Nitric Oxide/cGMP Signaling Pathway Protects RAW264 Cells Against Nitric Oxide-Induced Apoptosis by Inhibiting the Activation of p38 Mitogen-Activated Protein Kinase

The functional role of p53 in nitric oxide (NO)-mediated vascular smooth muscle cell (VSMC) apoptosis remains unknown. In this study, VSMC from p53−/− and p53+/+ murine aortas were exposed to exogenous or endogenous sources of NO. Unexpectedly, p53−/− VSMC were much more sensitive to the proapoptotic effects of NO than were p53+/+ VSMC. Furthermore, this paradox appeared to be specific to NO, because other proapoptotic agents did not demonstrate this differential effect on p53−/− cells. NO-induced apoptosis in p53−/− VSMC occurred independently of cGMP generation. However, mitogen-activated protein kinase (MAPK) pathways appeared to play a significant role. Treatment of the p53−/− VSMC with S-nitroso- N-acetylpenicillamine resulted in a marked activation of p38 MAPK and, to a lesser extent, of c-Jun NH2-terminal kinase, mitogen-activated protein kinase kinase (MEK) 1/2, and p42/44 (extracellular signal-regulated kinase, ERK). Furthermore, basal activity of the MEK-p42/44 (ERK) pathway was increased in the p53+/+ VSMC. Inhibition of p38 MAPK with SB-203580 or of MEK1/2 with PD-98059 blocked NO-induced apoptosis. Therefore, p53 may protect VSMC against NO-mediated apoptosis, in part, through differential regulation of MAPK pathways.

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Filamin B Serves as a Molecular Scaffold for Type I Interferon-induced c-Jun NH2-terminal Kinase Signaling Pathway

Molecular Biology of the Cell ◽

10.1091/mbc.e08-06-0576 ◽

2008 ◽

Vol 19 (12) ◽

pp. 5116-5130 ◽

Cited By ~ 26

Author(s):

Young Joo Jeon ◽

Joon Seok Choi ◽

Jung Yun Lee ◽

Kyung Ryun Yu ◽

Seung Hyeun Ka ◽

...

Keyword(s):

Protein Kinase ◽

Signaling Pathway ◽

Mitogen Activated Protein Kinase ◽

Type I ◽

Molecular Scaffold ◽

Filamin B ◽

Mitogen Activated Protein ◽

Induced Apoptosis ◽

Jnk Cascade ◽

Protein Kinase Kinase

Type I interferons (IFNs) activate Janus tyrosine kinase-signal transducer and activator of transcription pathway for exerting pleiotropic biological effects, including antiviral, antiproliferative, and immunomodulatory responses. Here, we demonstrate that filamin B functions as a scaffold that links between activated Rac1 and a c-Jun NH2-terminal kinase (JNK) cascade module for mediating type I IFN signaling. Filamin B interacted with Rac1, mitogen-activated protein kinase kinase kinase 1, mitogen-activated protein kinase kinase 4, and JNK. Filamin B markedly enhanced IFNα-dependent Rac1 activation and the sequential activation of the JNK cascade members. Complementation assays using M2 melanoma cells revealed that filamin B, but not filamin A, is required for IFNα-dependent activation of JNK. Furthermore, filamin B promoted IFNα-induced apoptosis, whereas short hairpin RNA-mediated knockdown of filamin B prevented it. These results establish a novel function of filamin B as a molecular scaffold in the JNK signaling pathway for type I IFN-induced apoptosis, thus providing the biological basis for antitumor and antiviral functions of type I IFNs.

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