Dataset Information

TCR-induced, PKC-?-mediated NF-?B activation is regulated by a caspase-8-caspase-9-caspase-3 cascade.

ABSTRACT: It has been documented that caspase-8, a central player in apoptosis, is also crucial for TCR-mediated NF-?B activation. However, whether other caspases are also involved this process is unknown. In this report, we showed that in addition to caspase-8, caspase-9 is required for TCR-mediated NF-?B activation. Caspase-9 induces activation of PKC-?, phosphorylation of Bcl10 and NF-?B activation in a caspase-3-dependent manner, but it appears that Bcl10 phosphorylation is uncoupled from NF-?B activation. Furthermore, caspase-8 lies upstream of caspase-9 during T cell activation. Therefore, TCR ligation elicits a caspase cascade involving caspase-8, caspase-9 and caspase-3 which initiates PKC-?-dependent pathway leading to NF-?B activation and PKC-?-independent Bcl10 phosphorylation which limits NF-kB activity.

SUBMITTER: Zhao Y

PROVIDER: S-EPMC4107081 | biostudies-literature | 2014 Jul

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

TCR-induced, PKC-θ-mediated NF-κB activation is regulated by a caspase-8-caspase-9-caspase-3 cascade.

Zhao Yixia Y Lei Minxiang M Wang Zhaoyuan Z Qiao Guilin G Yang Tianlun T Zhang Jian J

Biochemical and biophysical research communications 20140609 1

It has been documented that caspase-8, a central player in apoptosis, is also crucial for TCR-mediated NF-κB activation. However, whether other caspases are also involved this process is unknown. In this report, we showed that in addition to caspase-8, caspase-9 is required for TCR-mediated NF-κB activation. Caspase-9 induces activation of PKC-θ, phosphorylation of Bcl10 and NF-κB activation in a caspase-3-dependent manner, but it appears that Bcl10 phosphorylation is uncoupled from NF-κB activa ...[more]

PMID: 24924627

Similar Datasets

Project description:BackgroundWorsened stroke outcomes with hypertension comorbidity are insensitive to blood pressure-lowering therapies. In an experimental stroke model with comorbid hypertension, we investigated causal roles of ang II (angiotensin II)-mediated stimulation of the brain WNK (with no lysine [K] kinases)-SPAK (STE20/SPS1-related proline/alanine-rich kinase)-NKCC1 (Na-K-Cl cotransporter) complex in worsened outcomes.MethodsSaline- or ang II-infused C57BL/6J male mice underwent stroke induced by permanent occlusion of the distal branches of the middle cerebral artery. Mice were randomly assigned to receive either vehicle dimethyl sulfoxide/PBS (2 mL/kg body weight/day, IP), a novel SPAK inhibitor, 5-chloro-N-(5-chloro-4-((4-chlorophenyl)(cyano)methyl)-2-methylphenyl)-2-hydroxybenzamide (ZT-1a' 5 mg/kg per day, IP) or a NF-κB (nuclear factor-κB) inhibitor TAT-NBD (transactivator of transcription-NEMO-binding domain' 20 mg/kg per day, IP). Activation of brain NF-κB and WNK-SPAK-NKCC1 cascade as well as ischemic stroke outcomes were examined.ResultsStroke triggered a 2- to 5-fold increase of WNK (isoforms 1, 2, 4), SPAK/OSR1 (oxidative stress-responsive kinase 1), and NKCC1 protein in the ang II-infused hypertensive mouse brains at 24 hours after stroke, which was associated with increased nuclear translocation of phospho-NF-κB protein in the cortical neurons (a Pearson correlation r of 0.77, P<0.005). The upregulation of WNK-SPAK-NKCC1 cascade proteins resulted from increased NF-κB recruitment on Wnk1, Wnk2, Wnk4, Spak, and Nkcc1 gene promoters and was attenuated by NF-κB inhibitor TAT-NBD. Poststroke administration of SPAK inhibitor ZT-1a significantly reduced WNK-SPAK-NKCC1 complex activation, brain lesion size, and neurological function deficits in the ang II-hypertensive mice without affecting blood pressure and cerebral blood flow.ConclusionsThe ang II-induced stimulation of NF-κB transcriptional activity upregulates brain WNK-SPAK-NKCC1 cascade and contributes to worsened ischemic stroke outcomes, illustrating the brain WNK-SPAK-NKCC1 complex as a therapeutic target for stroke with comorbid hypertension.

Dataset Information

TCR-induced, PKC-?-mediated NF-?B activation is regulated by a caspase-8-caspase-9-caspase-3 cascade.

Publications

TCR-induced, PKC-θ-mediated NF-κB activation is regulated by a caspase-8-caspase-9-caspase-3 cascade.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets