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Induction of heme oxygenase-1 and heat shock protein 70 in rat hepatocytes: The role of calcium signaling


Stress response genes including heat shock proteins are induced under a variety of conditions to confer cellular protection. This study investigated the role of calcium signaling in the induction of two stress response genes, heme oxygenase-1/hsp32 and hsp70, in isolated rat hepatocytes. Both genes were induced by cellular glutathione depletion. This induction could be inhibited by BAPTA-AM. Culturing in a calcium-free medium prevented the induction of hsp70 gene expression after glutathione depletion without affecting heme oxygenase-1 gene expression. Thapsigargin increased the gene expression of heme oxygenase-1 but not that of hsp70. Thapsigargin-induced heme oxygenase-1 induction was completely inhibited by BAPTA-AM. Incubation with the Ca2+-ionophore A23187 augmented heme oxygenase-1 (two-fold) and hsp70 (5.2-fold) mRNA levels. Our data suggests a significant role of Ca2+-dependent pathways in the induction of the two stress genes. An increase in the cytoplasmic Ca2+ activity seems to play a key role in the cascade of signaling leading to the induction of the two genes. However, the source of Ca2+ that fluxes into the cytoplasm seems to be different. Our data provides evidence for a compartmentalization of calcium fluxes, i.e. the Ca2+ flux from intracellular stores (e.g. the endoplasmic reticulum) plays a major role in the induction of heme oxygenase-1. By contrast, Ca2+ flux from the extracellular medium seems to be a mechanism initiating the cellular signaling cascade leading to hsp70 gene induction.



activator protein-1


(1,2-bis(o-amino-phenoxy)ethane-N,N,N′,N′-tetra (acetoxymethyl)esther






endoplasmic reticulum




heme oxygenase-1


heat shock protein


Krebs-Henseleit buffer


phosphate buffered saline


2,6 dimethyl-2,5 heptadien-4-on (phorone)/buthionine sulfoximine




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Correspondence to Inge Bauer.

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Silomon, M., Bauer, I., Bauer, M. et al. Induction of heme oxygenase-1 and heat shock protein 70 in rat hepatocytes: The role of calcium signaling. Cell Mol Biol Lett 12, 25–38 (2007).

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Key words

  • Stress response genes
  • Hepatocytes
  • Calcium
  • Gene expression