Tumor necrosis factor receptor‐associated protein 1 regulates cell adhesion and synaptic morphology via modulation of N‐cadherin expression

Abstract

1 These authors contributed equally to this study.Abbreviations used: DiI, 1,1¢-dioctadecyl-3,3,3¢,3¢-tetramethylindocarbocyanine perchlorate; HSP90, heat shock protein 90; PBS, phosphate buffered saline; siRNA, small interfering RNA; siTRAP1, siRNAs against TRAP1; SNP, single nucleotide polymorphism; STAT, Signal Transducers and Activator of Transcription; TBS, Tris-bufferd saline; TNF, tumor necrosis factor; TNFR, tumor necrosis factor receptor; TRAP1, tumor necrosis factor receptor-associated protein 1. AbstractAn increase in serum tumor necrosis factor-a (TNF-a) levels is closely related to the pathogenesis of major depression. However, the underlying molecular mechanism between this increase and impairment of brain function remains elusive. To better understand TNF-a/TNF receptor 1 signaling in the brain, we analyzed the brain distribution and function of tumor necrosis factor receptor-associated protein 1 (TRAP1). Here we show that TRAP1 is broadly expressed in neurons in the mouse brain, including regions that are implicated in the pathogenesis of major depression. We demonstrate that small interfering RNA-mediated knockdown of TRAP1 in a neuronal cell line decreases tyrosine phosphorylation of STAT3, followed by a reduction of the transcription factor E2F1, resulting in a down-regulation of N-cadherin, and affects the adhesive properties of the cells. In addition, in cultured hippocampal neurons, reduced expression of N-cadherin by TRAP1 knockdown influences the morphology of dendritic spines. We also report a significant association between several single nucleotide polymorphisms in the TRAP1 gene and major depression. Our findings indicate that TRAP1 mediates TNF-a/ TNF receptor 1 signaling to modulate N-cadherin expression and to regulate cell adhesion and synaptic morphology, which may contribute to the pathogenesis of major depression.

Effects of promoter methylation on increased expression of polyamine biosynthetic genes in suicide

“…In this study, we show significant site-specific decreases in DNA methylation in the promoter region of ARG2 and AMD1 that are correlated with the increases in levels of expression of these genes in suicide completers. Although we have not investigated the exact mechanism by which DNA methylation may act on the expression of ARG2 and AMD1, a recent study by Kubota and colleagues showed that decreases in E2F transcription factor 1 (E2F-1) are associated with decreased expression of genes related to the pathogenesis of major depression (Kubota et al, 2009). Interestingly, our results show decreases in DNA methylation in the promoter region of ARG2 and AMD1 in an area where E2F-1 is predicted to bind.…”

TRAP1 controls cell migration of cancer cells in metabolic stress conditions: Correlations with AKT/p70S6K pathways

“…This seems to be mediated by higher expression of genes promoting cell-cell and cell-matrix adhesion like cadherins, which are known to play critical roles in the processes of invasion and metastasis [27]. Moreover, Kubota et al [28] have reported that siRNA-mediated knockdown of TRAP1 in a neuronal cell line resulted in down-regulation of N-cadherin and affected the adhesive properties of the cells.…”

Cadherins in Brain Morphogenesis and Wiring

“…Similarly, ␦-catenin is involved in spine morphogenesis via the regulation of small RhoGTPases (5, 19). Moreover, tumor necrosis factor (TNF)-␣/TNF receptor signaling, which is implicated in the pathogenesis of major depression, was shown to be important to maintain N-cadherin expression that is required for normal spine morphogenesis (175). Thus spine morphogenesis by cadherins seems to be regulated in various ways.…”