Journal Article

The neuronal apoptosis inhibitory protein suppresses neuronal differentiation and apoptosis in PC12 cells

Rudolf Götz, Christoph Karch, Matthew R. Digby, Jakob Troppmair, Ulf R. Rapp and Michael Sendtner

in Human Molecular Genetics

Volume 9, issue 17, pages 2479-2489
Published in print October 2000 | ISSN: 0964-6906
Published online October 2000 | e-ISSN: 1460-2083 | DOI: https://dx.doi.org/10.1093/hmg/9.17.2479
The neuronal apoptosis inhibitory protein suppresses neuronal differentiation and apoptosis in PC12 cells

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The human neuronal apoptosis inhibitory protein (NAIP) gene has been discovered as a candidate gene for spinal muscular atrophy, a genetic disorder characterized by motor neuron loss in the spinal cord. The telomeric NAIP gene on human chromosome 5 is deleted together with survival motor neurons (SMN) in many cases of the most severe forms of the disorder. NAIP, c-IAP1 (inhibitor of apoptosis-1), c-IAP2, X-IAP, survivin and Apollon comprise the mammalian inhibitors of the apoptosis family and contain an N-terminal domain with 1–3 imperfect repeats of an ∼65 amino acids domain named the baculovirus IAP repeat (BIR) motif. We identified six NAIP genes in the mouse genome which were found to be expressed in a broad range of tissues. Furthermore, we have investigated the effects of NAIP in the rat pheochromocytoma PC12 cell line. These cells differentiate in the presence of nerve growth factor (NGF) into cells that resemble sympathetic neurons. We observed that NAIP overexpression impaired NGF-induced neurite outgrowth. The BIR motifs of NAIP (residues 1345) were not required for this effect. However, the BIR domains of NAIP were essential to prevent apoptosis in PC12 cells after NGF deprivation or TNF-α receptor stimulation. Expression of full-length but not BIR-deleted-NAIP protects against cell death. This correlates with reduced activity of the cell death effector protease, caspase-3, in lysates of NAIP-PC12 cells, as measured by cleavage of the fluorogenic tetrapeptide substrate Asp-Glu-Val-Asp. Thus, unregulation of cellular differentiation and/or caspase suppression may contribute to motoneuron dysfunction and cell death in spinal muscular atrophy where NAIP is mutated.

Journal Article.  7476 words.  Illustrated.

Subjects: Genetics and Genomics

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