A peptide inhibitor of cytochrome
            <i>c</i>
            /inositol 1,4,5-trisphosphate receptor binding blocks intrinsic and extrinsic cell death pathways

Boehning, Darren; Rossum, Damian B. van; Patterson, Randen L.; Snyder, Solomon H.

doi:10.1073/pnas.0409650102

Cited by 117 publications

(119 citation statements)

References 44 publications

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“…This feedforward amplification manifested by sustained increases in cytosolic Ca 2 þ during early apoptosis elicits massive release of cytochrome c from all mitochondria. 86 For instance, in neurons, cytochrome c release at a focal point within the cell such as the cell body or neurites can create a wave of cytochrome c release throughout the cell body and cause further damage.…”

Section: Gangliosides As Propagators Of the Er Stress-and Mitochondrimentioning

confidence: 99%

Gangliosides as apoptotic signals in ER stress response

d’Azzo

Tessitore²,

Sano

2006

Cell Death Differ

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Renewed attention has been given lately to gangliosides and to their function as intracellular messengers of the adaptive responses to stress. Gangliosides are vital components of cell membranes; therefore, deleterious consequences can result from changes in their chemical composition and concentration, that is, membrane dynamics and structure can be altered as can the behavior of other membrane proteins. The importance of gangliosides in human health is evident in neurodegenerative diseases associated with defects in their degradation. As key modulators of intracellular calcium flux, gangliosides are involved in cellular processes downstream of calcium signaling. In this review, we focus on the effect of ganglioside accumulation on the endoplasmic reticulum calcium homeostasis and on the integrity of the mitochondrial membranes. We discuss how these events elicit an apoptotic program that ultimately leads to cell death. Owing to interorganelle crosstalk, these events are not necessarily self-contained, and gangliosides may serve as the common factor.

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Section: Gangliosides As Propagators Of the Er Stress-and Mitochondrimentioning

confidence: 99%

Gangliosides as apoptotic signals in ER stress response

d’Azzo

Tessitore²,

Sano

2006

Cell Death Differ

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“…Through these regulatory mechanisms, IP 3 R modulates diverse cellular functions, which include, but are not limited to, contraction/excitation, gene expression, cellular growth and apoptosis. 13,19 On the basis of these premises, we decided to investigate the contribution of IP 3 R to the regulation of autophagy. Here, we report that the depletion of IP 3 R or its inhibition triggers rapid autophagy affecting both ER and mitochondria.…”

mentioning

confidence: 99%

Regulation of autophagy by the inositol trisphosphate receptor

et al. 2007

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The reduction of intracellular 1,4,5-inositol trisphosphate (IP 3 ) levels stimulates autophagy, whereas the enhancement of IP 3 levels inhibits autophagy induced by nutrient depletion. Here, we show that knockdown of the IP 3 receptor (IP 3 R) with small interfering RNAs and pharmacological IP 3 R blockade is a strong stimulus for the induction of autophagy. The IP 3 R is known to reside in the membranes of the endoplasmic reticulum (ER) as well as within ER-mitochondrial contact sites, and IP 3 R blockade triggered the autophagy of both ER and mitochondria, as exactly observed in starvation-induced autophagy. ER stressors such as tunicamycin and thapsigargin also induced autophagy of ER and, to less extent, of mitochondria. Autophagy triggered by starvation or IP 3 R blockade was inhibited by Bcl-2 and Bcl-X L specifically targeted to ER but not Bcl-2 or Bcl-X L proteins targeted to mitochondria. In contrast, ER stress-induced autophagy was not inhibited by Bcl-2 and Bcl-X L . Autophagy promoted by IP 3 R inhibition could not be attributed to a modulation of steady-state Ca 2 þ levels in the ER or in the cytosol, yet involved the obligate contribution of Beclin-1, autophagy-related gene (Atg)5, Atg10, Atg12 and hVps34. Altogether, these results strongly suggest that IP 3 R exerts a major role in the physiological control of autophagy. The first step of macroautophagy consists in the gradual envelopment of cytoplasmic material (cytosol and/or organelles) in the phagophore, a cistern that finally sequesters cytoplasmic material in autophagosomes (also called autophagic vacuoles (AVs)) lined by two membranes. Autophagosomes then undergo a progressive maturation by fusion with endosomes and/or lysosomes. This latter step creates autolysosomes in which the inner membrane as well as the luminal content of the AVs is degraded by lysosomal enzymes. The process of autophagy is controlled by a series of evolutionary conserved genes, the atg genes, whose products are essential for specific steps of the autophagic process. 1,2One of the strongest triggers of autophagy is nutrient stress. 3,4 In response to starvation, cells degrade nonessential components thereby generating nutrients for meeting the cell's energetic demand as well as for vital biosynthetic reactions. In such circumstances, when autophagy is an adaptation, inhibition of autophagy has a negative impact on cell survival. For example, mice lacking the atg5 gene survive without any major developmental defect until birth, yet succumb to the stressful neonatal period unless puppies are force-fed with milk within the first hours after birth.5 Similarly, human cell lines cultured in nutrient-free media mount a cytoprotective autophagic response. Suppression of autophagy by chemical inhibitors or knockdown of essential genes thus sensitize cells to starvation-induced cell death. 6,7Autophagy inhibition also sensitizes cells to the depletion of obligatory growth (or survival) factors resulting in a decrease of nutrient import through the plasma membrane. For example...

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“…The wide use of acylation in general for peptide delivery (Adachi et al, 1999b;Boehning et al, 2005) and of myristoylation in particular (Eichholtz et al, 1993;Kelemen et al, 2002;Niv et al, 2004) made it likely that also the present peptides entered into the cytoplasm. To confirm this assumption, 100 mM of fluorescence-labelled derivatives of peptide 18AD and its non-myristoylated equivalent were added to suspensions of 7TD1 cells.…”

Section: Resultsmentioning

confidence: 99%

“…In contrast, inhibition by the somatostatin analogs octreotide or RC-160 of the proliferation of myeloma cell lines (Georgii-Hemming et al, 1999), or a human oral carcinoma cell line (Dasgupta et al, 2000), respectively, occurred in the nM concentration range, and the latter peptide was more potent when myristoylated. Also the displacement of cytochrome C from IP3-receptor and caspase inhibition by a BODIPY-conjugated acidic peptide occurred with IC 50 in the nM range (Boehning et al, 2005).…”

Section: Proliferation Inhibition By a Gp130-derived Peptide A Haushementioning

confidence: 97%

“…The lack of disruption of the Hckgp130 complex by peptide 18AD added to lysates may be explained by altered distribution and accessibility of the myristoylated peptide in lysates containing traces of detergent. The minimal dose of peptide 18ADnm Proliferation inhibition by a gp130-derived peptide A Hausherr et al required for disrupting the association of gp130 and Hck was B50 mM (Figure 6b), whereas often peptide concentrations of 20 mM and below were sufficient for displacing proteins from associations (Adachi et al, 1999a, b;Kardinal et al, 2000;Boehning et al, 2005), although up to 1 mM was used for disrupting pre-existing complexes (Posern et al, 1998). The association of Hck and gp130 and its interruption by peptide 18AD were confirmed by peptide competition and affinity pull-down analyses using overexpression of the involved proteins and applying a peptide concentration of 750 mM (Figure 6c, d).…”

Section: Proliferation Inhibition By a Gp130-derived Peptide A Haushementioning

confidence: 99%

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Inhibition of IL-6-dependent growth of myeloma cells by an acidic peptide repressing the gp130-mediated activation of Src family kinases

Hausherr¹,

Tavares²,

Schäffer³

et al. 2007

Oncogene

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An acidic domain (AD) of gp130 was previously found to interact with the Src family kinase (SFK) Hck. Here, the influence of myristoylated peptides derived from this AD was assessed in the mouse myeloma cell line, 7TD1. The IL-6-dependent growth of 7TD1 cells was reduced by B75%, if 100 lM of myristoylated 18mer peptide (18AD) was included in the growth medium, but was unaffected by a control peptide with scrambled sequence (18sc). A similar differential inhibition by peptides 18AD and 18sc was observed for the erythropoietin-dependent growth of BaF-EH cells expressing chimeric erythropoietin receptor-gp130 and human Hck and for the human myeloma cell line INA-6. While the peptide 18AD concentration inhibiting 50% was B30 lM in 7TD1 and BaF-EH cells, peptide 18AD did not significantly inhibit growth of IL-6-independent MM1.S myeloma and OKT1 hybridoma cells or of BaF-EH cells supplied with IL-3. Treatment with 100 lM peptide 18AD caused the same degree or 60% of apoptosis induction as IL-6 deprivation in 7TD1 or INA-6 cells, respectively. Co-immunoprecipitation experiments revealed that peptide 18AD interfered with the association of Hck and gp130 in 7TD1 lysates in a concentrationdependent manner. IL-6-treatment of INA-6 cells induced the kinase activities of Fyn, Lyn and Hck, but not Src, and the IL-6-induced SFK activities were inhibited by peptide 18AD. Expression in 7TD1 cells of a kinaseinactive Hck mutant (K269R) elicited a dominantnegative effect on cell number increases providing further evidence that SFKs are required for gp130 signalling in myeloma cells.

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A peptide inhibitor of cytochrome c /inositol 1,4,5-trisphosphate receptor binding blocks intrinsic and extrinsic cell death pathways

Cited by 117 publications

References 44 publications

Gangliosides as apoptotic signals in ER stress response

Gangliosides as apoptotic signals in ER stress response

Regulation of autophagy by the inositol trisphosphate receptor

Inhibition of IL-6-dependent growth of myeloma cells by an acidic peptide repressing the gp130-mediated activation of Src family kinases

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