsu
    Department of Pediatrics, Dokkyo Medical University
  • Miyagi Jun-ichi
    Department of Endocrinology and Metabolism, Department of Internal Medicine, University of the Ryukyus, School of Medicine
  • Ohama Kiyoto
    Department of Endocrinology and Metabolism, Department of Internal Medicine, University of the Ryukyus, School of Medicine
  • Masuda Masato
    Department of Endocrinology and Metabolism, Department of Internal Medicine, University of the Ryukyus, School of Medicine
  • Nagasaki Akitoshi
    Department of Endocrinology and Metabolism, Department of Internal Medicine, University of the Ryukyus, School of Medicine
  • Matsui Hirotaka
    Department of Developmental Biology and Molecular Oncology, Research Institute for Radiation Biology and Medicine, Hiroshima University
  • Inaba Toshiya
    Department of Developmental Biology and Molecular Oncology, Research Institute for Radiation Biology and Medicine, Hiroshima University
  • Furukawa Yusuke
    Division of Stem Cell Regulation Center for Molecular Medicine, Jichi Medical School
  • Takasu Nobuyuki
    Department of Endocrinology and Metabolism, Department of Internal Medicine, University of the Ryukyus, School of Medicine

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Abstract

Survivin, a member of the inhibitor of apoptosis protein (IAP) family, has been widely studied because of its aberrant expression in human cancer. Survivin has multiple functions, including cell-cycle regulation at mitosis, inhibition of apoptosis and caspase-independent cytoprotection. Clinical studies have shown that survivin is associated with resistance to treatment and its expression is linked to poor prognosis. Recent studies indicated that Ras pathways up-regulate survivin expression in hematopoietic cells. Here we analyzed downstream pathways of Ras in interleukin-3 (IL-3)-dependent Baf-3 murine-derived pro-B lymphocytic cells that express constitutively active Ras mutants, using signaling pathway-specific inhibitors. Both mitogen-activated protein kinase (MAPK) and phosphatidylinositol-3 kinase (PI3-K) pathways are involved in the induction of survivin. Downstream of PI3-K, the signaling pathway is composed of two kinases, Akt and mammalian target of rapamycin (mTOR) pathways. In the downstream targets of PI3-K, mTOR but not Akt is responsible for survivin expression. Using a counterflow centrifugal elutriator, we observed G2/M phase-dominant survivin expression in Baf-3 cells. Interestingly, constitutively active Ras mutants also induced survivin in a cell cycle-dependent manner. Reporter assays of the survivin gene promoter revealed a transcriptional regulatory cis-acting region that is responsible for Ras signaling, indicating that Ras increases the transcription of the survivin gene through specific enhancer elements. These data illustrate the pathways regulating survivin expression by Ras. Ras activates the MAPK, PI3-K and mTOR pathways, and these signals enhance survivin transcription. Our data will provide the new information about mechanisms of survivin expression by Ras-signalling pathways.

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