Abstract
Defective heme synthesis may cause acute porphyrias, which are associated with a wide array of neurological disturbances involving both the central and peripheral nervous systems. Thus, the understanding of the roles of heme in neuronal cell function may provide insights into the molecular events underlying the pathogenesis of neuropathies associated with defective heme synthesis. In this report, we use rat pheochromocytoma (PC12) clonal cells as a model system for studying the role of heme in neuronal cell survival. We examined the effects of inhibition of heme synthesis on signaling pathways and gene expression in nerve growth factor (NGF)-induced PC12 cells. We found that succinyl acetone-induced heme deficiency selectively caused apoptosis in NGF-induced PC12 cells. Further, we found that in succinyl acetone-treated, NGF-induced cells, the pro-survival Ras-ERK1/2 signaling pathway was inactivated and the pro-apoptotic JNK signaling pathway was activated. In these cells, the activation of caspase and the cleavage of nuclear poly (ADP-ribose) polymerase (PARP) were also evident. Importantly, microarray gene expression analysis showed that more than 20 key neuronal genes that were induced by NGF were suppressed by succinyl acetone. These genes include those encoding survival motor neuron protein, synaptic vesicle protein SVOP, and neural cell adhesion molecule NCAM. These results indicate that heme is important for neuronal cell signaling and the proper functioning of neuronal cells.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Animals
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Apoptosis / drug effects
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Apoptosis / genetics*
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Caspases / drug effects
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Caspases / metabolism
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Cell Survival / drug effects
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Cell Survival / genetics
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Collagen Type XI / drug effects
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Collagen Type XI / metabolism
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Cyclic AMP Response Element-Binding Protein / drug effects
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Cyclic AMP Response Element-Binding Protein / genetics
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Cyclic AMP Response Element-Binding Protein / metabolism
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Down-Regulation / drug effects
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Down-Regulation / physiology
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Enzyme Inhibitors
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Gene Expression Regulation, Enzymologic / drug effects
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Gene Expression Regulation, Enzymologic / genetics*
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Heme / biosynthesis
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Heme / deficiency*
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Heptanoates
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MAP Kinase Signaling System / drug effects
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MAP Kinase Signaling System / physiology
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Membrane Proteins / drug effects
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Membrane Proteins / genetics
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Membrane Proteins / metabolism
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Nerve Degeneration / genetics*
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Nerve Degeneration / metabolism
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Nerve Degeneration / physiopathology
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Nerve Tissue Proteins / drug effects
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Nerve Tissue Proteins / genetics
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Nerve Tissue Proteins / metabolism
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Neural Cell Adhesion Molecules / drug effects
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Neural Cell Adhesion Molecules / genetics
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Neural Cell Adhesion Molecules / metabolism
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Neurons / drug effects
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Neurons / metabolism*
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Neurons / pathology
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PC12 Cells
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Poly (ADP-Ribose) Polymerase-1
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Poly(ADP-ribose) Polymerases
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Porphyrias / complications*
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Porphyrias / metabolism
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Porphyrias / physiopathology
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RNA, Messenger / drug effects
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RNA, Messenger / metabolism
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RNA-Binding Proteins / drug effects
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RNA-Binding Proteins / genetics
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RNA-Binding Proteins / metabolism
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Rats
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SMN Complex Proteins
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Up-Regulation / drug effects
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Up-Regulation / physiology
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Vesicular Transport Proteins / drug effects
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Vesicular Transport Proteins / genetics
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Vesicular Transport Proteins / metabolism
Substances
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Collagen Type XI
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Cyclic AMP Response Element-Binding Protein
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Enzyme Inhibitors
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Heptanoates
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Membrane Proteins
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Nerve Tissue Proteins
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Neural Cell Adhesion Molecules
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RNA, Messenger
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RNA-Binding Proteins
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SMN Complex Proteins
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Svop protein, rat
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Vesicular Transport Proteins
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Heme
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succinylacetone
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Parp1 protein, rat
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Poly (ADP-Ribose) Polymerase-1
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Poly(ADP-ribose) Polymerases
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Caspases