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Upregulation of human PINK1 gene expression by NF?B signalling.

ABSTRACT: Parkinson's disease (PD) is one of the major neurodegenerative disorders. Mitochondrial malfunction is implicated in PD pathogenesis. Phosphatase and tensin homolog deleted on chromosome 10 (PTEN)-induced putative kinase 1 (PINK1), a serine/threonine kinase, plays an important role in the quality control of mitochondria and more than 70 PINK1 mutations have been identified to cause early-onset PD. However, the regulation of PINK1 gene expression remains elusive. In the present study, we identified the transcription start site (TSS) of the human PINK1 gene using switching mechanism at 5'end of RNA transcription (SMART RACE) assay. The TSS is located at 91 bp upstream of the translation start site ATG. The region with 104 bp was identified as the minimal promoter region by deletion analysis followed by dual luciferase assay. Four functional cis-acting nuclear factor kappa-light-chain-enhancer of activated B cells (NF?B)-binding sites within the PINK1 promoter were identified. NF?B overexpression led to the up-regulation of PINK1 expression in both HEK293 cells and SH-SY5Y cells. Consistently, lipopolysaccharide (LPS), a strong activator of NF?B, significantly increased PINK1 expression in SH-SY5Y cells. Taken together, our results clearly suggested that PINK1 expression is tightly regulated at its transcription level and NF?B is a positive regulator for PINK1 expression.

SUBMITTER: Duan X

PROVIDER: S-EPMC4237968 | biostudies-literature | 2014 Aug

REPOSITORIES: biostudies-literature

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Upregulation of human PINK1 gene expression by NFκB signalling.

Duan Xiaoling X Tong Jade J Xu Qin Q Wu Yili Y Cai Fang F Li Tingyu T Song Weihong W

Molecular brain 20140811

Parkinson's disease (PD) is one of the major neurodegenerative disorders. Mitochondrial malfunction is implicated in PD pathogenesis. Phosphatase and tensin homolog deleted on chromosome 10 (PTEN)-induced putative kinase 1 (PINK1), a serine/threonine kinase, plays an important role in the quality control of mitochondria and more than 70 PINK1 mutations have been identified to cause early-onset PD. However, the regulation of PINK1 gene expression remains elusive. In the present study, we identifi ...[more]

PMID: 25108683

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Project description:Despite extensive investigations, restenosis, which is characterized primarily by neointima formation, remains an unsolved clinical problem after vascular interventions. A recent study has shown that CD40 signaling through TNF receptor associated factor 6 (TRAF6) plays a key role in neointima formation after carotid artery injury; however, underlying mechanisms are not clearly elucidated. Because neointima formation may vary significantly depending on the type of injury, we first assessed the effect of CD40 deficiency on neointima formation in 2 injury models, carotid artery ligation and femoral artery denudation injury. Compared with wild-type mice, CD40 deficiency significantly reduced neointima formation and lumen stenosis in two different models. Further, we investigated the mechanism by which CD40 signaling affects neointima formation after arterial injury. In wild-type mice, the expression levels of CD40, several TRAF proteins, including TRAF1, TRAF2, TRAF3, TRAF5, and TRAF6, as well as total NF-kB p65 and phospho-NF-kB p65, in the carotid artery were markedly upregulated within 3-7 days after carotid ligation. Deficiency of CD40 abolished the injury-induced upregulation of TRAFs including TRAF6 and NF-kB-p65 in the injured vessel wall. Further, CD40(-/-) mice showed a significant decrease in the recruitment of neutrophils (at 3, 7d) and macrophages (at 7, 21d) into injured artery; this effect was most likely attributed to inhibition of NF-kB activation and marked downregulation of NF-kB-related gene expression, including cytokines (TNF?, IL-1?, IL-6), chemokines (MCP-1), and adhesion molecules (ICAM-1, VCAM-1). Moreover, neutrophil recruitment in a model of thioglycollate-induced peritonitis is impaired in CD40-deficient mice. In vitro data revealed that CD40 deficiency blocked CD40L-induced NF-kB p65 nuclear translocation in leukocytes. Altogether, our data identified for the first time that CD40 is essential in the upregulation of TRAF6, NF-kB activation, and NF-kB-dependent proinflammatory genes in vivo. Our findings firmly established the role for CD40 in neointima formation in 2 distinct injury models.

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Upregulation of human PINK1 gene expression by NF?B signalling.

Publications

Upregulation of human PINK1 gene expression by NFκB signalling.

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