TRAF Family Proteins Interact with the Common Neurotrophin Receptor and Modulate Apoptosis Induction

Ye, Xin; Mehlen, Patrick; Rabizadeh, Shahrooz; VanArsdale, Todd; Zhang, Heying; Shin, Hwain; Wang, James J.-L.; Leo, Eugen; Zapata, Juán M.; Hauser, Craig A.; Reed, John C.; Bredesen, Dale E.

doi:10.1074/jbc.274.42.30202

Cited by 172 publications

(129 citation statements)

References 50 publications

(55 reference statements)

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“…72 The presence of TRAF2 or TRAF6 proteins in the cytoplasm of motor neurons sequesters the death receptors, aiding in survival of the neuron. 73,74 However, E2F-1 located in the cytoplasm may induce complex formation with TRAF proteins to impede their function, thus releasing death receptors that could now induce cell death via the p75 NTR pathway or other death receptor pathways. [72][73][74] There is indeed precedence to the interactions of E2F-1 with the TRAF proteins in other cell types.…”

Section: Discussionmentioning

confidence: 99%

“…73,74 However, E2F-1 located in the cytoplasm may induce complex formation with TRAF proteins to impede their function, thus releasing death receptors that could now induce cell death via the p75 NTR pathway or other death receptor pathways. [72][73][74] There is indeed precedence to the interactions of E2F-1 with the TRAF proteins in other cell types. 72 This hypothesis warrants further investigation.…”

Section: Discussionmentioning

confidence: 99%

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Alterations in G1 to S Phase Cell-Cycle Regulators during Amyotrophic Lateral Sclerosis

Ranganathan

Bowser

2003

The American Journal of Pathology

150

111

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Amyotrophic lateral sclerosis (ALS) is characterizedby progressive degeneration of the motor neurons in the cerebral cortex, brain stem, and spinal cord. However, the mechanisms that regulate the initiation and/or progression of motor neuron loss in this disease remain enigmatic. Cell-cycle proteins and transcriptional regulators such as cyclins, cyclin-associated kinases, the retinoblastoma gene product (pRb), and E2F-1 function during cellular proliferation, differentiation, and cell death pathways. Recent data has implicated increased expression and activation of various cell-cycle proteins in neuronal cell death. We have examined the expression and subcellular distribution of G 1 to S phase cell-cycle regulators in the spinal cord, motor cortex, and sensory cortex from clinically and neuropathologically diagnosed sporadic ALS cases and age-matched controls. Our results indicate hyperphosphorylation of the retinoblastoma protein in motor neurons during ALS, concurrent with increased levels of cyclin D, and redistribution of E2F-1 into the cytoplasm of motor neurons and glia. These data suggest that G 1 to S phase activation occurs during ALS and may participate in molecular mechanisms regulating motor neuron death. Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease exemplified by neuronal loss in the motor cortex, brainstem, and spinal cord ventral horn. This progressive neurodegeneration results in muscle atrophy, paralysis, and death. Disease onset may occur at any age but is most common between 40 to 70 years of age. The average time interval from diagnosis to mortality is ϳ4 years. 1,2 Familial ALS comprises a fraction (5 to 10%) of ALS cases and is predominantly inherited in an autosomal dominant manner and includes mutations in the SOD1 and the ALS2 genes. [3][4][5][6][7] The etiology of ALS is thought to be multifactorial. Factors believed to participate in motor neuron degeneration include glutamate-mediated excitotoxicity, free radical accumulation because of oxidative stress, increased intracellular calcium, mitochondrial dysfunction, cytoskeletal abnormalities, astrogliosis, and genetic mutations. 8 -13 Neuronal dysfunction because of retrograde degeneration of the presynaptic axons may occur as the result of insufficient release of activity-dependent target-derived neurotrophic factors. 14 One important consequence of inappropriate trophic factor support is altered intracellular signaling to the nucleus. Signaling from the cell surface to the nucleus modulates chromatin structure and the activity of transcription factors, resulting in altered gene transcription. One potential mechanism leading to neuronal death in ALS includes altered expression of pro-and anti-apoptotic genes. 15 Another potential cell death mechanism is the inappropriate expression or activation of cell-cycle proteins. 16 The cell cycle is associated with the phasespecific expression or modification of defined sets of cell-cycle regulatory genes that regulate cellular proliferation, differentiation or entry into...

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Alterations in G1 to S Phase Cell-Cycle Regulators during Amyotrophic Lateral Sclerosis

Ranganathan

Bowser

2003

The American Journal of Pathology

150

111

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“…2,8 It is also possible that the decision between ligand-induced apoptosis and ligand-inhibited apoptosis mediated by p75 NTR may depend on specific downstream mediators: for example, the interaction of p75 NTR with NADE induces apoptosis following ligand binding; 93 in contrast, TRAF2 has been shown to interact preferentially with monomeric p75 NTR and to induce apoptosis in the absence of NGF. 94 Other potential death-mediating p75 NTR interactors include NRAGE 49 and NRIF. 95 Another proapoptotic transmembrane protein has been identified that has a death domain very similar to that of p75 NTR , and this protein interacts with p75 NTR .…”

Section: Patched: Hedging Bets On Neural Tube Developmentmentioning

confidence: 99%

Receptors that mediate cellular dependence

2005

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Cells depend for their survival on stimulation by trophic factors and other prosurvival signals, the withdrawal of which induces apoptosis, both via the loss of antiapoptotic signaling and the activation of proapoptotic signaling via specific receptors. These receptors, dubbed dependence receptors, activate apoptotic pathways following the withdrawal of trophic factors and other supportive stimuli. Such receptors may feature in developmental cell death, carcinogenesis (including metastasis), neurodegeneration, and possibly subapoptotic events such as neurite retraction and somal atrophy. Mechanistic studies of dependence receptors suggest that these receptors form ligand-dependent complexes that include specific caspases. Complex formation in the absence of ligand leads to caspase activation by a mechanism that is typically dependent on caspase cleavage of the receptor itself, releasing proapoptotic peptides. Cellular dependence receptors, considered in the aggregate, may thus form a system of molecular integration, analogous to the electrical integration system provided by dendritic arbors in the nervous system.

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“…Several reports suggested that TRAF4 could be recruited to different TNFR and TLR signalling pathways (Krajewska et al, 1998;Ye et al, 1999;Esparza and Arch, 2004;Takeshita et al, 2005), and in mitogen-activated protein kinase (MAPK) pathways (Xu et al, 2002;Abell and Johnson, 2005;Li et al, 2005) but in vivo evidence of such a role is still missing. Mice deficient for TRAF4 exhibit clear ontogenic defects affecting neural tube closure, tracheal formation and skeletal patterning, phenotypes that might be linked to abnormal cell migration (Regnier et al, 2002).…”

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confidence: 99%

TRAF4 overexpression is a common characteristic of human carcinomas

et al. 2006

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Tumor necrosis factor receptor (TNFR) associated factor 4 (TRAF4) was initially identified as a gene amplified and overexpressed in breast carcinomas. Our aim was to evaluate whether TRAF4 protein overexpression exists in other cancer types. Immunohistochemistry analysis of tumor samples from 623 patients with 20 different tumor types showed that TRAF4 was overexpressed in 268 tumors (43%), including 82 of 137 lung adenocarcinomas (60%). Interestingly, 32 primary tumors and their matching metastases exhibited mostly similar TRAF4 expression pattern. TRAF4 protein overexpression was limited to cancer cells and the subcellular localization was consistently cytoplasmic in a large majority of cases. To investigate changes in TRAF4 gene copy number, 125 cases from six different types of carcinomas were also analysed by fluorescence in situ hybridization. Out of the 28 cases (22%) showing an increased TRAF4 gene copy number, 23 (82%) were overexpressing the protein. Thus, TRAF4 gene amplification is one of the mechanisms responsible for TRAF4 protein overexpression in human cancers. Considering that TRAF4 is located at 17q11.2 in a region of amplification devoid of known oncogenes and is commonly overexpressed in cancer, our data support an oncogenic role for TRAF4. Oncogene Keywords: TRAF4; chromosome 17q11; ERBB2; amplification; lung TRAF proteins belong to a family of cytoplasmic adaptors involved in the signalling cascade activated by receptors of the TNFR and interleukin-1/Toll-like receptor (IL-1R/TLR) families (Chung et al., 2002). Six TRAF proteins that share common structural features, including a carboxy-terminal TRAF domain, are encoded by the mammalian genome. Their main functions are exerted in the immune system where they regulate intracellular signalling pathways leading to the activation of a common set of transcription factors including NF-kB and AP-1 (Aggarwal, 2003).Unlike other members of the TRAF family, the biological function of TRAF4 remains elusive. Several reports suggested that TRAF4 could be recruited to different TNFR and TLR signalling pathways (Krajewska et al., 1998;Ye et al., 1999;Esparza and Arch, 2004;Takeshita et al., 2005), and in mitogen-activated protein kinase (MAPK) pathways (Xu et al., 2002;Abell and Johnson, 2005;Li et al., 2005) but in vivo evidence of such a role is still missing. Mice deficient for TRAF4 exhibit clear ontogenic defects affecting neural tube closure, tracheal formation and skeletal patterning, phenotypes that might be linked to abnormal cell migration (Regnier et al., 2002).TRAF4 was the first member of the TRAF protein family found upregulated in human carcinomas. Indeed, the TRAF4 cDNA was initially isolated from metastatic breast cancer Tomasetto et al., 1995), where the TRAF4 gene was amplified, leading to overexpression of the gene product (Bieche et al., 1996). Detailed analysis of the amplification pattern of five genes located on the long arm of the chromosome 17, including the ERBB2 oncogene (Slamon et al., 1989), revealed the existence of at least...

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TRAF Family Proteins Interact with the Common Neurotrophin Receptor and Modulate Apoptosis Induction

Cited by 172 publications

References 50 publications

Alterations in G1 to S Phase Cell-Cycle Regulators during Amyotrophic Lateral Sclerosis

Alterations in G1 to S Phase Cell-Cycle Regulators during Amyotrophic Lateral Sclerosis

Receptors that mediate cellular dependence

TRAF4 overexpression is a common characteristic of human carcinomas

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