Tumor necrosis factor α triggers proliferation of adult neural stem cells via IKK/NF-κB signaling

Widera, Darius; Mikenberg, Ilja; Elvers, Margitta; Kaltschmidt, Christian; Kaltschmidt, Barbara

doi:10.1186/1471-2202-7-64

Cited by 190 publications

(98 citation statements)

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“…We identified a reduced activation of the FAK-Pi3K-AKT-NFkB pathway in patients and mutant mice; this is in line with previous results in cancer cells 4. Mutations in other positive regulators of NFkB, which is involved in a variety of biological processes including neurogenesis and cell survival,16–19 have been reported in patients with intellectual disability 20,21. The role of NFkB signaling in the brain is not yet well understood, and PTRH2 provides an additional link as to how NFkB integrates signals from the ECM to intracellular processes.…”

Section: Resultssupporting

confidence: 89%

Mutations in PTRH2 cause novel infantile‐onset multisystem disease with intellectual disability, microcephaly, progressive ataxia, and muscle weakness

Matter

Issa-Jahns

et al. 2014

Ann Clin Transl Neurol

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ObjectiveTo identify the cause of a so-far unreported phenotype of infantile-onset multisystem neurologic, endocrine, and pancreatic disease (IMNEPD).MethodsWe characterized a consanguineous family of Yazidian-Turkish descent with IMNEPD. The two affected children suffer from intellectual disability, postnatal microcephaly, growth retardation, progressive ataxia, distal muscle weakness, peripheral demyelinating sensorimotor neuropathy, sensorineural deafness, exocrine pancreas insufficiency, hypothyroidism, and show signs of liver fibrosis. We performed whole-exome sequencing followed by bioinformatic analysis and Sanger sequencing on affected and unaffected family members. The effect of mutations in the candidate gene was studied in wild-type and mutant mice and in patient and control fibroblasts.ResultsIn a consanguineous family with two individuals with IMNEPD, we identified a homozygous frameshift mutation in the previously not disease-associated peptidyl-tRNA hydrolase 2 (PTRH2) gene. PTRH2 encodes a primarily mitochondrial protein involved in integrin-mediated cell survival and apoptosis signaling. We show that PTRH2 is highly expressed in the developing brain and is a key determinant in maintaining cell survival during human tissue development. Moreover, we link PTRH2 to the mTOR pathway and thus the control of cell size. The pathology suggested by the human phenotype and neuroimaging studies is supported by analysis of mutant mice and patient fibroblasts.InterpretationWe report a novel disease phenotype, show that the genetic cause is a homozygous mutation in the PTRH2 gene, and demonstrate functional effects in mouse and human tissues. Mutations in PTRH2 should be considered in patients with undiagnosed multisystem neurologic, endocrine, and pancreatic disease.

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Section: Resultssupporting

confidence: 89%

Mutations in PTRH2 cause novel infantile‐onset multisystem disease with intellectual disability, microcephaly, progressive ataxia, and muscle weakness

Matter

Issa-Jahns

et al. 2014

Ann Clin Transl Neurol

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“…TNFα treatment inhibited the proliferation of neurospheres obtained from striatum and SVZ without affecting cell survival and did not affect NPCs lineage fate after differentiation (Ben-Hur et al 2003; Iosif et al 2008). In contrast, TNFα treatment promoted NPCs proliferation in culture (Widera et al 2006). Exposure of NPCs to TNFα enhanced astrogliogenesis and inhibited neuronal differentiation, and percentages of newborn neurons reduced and percentages of astrocytes increased (Keohane et al 2010; Lan et al 2012; Liu et al 2005).…”

Section: Extracellular Signals Within the Neurovascular Unit For Nmentioning

confidence: 99%

Help-me signaling: Non-cell autonomous mechanisms of neuroprotection and neurorecovery

Xing

2017

Progress in Neurobiology

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Self-preservation is required for life. At the cellular level, this fundamental principle is expressed in the form of molecular mechanisms for preconditioning and tolerance. When the cell is threatened, internal cascades of survival signaling become triggered to protect against cell death and defend against future insults. Recently, however, emerging findings suggest that this principle of self-preservation may involve not only intracellular signals; the release of extracellular signals may provide a way to recruit adjacent cells into an amplified protective program. In the central nervous system where multiple cell types co-exist, this mechanism would allow threatened neurons to “ask for help” from glial and vascular compartments. In this review, we describe this new concept of help-me signaling, wherein damaged or diseased neurons release signals that may shift glial and vascular cells into potentially beneficial phenotypes, and help remodel the neurovascular unit. Understanding and dissecting these non-cell autonomous mechanisms of self-preservation in the CNS may lead to novel opportunities for neuroprotection and neurorecovery.

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“…A key mechanism of TNF-induced cell proliferation is the expression of cyclin D1 through IKK/NF-B (36,37). Cyclin D1 expression and nuclear translocation are increased in the G 1 phase of the cell cycle, where it associates with CDK4 and CDK6 to induce the S phase entry of cells.…”

Section: Activation Of Plk1 By Nocodazole Sustains Phosphorylation Ofmentioning

confidence: 99%

Regulation of IκB Kinase Complex by Phosphorylation of γ-Binding Domain of IκB Kinase β by Polo-like Kinase 1

Higashimoto

Chan

Lee

et al. 2008

Journal of Biological Chemistry

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IB kinase (IKK) complex is a key regulator of NF-B pathways. Signal-induced interaction of the IKK␥ (NEMO) subunit with the C-terminal IKK␥/NEMO-binding domain (␥BD) of IKK␤ is an essential interaction for IKK regulation.Underlying regulatory mechanism(s) of this interaction are not known. Phosphorylation of ␥BD has been suggested to play a regulatory role for IKK activation. However, a kinase that phosphorylates ␥BD has not been identified. In this study, we used a C-terminal fragment of IKK␤ as substrate and purified Polo-like kinase 1 (Plk1) from HeLa cell extracts by standard chromatography as a ␥BD kinase. Plk1 phosphorylates serines 733, 740, and 750 in the ␥BD of ⌱⌲⌲␤ in vitro. Phosphorylating ␥BD with Plk1 decreased its affinity for IKK␥ in pulldown assay. We generated phosphoantibodies against serine 740 and showed that ␥BD is phosphorylated in vivo. IB kinase complex (IKK)2 regulates signal-induced activation of nuclear factor B (NF-B) family transcription factors (1). IKK phosphorylates inhibitor B (IB) proteins, targeting them for ubiquitin-dependent proteasomal degradation (1-4). Classical IKK complex was identified as containing two kinase subunits, IKK␣ and IKK␤, and the regulatory IKK␥ (also called NEMO) protein (5-7). Additional IKK-related proteins have been identified, but it does not appear that they are associated with IKK. Native IKK is found in large protein complexes ranging from 600 to 900 kDa (5-7). Yeast reconstitution of human IKK shows that one catalytic kinase subunit and the IKK␥ are sufficient to form large IKK complexes similar in size to the native IKK from HeLa cells (8).Regulation of the IKK complex by upstream signaling involves phosphorylation/de-phosphorylation and ubiquitination/de-ubiquitination of IKK subunits and upstream regulators (9 -17). The kinase domain of IKK␣ and IKK␤ contains the signature domain of mitogen-activated protein kinase kinase (MAPKK) and the corresponding activation T loop sequences (6). The T loop phospho-acceptor sites, serines 176 and 180 in IKK␣ and serines 177 and 181 in IKK␤, are phosphorylated by kinases such as NIK, DNA-PK, NAK, and LKB (1). The T loop serines can also be autophosphorylated within the IKK complex in an IKK␥-dependent manner in the reconstituted IKK complex in yeast (8).Phosphorylation of the C-terminal region of IKK␤ has been implicated in the regulation of the IKK complex. Delhase et al. (18) showed that the C terminus of IKK␤ is phosphorylated in vivo on several serine residues, and this phosphorylation increases upon cell stimulation by TNF␣. They further showed that expression of an IKK␤ mutant in which 10 serines immediately adjacent to the HLH (not including the serines within and adjacent to the ␥BD) are mutated to alanine in HeLa cells generates IKK complexes with prolonged activation kinetics (18). This suggested that TNF-induced phosphorylation of the C terminus of IKK␤ is important for down-regulation of IKK (18). May et al. (19) showed that mutating a serine residue in the ␥BD (Ser-740) to glutamate reduced ...

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Tumor necrosis factor α triggers proliferation of adult neural stem cells via IKK/NF-κB signaling

Cited by 190 publications

References 50 publications

Mutations in PTRH2 cause novel infantile‐onset multisystem disease with intellectual disability, microcephaly, progressive ataxia, and muscle weakness

Mutations in PTRH2 cause novel infantile‐onset multisystem disease with intellectual disability, microcephaly, progressive ataxia, and muscle weakness

Help-me signaling: Non-cell autonomous mechanisms of neuroprotection and neurorecovery

Regulation of IκB Kinase Complex by Phosphorylation of γ-Binding Domain of IκB Kinase β by Polo-like Kinase 1

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