Hiroshi Hada1, Takuma Shiraki2, Miki Watanabe-Matsui3, Kazuhiko Igarashi4. 1. Department of Biochemistry, and Center for Regulatory Epigenome and Disease, Tohoku University Graduate School of Medicine, Sendai 980-8575, Japan; CREST, Japan Science and Technology Agency, Sendai 980-8575, Japan. 2. Faculty of Biology-Oriented Science and Technology, Kinki University, Nishimitani, Kinokawashi, Wakayama 649-6493, Japan. 3. Department of Biochemistry, and Center for Regulatory Epigenome and Disease, Tohoku University Graduate School of Medicine, Sendai 980-8575, Japan. 4. Department of Biochemistry, and Center for Regulatory Epigenome and Disease, Tohoku University Graduate School of Medicine, Sendai 980-8575, Japan; CREST, Japan Science and Technology Agency, Sendai 980-8575, Japan. Electronic address: igarashi@med.tohoku.ac.jp.
Abstract
BACKGROUND: Intracellular heme plays versatile roles in a variety of physiological processes including mitochondrial respiration. Heme also induces the expression of genes such as heme oxygenase-1 (HO-1) by inactivating the transcription repressor Bach1 through direct binding. However, the source of heme for the regulation of the Bach1-HO-1 axis has been unclear. Considering that extracellular heme exists as a complex with hemopexin (Hx) in serum under the physiological conditions, heme-Hx complex may deliver heme for the gene regulation. METHODS: Using a mammalian expression system, high secretory recombinant Hx (rHx) was developed. We examined the effects of rHx-bound heme on HO-1 expression and Bach1 in Hepa-1c1c7 liver cells and THP-1 macrophage cells. We investigated the uptake pathway of rHx-bound heme by treating cells with chlorpromazine (CPZ). RESULTS: rHx-bound heme induced the expression of HO-1 and decreased the level of Bach1 protein. CPZ inhibited the induction of the HO-1 expression by rHx-bound heme. CONCLUSION: rHx-bound heme was internalized into the cells via endocytosis, resulting in HO-1 expression and inactivation of Bach1. GENERAL SIGNIFICANCE: The Bach1-dependent repression of the HO-1 expression is under the control of the Hx-dependent uptake of extracellular heme. Heme may regulate Bach1 as an extracellular signaling molecule.
BACKGROUND: Intracellular heme plays versatile roles in a variety of physiological processes including mitochondrial respiration. Heme also induces the expression of genes such as heme oxygenase-1 (HO-1) by inactivating the transcription repressor Bach1 through direct binding. However, the source of heme for the regulation of the Bach1-HO-1 axis has been unclear. Considering that extracellular heme exists as a complex with hemopexin (Hx) in serum under the physiological conditions, heme-Hx complex may deliver heme for the gene regulation. METHODS: Using a mammalian expression system, high secretory recombinant Hx (rHx) was developed. We examined the effects of rHx-bound heme on HO-1 expression and Bach1 in Hepa-1c1c7 liver cells and THP-1 macrophage cells. We investigated the uptake pathway of rHx-bound heme by treating cells with chlorpromazine (CPZ). RESULTS:rHx-bound heme induced the expression of HO-1 and decreased the level of Bach1 protein. CPZ inhibited the induction of the HO-1 expression by rHx-bound heme. CONCLUSION:rHx-bound heme was internalized into the cells via endocytosis, resulting in HO-1 expression and inactivation of Bach1. GENERAL SIGNIFICANCE: The Bach1-dependent repression of the HO-1 expression is under the control of the Hx-dependent uptake of extracellular heme. Heme may regulate Bach1 as an extracellular signaling molecule.
Authors: Tze Yan Lee; Logeswaran Muniandy; Lai Kuan Teh; Maha Abdullah; Elizabeth George; Jameela Sathar; Mei I Lai Journal: Turk J Haematol Date: 2015-08-06 Impact factor: 1.831