Up-regulation of Hrk, a regulator of cell death, in retinal ganglion cells of axotomized rat retina

Wakabayashi, Taku; Kosaka, Jun; Hommura, Sachiko

doi:10.1016/s0304-3940(01)02487-9

Cited by 27 publications

(28 citation statements)

References 15 publications

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“…9,10 The initial studies demonstrated that Hrk expression is relatively restricted to the brain and in the lymphoid tissues, 9,10 suggesting that Hrk may have a specific role in these tissues. Consistent with this idea, induction of Hrk expression has been demonstrated in NGF-deprived sympathetic neurons, 9 in apoptosis of cortical neurons after amyloid-b protein exposure, 11 in apoptotic cerebellar granule neurons cultured under a low potassium condition, 12 in spinal neurons of amyotrophic lateral sclerosis patients, 13 in retinal ganglion cells of axontomized retina, 14 as well as in growth factor-deprived hematopoietic cells. 15 Although Hrk expression has also been detected in blastomere undergoing fragmentation during embryonic development, 16 these characteristic patterns of Hrk expression strongly suggest that this BH3-only protein may have a specific role in initiating neuronal and hematopoietic cell apoptosis under physiological and pathological conditions.…”

Section: Introductionmentioning

confidence: 57%

Physical and functional interaction between BH3-only protein Hrk and mitochondrial pore-forming protein p32

Sunayama

Ando²,

Itoh³

et al. 2004

Cell Death Differ

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Bcl-2 homology domain (BH) 3-only proteins of the proapoptotic Bcl-2 subfamily play a key role as initiators of mitochondria-dependent apoptosis. To date, at least 10 mammalian BH3-only proteins have been identified, and it is now being realized that they have different roles and mechanisms of regulation in the transduction of apoptotic signals to mitochondria. Hrk/DP5 is one of the mammalian BH3-only proteins implicated in a variety of physiological and pathological apoptosis, yet the molecular mechanism involved in Hrk-mediated apoptosis remains poorly understood. In an attempt to identify cellular proteins participating in Hrkmediated apoptosis, we have conducted yeast two-hybrid screening for Hrk-interacting proteins and isolated p32, a mitochondrial protein that has been shown to form a channel consisting of its homotrimer. In vitro binding, co-immunoprecipitation, as well as immunocytochemical analyses verified specific interaction and colocalization of Hrk and p32, both of which depended on the presence of the highly conserved C-terminal region of p32. Importantly, Hrk-induced apoptosis was suppressed by the expression of p32 mutants lacking the N-terminal mitochondrial signal sequence (p32 (74-282)) and the conserved C-terminal region (p32 (1-221)), which are expected to inhibit binding of Hrk competitively to the endogenous p32 protein and to disrupt the channel function of p32, respectively. Furthermore, small interfering RNA-mediated knockdown of p32 conferred protection against Hrk-induced apoptosis. Altogether, these results suggest that p32 may be a key molecule that links Hrk to mitochondria and is critically involved in the regulation of Hrk-mediated apoptosis.

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Section: Introductionmentioning

confidence: 57%

Physical and functional interaction between BH3-only protein Hrk and mitochondrial pore-forming protein p32

Sunayama

Ando²,

Itoh³

et al. 2004

Cell Death Differ

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“…Hence, two options are available to photoreceptors in response to apoptotic stimuli. First, components required for caspase-dependent apoptosis may be reexpressed; for instance, Bim and Hrk are upregulated in axotomized retinal ganglion cells before apoptosis (Wakabayashi et al, 2002;Napankangas et al, 2003). Alternatively, a caspase-independent death pathway, which we observed in a number of models of retinal degeneration, may be activated.…”

Section: Discussionmentioning

confidence: 96%

Bim Expression Indicates the Pathway to Retinal Cell Death in Development and Degeneration

Doonan

Donovan²,

Gómez‐Vicente³

et al. 2007

J. Neurosci.

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Programmed cell death (PCD) during development of the mouse retina involves activation of the mitochondrial pathway. Previous work has shown that the multidomain Bcl-2 family proteins Bax and Bak are fundamentally involved in this process. To induce mitochondrial membrane permeabilization, Bax and Bak require that prosurvival members of the family be inactivated by binding of "BH3-only" members. We showed previously that the BH3-only protein BimEL is highly expressed during postnatal retinal development but decreases dramatically thereafter. The purpose of this study was to investigate a possible role for Bim, in retinal development and degeneration, upstream of Bax and Bak. Bim Ϫ/Ϫ mice analyzed for defective retinal development exhibit an increase in retinal thickness and a delay in PCD, thereby confirming a role for Bim. We also demonstrate that in response to certain death stimuli, bim ϩ/ϩ retinal explants upregulate BimEL leading to caspase activation and cell death, whereas bim Ϫ/Ϫ explants are resistant to apoptosis. Finally, we analyzed Bim expression in the retinal degeneration (rd) mouse, an in vivo model of retinal degeneration. Bim isoforms, which decrease during development, are not reexpressed during retinal degeneration and ultimately photoreceptor cells die by a caspase-independent mechanism. Thus, we conclude that in cases in which BimEL is reexpressed during pathological cell death, developmental cell death pathways are reactivated. However, the absence of BimEL expression correlates with caspase-independent death in the rd model.

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“…28, 29 As well as being induced by NGF withdrawal, the dp5 mRNA also increases in level in CGNs deprived of KCl and serum, cortical neurons treated with neurotoxic concentrations of amyloid b peptide, retinal ganglion cells of axotomized rat retinas, axotomized postnatal mouse motoneurons and in the spinal cords of human amyotrophic lateral sclerosis (ALS) patients compared to non-ALS controls. 27,[30][31][32][33] The function of the DP5 protein in neurons has been studied in gain-of-function and loss-of-function experiments. Overexpression of DP5 in microinjected sympathetic neurons induces apoptosis and this can be inhibited by coexpression of antiapoptotic Bcl-2.…”

Section: Ngf Withdrawal-induced Death Requires Transcription and Invomentioning

confidence: 99%

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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Up-regulation of Hrk, a regulator of cell death, in retinal ganglion cells of axotomized rat retina

Cited by 27 publications

References 15 publications

Physical and functional interaction between BH3-only protein Hrk and mitochondrial pore-forming protein p32

Physical and functional interaction between BH3-only protein Hrk and mitochondrial pore-forming protein p32

Bim Expression Indicates the Pathway to Retinal Cell Death in Development and Degeneration

BH3-only proteins: key regulators of neuronal apoptosis

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