Compromised proteasome degradation elevates neuronal nitric oxide synthase levels and induces apoptotic cell death.

Archives of Biochemistry and Biophysics
Philip Y Lam, E Cadenas

Abstract

The significance of impairment of proteasome activity in PC12 cells was examined in connection with nitrative/nitrosative stress and apoptotic cell death. Treatment of differentiated PC12 cells with MG132, a proteasome inhibitor, elicited a dose- and time-dependent increase in neuronal nitric oxide synthase (nNOS) protein levels, decreased cell viability, and increased cytotoxicity. Viability and cytotoxicity were ameliorated by L-NAME (a broad NOS inhibitor). Nitric oxide/peroxynitrite formation was increased upon treatment of PC12 cells with MG132 and decreased upon treatment with the combination of MG132 and 7-NI (a specific inhibitor of nNOS). The decreases in cell viability appeared to be effected by an activation of JNK and its effect on mitochondrial Bcl-x(L) phosphorylation. These effects are strengthened by the activation of caspase-9 along with increased caspase-3 activity upon treatment of PC12 cells with MG132. These results suggest that impairment of proteasome activity and consequent increases in nNOS levels lead to a nitrative stress that involves the coordinated response of JNK cytosolic signaling and mitochondrion-driven apoptotic pathways.

References

Jun 30, 2000·Current Opinion in Cell Biology·M Crompton
Oct 3, 2002·Journal of Neurochemistry·María Delgado-EstebanJose M Medina
Nov 25, 2003·Oncogene·David G BreckenridgeGordon C Shore
May 13, 2005·Mechanisms of Ageing and Development·B-Y ZengP Jenner
Jan 18, 2006·Cell Death and Differentiation·J J ShackaA G Estévez
Feb 21, 2006·Antioxidants & Redox Signaling·Qunxing DingJeffrey N Keller
Apr 18, 2006·Biochimica Et Biophysica Acta·Alberto BoverisJuanita Bustamante

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Citations

Jun 3, 2008·Chemical Research in Toxicology·Yoshichika KawaiToshihiko Osawa
Jul 17, 2012·Molecular Medicine Reports·Xiao ChengLi-Hua Zhou
Nov 30, 2018·Journal of Experimental & Clinical Cancer Research : CR·Iris C SalaroglioJoanna Kopecka
Jan 23, 2009·Archives of Biochemistry and Biophysics·Juan J Poderoso

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