Nerve Growth Factor (NGF) Down-regulates the Bcl-2 Homology 3 (BH3) Domain-only Protein Bim and Suppresses Its Proapoptotic Activity by Phosphorylation

Biswas, Subhas C.; Greene, Lloyd A.

doi:10.1074/jbc.m208086200

Cited by 169 publications

(182 citation statements)

References 31 publications

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“…Biswas and Greene showed that in PC12 cells, NGF can induce phosphorylation of Bim EL and that this is mediated via the MEK/ERK pathway, but the sites in Bim phosphorylated by ERK were not identified in this study. 44 ERK-mediated phosphorylation of Bim EL was also observed by Ley et al in serum-treated fibroblasts. 45 These authors showed that this phosphorylation leads to the ubiquitylation and degradation of Bim via the proteasome, that is, ERK-mediated phosphorylation reduces the stability of the Bim protein.…”

Section: Post-translational Regulation Of Bim and Bad By Phosphorylationsupporting

confidence: 68%

BH3-only proteins: key regulators of neuronal apoptosis

Ham

Towers²,

Gilley³

et al. 2005

Cell Death Differ

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The molecular mechanisms of neuronal apoptosis have been intensively studied because a considerable amount of apoptosis occurs during the normal development of the mammalian nervous system. This death is important for establishing neuronal populations of the correct size and for ensuring that neurons that contact inappropriate targets are eliminated. 1,2 A second reason for the interest in this area is that there is increasing evidence that apoptosis is one of the mechanisms of neuronal death following acute injuries to the nervous system, such as stroke or traumatic brain injury, and neurons often die by apoptosis in cell culture and animal models of chronic human neurodegenerative disorders. 2 The aim of this article is to review recent work on the function and regulation of the BH3-only subfamily of Bcl-2 proteins in neurons, with an emphasis on studies with sympathetic neurons, cerebellar granule neurons (CGNs) and motoneurons, the best studied in vitro models of neuronal apoptosis, and work that has involved the analysis of neurons from mutant mice.

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Section: Post-translational Regulation Of Bim and Bad By Phosphorylationsupporting

confidence: 68%

BH3-only proteins: key regulators of neuronal apoptosis

Ham

Towers²,

Gilley³

et al. 2005

Cell Death Differ

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“…NGF stimulation of PC12 cells was reported to promote the ERK1/2-dependent phosphorylation of Bim L as well as Bim EL , 26 while mutation of Ser44 (Ser104 in Bim EL ) abolished the ERK1/2-dependent phosphorylation of Bim L in FL5.12 cells. 32 Since Ser44 is a prolinedirected site, this suggested that ERK1/2 might directly phosphorylate Bim L .…”

Section: Phosphorylation Of Other Bim Isoforms By Erk1/2: a Question mentioning

confidence: 99%

“…There is some precedent for this in the ability of c-Jun to provide a docking site for JNK, which then phosphorylates the c-Jun dimer partner, JunD, which otherwise fails to bind JNK directly. 40 Despite these reports, 26,32 other studies suggest that Bim L is not phosphorylated following activation of ERK1/2. [29][30][31]33 Aside from caveats regarding different cell types or stimulation conditions, an alternative explanation for this confusion is that another Bim splice variant is actually being studied.…”

Section: Phosphorylation Of Other Bim Isoforms By Erk1/2: a Question mentioning

confidence: 99%

“…18 Subsequently, it has been shown that CEP-1347, a mixed-lineage kinase-3 inhibitor, prevents activation of JNK, the induction of Bim and reduces the apoptotic response to NGF withdrawal. 25,26 This mode of regulation may be confined to neuronal cell types since c-Jun is not required for Bim expression in fibroblasts 21 and JNK activation is not a ubiquitous response to withdrawal of survival factors.…”

Section: Bim As a Sensor Of Survival Factors And Trophic Supportmentioning

confidence: 99%

“…26 The use of U0126, an inhibitor of MEK1/2 and MEK5, implicated either the ERK1/2 or ERK5 pathways 26 (both activated by NGF), but the identity of the kinase responsible, the phosphorylation sites or the effect on Bim EL were not resolved. Subsequent studies in fibroblasts, using the conditional kinase DRaf-1:ER*, confirmed that selective activation of the ERK1/2 pathway was sufficient to promote the phosphorylation of Bim EL at multiple sites but did not apparently influence the phosphorylation of Bim S or Bim L .…”

Section: Phosphorylation Of Bim El By Erk1/2mentioning

confidence: 99%

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Regulatory phosphorylation of Bim: sorting out the ERK from the JNK

et al. 2005

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Prosurvival and proapoptotic intracellular signaling in rat spiral ganglion neurons in vivo after the loss of hair cells

Alam

Robinson

Huang

et al. 2007

J of Comparative Neurology

100

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Neurons depend on afferent input for survival. Rats were given daily kanamycin injections from P8 to P16 to destroy hair cells, the sole afferent input to spiral ganglion neurons (SGNs). Most SGNs die over an approximately 14-week period after deafferentation. During this period, the SGN population is heterogeneous. At any given time, some SGNs exhibit apoptotic markers--TUNEL and cytochrome c loss--whereas others appear nonapoptotic. We asked whether differences among SGNs in intracellular signaling relevant to apoptotic regulation could account for this heterogeneity. cAMP response element binding protein (CREB) phosphorylation, which reflects neurotrophic signaling, is reduced in many SGNs at P16, P23, and P32, when SGNs begin to die. In particular, nearly all apoptotic SGNs exhibit reduced phospho-CREB, implying that apoptosis is due to insufficient neurotrophic support. However, >32% of SGNs maintain high phospho-CREB levels, implying access to neurotrophic support. By P60, when approximately 50% of the SGNs have died, phospho-CREB levels in surviving neurons are not reduced, and SGN death is no longer correlated with reduced phospho-CREB. Activity in the proapoptotic Jun N-terminal kinase (JNK)-Jun signaling pathway is elevated in SGNs during the cell death period. This too is heterogeneous: <42% of the SGNs exhibited high phospho-Jun levels, but nearly all SGNs undergoing apoptosis exhibited elevated phospho-Jun. Thus, heterogeneity among SGNs in prosurvival and proapoptotic signaling is correlated with apoptosis. SGN death following deafferentation has an early phase in which apoptosis is correlated with reduced phospho-CREB and a later phase in which it is not. Proapoptotic JNK-Jun signaling is tightly correlated with SGN apoptosis.

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Nerve Growth Factor (NGF) Down-regulates the Bcl-2 Homology 3 (BH3) Domain-only Protein Bim and Suppresses Its Proapoptotic Activity by Phosphorylation

Cited by 169 publications

References 31 publications

BH3-only proteins: key regulators of neuronal apoptosis

BH3-only proteins: key regulators of neuronal apoptosis

Regulatory phosphorylation of Bim: sorting out the ERK from the JNK

Prosurvival and proapoptotic intracellular signaling in rat spiral ganglion neurons in vivo after the loss of hair cells

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