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Bruce D Carter

Publications and source records attributed to Bruce D Carter.

10 recordsLinked to original sources
PubMed2006

Ligand-dependent cleavage of the P75 neurotrophin receptor is necessary for NRIF nuclear translocation and apoptosis in sympathetic neurons.

The p75 neurotrophin receptor regulates neuronal survival, promoting it in some contexts yet activating apoptosis in others. The mechanism by which the receptor elicits these differential effects is poorly understood. Here, we demonstrate that p75 is cleaved by gamma-secretase in sympathetic neurons, specifically in response to proapoptotic ligands. This cleavage resulted in ubiquitination and subsequent nuclear translocation of NRIF, a DNA binding protein essential for p75-mediated apoptosis. Inhibition of gamma-secretase or expression of a mutant p75 resistant to this protease prevented receptor proteolysis, blocked NRIF nuclear entry, and prevented apoptosis. In contrast, overexpression of the p75 ICD resulted in NRIF nuclear accumulation and apoptosis. The receptor proteolysis and NRIF nuclear localization were also observed in vivo during naturally occurring cell death in the superior cervical ganglia. These results indicate that p75-mediated apoptosis requires gamma-secretase dependent release of its ICD, which facilitates nuclear translocation of NRIF.

Amyloid Precursor Protein Secretases↗
PubMed2005

TRAF6-mediated ubiquitination regulates nuclear translocation of NRIF, the p75 receptor interactor.

TRAF6 is an E3 ubiquitin ligase that mediates signaling from members of the tumor necrosis factor and Toll-like receptor superfamilies, including the p75 neurotrophin receptor. Recently, TRAF6 was shown to bind to another p75 cytoplasmic interactor, NRIF, and promote its nuclear localization. Here, we demonstrate that NRIF is a substrate for TRAF6-mediated K63 polyubiquitination and that this modification is necessary for its nuclear translocation. Activation of p75 resulted in NRIF polyubiquitination, association with TRAF6 and nuclear localization. NRIF was polyubiquitinated by TRAF6 in vitro and in cultured cells, and this was abrogated by mutation of K19 in the amino-terminus of NRIF. The K19R mutant NRIF displayed reduced TRAF6 association and neurotrophin-dependent nuclear localization. In neurons from traf6-/- mice, NRIF failed to enter the nucleus in response to p75 activation, and polyubiquitination and nuclear localization were attenuated in traf6-/- brain. Finally, unlike wild-type NRIF, the K19R NRIF failed to reconstitute p75-mediated apoptosis in nrif-/- neurons. These results reveal a unique mechanism of p75 signaling and a novel role for K63-linked ubiquitin chains.

Active Transport, Cell Nucleus↗
PubMed2005

Neurotrophin receptor interacting factor (NRIF) is an essential mediator of apoptotic signaling by the p75 neurotrophin receptor.

Activation of the p75 neurotrophin receptor leads to a variety of effects within the nervous system, including neuronal apoptosis. Both c-Jun N-terminal kinase (JNK) and the tumor suppressor p53 have been reported to be critical for this receptor to induce cell death; however, the mechanisms by which p75 activates these pathways is undetermined. Here we report that the neurotrophin receptor interacting factor (NRIF) is necessary for p75-dependent JNK activation and apoptosis. Upon nerve growth factor withdrawal, nrif-/- sympathetic neurons underwent apoptosis, whereas p75-mediated death was completely abrogated. The lack of cell death correlated with a lack of JNK activation in the nrif-/- neurons, suggesting that NRIF is a selective mediator for p75-dependent JNK activation and apoptosis. Moreover, we document that NRIF expression is sufficient to induce cell death through a mechanism that requires p53. Taken together, these results establish NRIF as an essential component of the p75 apoptotic pathway.

Adrenergic Fibers↗
PubMed2005

Neuronal apoptosis linked to EglN3 prolyl hydroxylase and familial pheochromocytoma genes: developmental culling and cancer.

Germline NF1, c-RET, SDH, and VHL mutations cause familial pheochromocytoma. Pheochromocytomas derive from sympathetic neuronal precursor cells. Many of these cells undergo c-Jun-dependent apoptosis during normal development as NGF becomes limiting. NF1 encodes a GAP for the NGF receptor TrkA, and NF1 mutations promote survival after NGF withdrawal. We found that pheochromocytoma-associated c-RET and VHL mutations lead to increased JunB, which blunts neuronal apoptosis after NGF withdrawal. We also found that the prolyl hydroxylase EglN3 acts downstream of c-Jun and is specifically required among the three EglN family members for apoptosis in this setting. Moreover, EglN3 proapoptotic activity requires SDH activity because EglN3 is feedback inhibited by succinate. These studies suggest that failure of developmental apoptosis plays a role in pheochromocytoma pathogenesis.

Adrenal Gland Neoplasms↗
PubMed2004

Neurotrophin signaling through the p75 receptor is deficient in traf6-/- mice.

Activation of the neurotrophin receptor p75 has been shown to elicit opposing cellular signals. Depending on the context of the cell, p75 will either promote survival or induce apoptosis after neurotrophin stimulation. p75-induced apoptosis occurs through activation of c-Jun N-terminal kinase (JNK), whereas the survival signal is mediated by nuclear factor kappaB (NFkappaB). The receptor proximal signals that produce these responses are unknown, although several molecules have been identified that associate with the intracellular domain of p75. One such interactor, TRAF6, a member of the tumor necrosis factor receptor-associated factor family, has been implicated in p75 signaling. To assess the role of TRAF6 in p75 signaling, we analyzed mice with this gene deleted. In Schwann cells isolated from traf6+/+ animals, NGF elicited an 80% increase in transcription of an NFkappaB reporter; however, in traf6-/- cells, the NGF response was abrogated. Similarly, NGF activation of JNK was not apparent in Schwann cells from mice lacking traf6. Deficiencies in p75 signaling in traf6-/- animals resulted in a loss of p75-mediated apoptosis. In sympathetic neurons cultured from traf6+/+ superior cervical ganglia (SCGs), there was an increase in JNK activation and apoptosis after BDNF binding to p75; however, traf6-/- neurons did not respond. In vivo during naturally occurring cell death, there was a 55.6% reduction in TUNEL (terminal deoxynucleotidyl transferase-mediated biotinylated UTP nick end labeling)-positive cells in the SCG of postnatal day 4 traf6-/- animals relative to traf6+/+ littermates. These results indicate that TRAF6 plays an essential role in mediating p75 signal transduction and induction of apoptosis.

Animals↗
PubMed2004

A functional interaction between the p75 neurotrophin receptor interacting factors, TRAF6 and NRIF.

Neurotrophin signaling through the p75 receptor regulates apoptosis within the nervous system both during development and in response to injury. Whereas a number of p75 interacting factors have been identified, how these upstream factors function in a coordinated manner to mediate receptor signaling is still unclear. Here, we report a functional interaction between TRAF6 and the neurotrophin receptor interacting factor (NRIF), two proteins known to associate with the intracellular domain of the p75 neurotrophin receptor. The association between NRIF and TRAF6 was direct and occurred with both endogenous and ectopically expressed proteins. A KRAB repressor domain of NRIF and the carboxyl-terminal, receptor-binding region of TRAF6 were required for the interaction. Co-expression of TRAF6 increased the levels of NRIF protein and induced its nuclear translocation. Reciprocally, NRIF enhanced TRAF6-mediated activation of the c-Jun NH2-terminal kinase (JNK) by 3-fold, while only modestly increasing the stimulation of NF-kappaB. The expression of both NRIF and TRAF6 was required for reconstituting p75 activation of JNK in HEK293 cells, whereas NRIF mutants lacking the TRAF6 interaction domain were unable to substitute for the full-length protein in facilitating activation of the kinase. These results suggest that NRIF and TRAF6 functionally interact to facilitate neurotrophin signaling through the p75 receptor.

Animals↗
PubMed2004

The p75 neurotrophin receptor: multiple interactors and numerous functions.

The neurotrophin receptor p75 (p75NTR), is involved in a diverse array of cellular responses, including apoptosis, neurite outgrowth and myelination. Stimulation of p75NTR with neurotrophin can activate multiple downstream signals, including the small GTP binding protein Rac, the transcription factor NF-kappa B and the stress activated kinase, JNK. How these signals are generated and regulated to produce a specific cellular effect has yet to be fully elucidated. A number of proteins have recently been shown to interact with the intracellular domain of p75NTR. Here, we review these p75NTR interacting factors and the current evidence as to how they contribute to the functional effects of p75NTR activation.

Animals↗
PubMed2003

Activation of the transcription factor NF-kappaB in Schwann cells is required for peripheral myelin formation.

Peripheral myelin formation is initiated by axonal cues that trigger a differentiation program in associated Schwann cells. Here, we define one essential differentiation signal: activation of the transcription factor NF-kappaB. In rat sciatic nerves, NF-kappaB was highly upregulated in pre-myelinating Schwann cells, and then its expression progressively declined until it was nearly absent in adults. Similarly, in co-cultures of Schwann cells and sensory neurons, NF-kappaB activation paralleled myelination, and blocking its activity or using cells from mice lacking the NF-kappaB subunit p65 markedly attenuated myelination. Inhibiting NF-kappaB also prevented activation of Oct-6, a transcription factor induced by axonal contact and required for proper myelin formation. These results show that the activation of NF-kappaB is an essential signal for the progression of axon-associated Schwann cells into a myelinating phenotype.

Animals↗