The proapoptotic factor Nix is coexpressed with Bcl-xL during terminal erythroid differentiation

Aerbajinai, Wulin; Giattina, Mara; Lee, Y. Terry; Raffeld, Mark; Miller, Jeffery L.

doi:10.1182/blood-2002-11-3324

Cited by 100 publications

(83 citation statements)

References 24 publications

(20 reference statements)

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“…Nix protein expression was also upregulated in response to both stimuli. Our data, together with two recent reports describing Nix upregulation during erythroid differentiation (Aerbajinai et al, 2003) and cardiomyopathy (Yussman et al, 2002), support a more generalized proapoptotic role for Nix protein within the cell.…”

Section: Discussionsupporting

confidence: 87%

“…Several studies have implicated Nix in hypoxiainduced cell death (Chen et al, 1999;Bruick, 2000;Yussman et al, 2002;Aerbajinai et al, 2003). Increases in Nix mRNA expression were first reported by Bruick who exposed CHO-K1 cells to hypoxia/serum deprivation (Bruick, 2000), although in that study the effect on Nix protein was not investigated.…”

Section: Discussionmentioning

confidence: 99%

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Differential Profile of Nix Upregulation and Translocation during Hypoxia/Ischaemia in Vivo Versus in Vitro

Birse-Archbold

Kerr

Jones

et al. 2005

J Cereb Blood Flow Metab

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Nix, a hypoxia-sensitive member of the Bcl-2 family, is upregulated at the mRNA level during hypoxia through induction of a hypoxia-inducible factor-1a (HIF-1a) response element in its promoter sequence. However, the mechanism(s) regulating Nix protein activation remain unclear. The present studies examine Nix protein expression and subcellular distribution in response to hypoxic stimuli in vivo and in culture and to two disparate apoptotic stimuli in vitro. Upregulation and translocation of Nix (by day 5) in hypoxic/serum-deprived CHO-K1 cells, was preceded by Bax activation (by day 4) and caspase-3 processing (by day 2), suggesting that initiation of cell death in vitro is a Nixindependent event. In contrast, an early Nix response (upregulation and translocation to the mitochondria) was observed after 6 h of middle cerebral artery occlusion in the rat. Nix translocation was observed in the ipsilateral cortex and striatum before other histological (infarct development, neuronal loss, apoptotic body formation) or biochemical (Bax activation or caspase-3 cleavage) markers of damage were detected. While fundamental differences between hypoxia/ischaemia in culture and in vivo likely explain the different temporal profiles of Nix, Bax, and caspase-3 activation observed, these studies show that like Bax, mitochondrial accumulation is a common event during Nix activation. These are the first studies to show upregulation and translocation of Nix in the ischaemic brain and suggest Nix to be a novel therapeutic target in ischaemic research. Moreover, Nix upregulation in staurosporine-treated SH-SY5Y cells and dexamethasone-treated A1.1 cells supports a more generalized role for Nix in apoptotic cell death.

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Section: Discussionsupporting

confidence: 87%

Section: Discussionmentioning

confidence: 99%

Differential Profile of Nix Upregulation and Translocation during Hypoxia/Ischaemia in Vivo Versus in Vitro

Birse-Archbold

Kerr

Jones

et al. 2005

J Cereb Blood Flow Metab

View full text Add to dashboard Cite

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“…For MnSOD and Bcl-X L mRNA analysis, cDNA was synthesized from 2 mg total RNA per sample, using oligo dT primers. PCR was performed in a Perkin-Elmer Model 480 Thermocycler (Emeryville, CA, USA) by incubating 0.2-0.4 mg of the templates with 6.2 mM of specific primers for mGlu1 and mGlu5 receptors, 88 for b-actin (sense 5 0 -GAAGAGCTAC GAGCTGCCTGA-3 0 ; antisense 5 0 -TGATCTTCATTCTGCTGGGTG-3 0 ), 6.6 mM of specific primers for MnSOD (sense 5 0 -GGCGCCCTGGAACCT CACAT-3 0 ; antisense 5 0 -ACACATCAATCCCCAGCAGT-3 0 ) according to Bernard et al, 33 and 7.3 mM of specific primers for Bcl-X L (sense 5 0 -GGATGGCCACTTACCTGA-3 0 ; antisense 5 0 -CGGTTGAAGCGTTCCTG-3 0 ) according to Aerbajinai et al 89 The templates were heated at 941C for 5 min. In total, 37 (mGlu1, mGlu5) or 35 (MnSOD, Bcl-X L , b-actin) temperature cycles were conducted as follows: denaturation at 941C for 1 min, annealing at 561C (mGlu1, mGlu5, MnSOD, b-actin) or 611C (Bcl-X L ) for 1 min and extension at 721C for 1 min.…”

Section: Reverse Transcriptase-polymerase Chain Reaction (Rt-pcr)mentioning

confidence: 99%

NF-κB factor c-Rel mediates neuroprotection elicited by mGlu5 receptor agonists against amyloid β-peptide toxicity

et al. 2005

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Opposite effects of nuclear factor-jB (NF-jB) on neuron survival rely on activation of diverse NF-jB factors. While p65 is necessary for glutamate-induced cell death, c-Rel mediates prosurvival effects of interleukin-1b. However, it is unknown whether activation of c-Rel-dependent pathways reduces neuron vulnerability to amyloid-b (Ab), a peptide implicated in Alzheimer's disease pathogenesis. We show that neuroprotection elicited by activation of metabotropic glutamate receptors type 5 (mGlu5) against Ab toxicity depends on cRel activation. Ab peptide induced NF-jB factors p50 and p65. The mGlu5 agonists activated c-Rel, besides p50 and p65, and the expression of manganese superoxide dismutase (MnSOD) and Bcl-X L . Targeting c-Rel expression by RNA interference suppressed the induction of both antiapoptotic genes. Targeting c-Rel or Bcl-X L prevented the prosurvival effect of mGlu5 agonists. Conversely, c-Rel overexpression or TATBcl-X L addition rescued neurons from Ab toxicity. These data demonstrate that mGlu5 receptor activation promotes a c-Reldependent antiapoptotic pathway responsible for neuroprotection against Ab peptide.

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“…On the other hand, GATA-1 remains uncleaved in erythroid cells undergoing terminal differentiation despite caspase activation (Zermati et al, 2001), which could be related to protection of GATA-1 by a chaperone protein in Epo-stimulating cells (unpublished data). Altogether, these results suggest that the mitochondrial pathway to caspase activation is tightly regulated along the erythroid pathway of differentiation, a regulation that involves Bcl-X L and probably other Bcl-2-related proteins at the mitochondrion level (Aerbajinai et al, 2003). Surprisingly enough, a membrane-associated Bcl-X L was reported also to protect mature erythrocytes, which lack mitochondria, from death (Walsh et al, 2002).…”

Section: Mitochondria Caspases and Hematopoietic Cell Differentiationmentioning

confidence: 91%

Mitochondria in hematopoiesis and hematological diseases

et al. 2006

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The proapoptotic factor Nix is coexpressed with Bcl-xL during terminal erythroid differentiation

Cited by 100 publications

References 24 publications

Differential Profile of Nix Upregulation and Translocation during Hypoxia/Ischaemia in Vivo Versus in Vitro

Differential Profile of Nix Upregulation and Translocation during Hypoxia/Ischaemia in Vivo Versus in Vitro

NF-κB factor c-Rel mediates neuroprotection elicited by mGlu5 receptor agonists against amyloid β-peptide toxicity

Mitochondria in hematopoiesis and hematological diseases

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