IGF-1 inhibits the mitochondrial apoptosis program in mesangial cells exposed to high glucose

Kang, Barinder; Urbonas, Arunas; Baddoo, Andrew; Baskin, S. I.; Malhotra, Ashwani; Meggs, Leonard G.

doi:10.1152/ajprenal.00209.2003

Cited by 69 publications

(81 citation statements)

References 50 publications

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“…Mouse monoclonal anti-cytochrome c antibody (BD Biosciences) was used at a dilution of 1:250, and the protein was detected by horseradish peroxidase-linked secondary antibody (1:3,000 dilution). Cytochrome c was detected and quantified in the cytosolic fraction as well as in the lysate fraction from different groups as described (22,23). Mitochondrial fractions were also probed for Bad and phospho-Bad Ser112 (1:500 antibody dilution; Cell Signaling); Erk and phosphoErk (1: 1,000 antibody dilution; Cell Signaling and Santa Cruz).…”

Section: Methodsmentioning

confidence: 99%

“…Activation of the protein kinase C (PKC) family of serine/threonine kinases has been well documented in diabetic myocardium (20,31) and is implicated in the modulation of numerous biological responses (38,41,42). Hyperglycemia and DM are associated with an exponential increase in oxidative stress (36), which is an event linked to the activation of the apoptosis gene program (21)(22)(23). The ε-isozyme of the PKC family transmits a survival signal in cardiac muscle cells (9) that targets the Bcl-2 family of proteins and mitochondria (3,4).…”

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confidence: 99%

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PKC-ε-dependent survival signals in diabetic hearts

Malhotra¹,

Begley²,

Kang³

et al. 2005

American Journal of Physiology-Heart and Circulatory Physiology

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Diabetes mellitus is complicated by the development of a primary cardiomyopathy, which contributes to the excess morbidity and mortality of this disorder. The protein kinase C (PKC) family of isozymes plays a key role in the cardiac phenotype expressed during postnatal development and in response to pathological stimuli. Hyperglycemia is an activating signal for cardiac PKC isozymes that modulate a myriad of cell events including cell death and survival. The ε-isozyme of the PKC family transmits a powerful survival signal in cardiac muscle cells. Accordingly, to test the hypothesis that endogenous activation of cardiac PKC-ε will protect against hyperglycemic cell injury and left ventricular dysfunction, diabetes mellitus was induced using streptozotocin in genetically engineered mice with cardiac-specific expression of the PKC-ε translocation activator [ψε-receptors for activated C kinase (ψε-RACK)]. The results demonstrate a striking PKC-ε cardioprotective phenotype in diabetic ψε-RACK (ε-agonist) mice that is characterized by inhibition of the hyperglycemia apoptosis signal, attenuation of hyperglycemia-mediated oxidative stress, and preservation of parameters of left ventricular pump function. Hearts of diabetic ε-agonist mice exhibited selective trafficking of PKC-ε to membrane and mitochondrial compartments, phosphorylation/inactivation of the mitochondrial Bad protein, and inhibition of cytochrome c release. We conclude that activation of endogenous PKC-ε in hearts of diabetic ε-agonist mice promotes the survival phenotype, attenuates markers of oxidative stress, and inhibits the negative inotropic properties of chronic hyperglycemia.

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Section: Methodsmentioning

confidence: 99%

mentioning

confidence: 99%

PKC-ε-dependent survival signals in diabetic hearts

Malhotra¹,

Begley²,

Kang³

et al. 2005

American Journal of Physiology-Heart and Circulatory Physiology

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“…For preparation of mitochondrial and cytosolic fractions, cell homogenates were centrifuged at 700 g for 10 min at 4 1C to separate nuclei (pellet), and supernatants were centrifuged at 10 000 g for 25 min at 4 1C to separate mitochondria (pellet) and cytosol (supernatant) (ApoAlert Cell Fractionation kit, Clontech; Kang et al, 2003). Nuclear fractions were isolated per the manufacturer's protocol (Nuclear Extraction kit, Panomics, Fremont, CA, USA).…”

Section: Subcellular Fractionationsmentioning

confidence: 99%

“…A shift in fluorescence from 590 to 527 nm indicates loss of membrane potential. Cells were incubated with JC-1 (10 ng/ml), for 30 min at 37 1C and analyzed and quantified by flow cytometry (Kang et al, 2003).…”

Section: Mitochondrial Membrane Potential Determinationmentioning

confidence: 99%

A novel pro-apoptotic function of RACK1: suppression of Src activity in the intrinsic and Akt pathways

Mamidipudi

Cartwright

2009

Oncogene

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Earlier we showed that RACK1 regulates growth of human colon cells by suppressing Src activity at G 1 and mitotic checkpoints. Here, we show that RACK1 also induces apoptosis of the cells, partly by inhibiting Src. In the intrinsic pathway, RACK1 inhibits expression of anti-apoptotic Bcl-2 and Bcl-X L , induces expression of proapoptotic Bim, targets Bim and Bax to the mitochondria, induces oligomerization of Bax (which requires Bim and inhibition of Src), depolarizes mitochondria membranes, releases cytochrome c, and activates caspases-9 and -3 and death substrates. Bax and Bim are required for RACK1-mediated mitochondrial cell death. RACK1-induced oligomerization of Bax is required for staurosporine-mediated cell death. RACK1 also induces apoptosis by blocking Src activation of the Akt cell survival pathway. This leads to activation of the transcription factor FOXO3, a potent inducer of apoptosis and G 1 arrest. Collectively, our results show that RACK1, partly by inhibiting Src, promotes mitochondrial cell death and blocks Akt-mediated cell survival. Thus, RACK1 inhibits growth and induces death of colon cells. Exploitation of these dual functions could lead to novel colon cancer therapies that mimic RACK1 function.

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“…Further, both PKC and PKC␦ have been implicated in mitochondrial K ATP channel regulation in ischemic preconditioning (Cohen et al 2000;Chen et al 2001). Finally, ERK and JNK kinases are targeted to mitochondria to phosphorylate apoptotic proteins, including Bcl-xl, Bcl-2, and BAD, and regulate apoptosis (Deng et al 2000;Kang et al 2003;Schroeter et al 2003;Brichese et al 2004). In short, Ser/Thr protein kinase targeting to mitochondria has significant impact on pro-or anti-apoptotic factors, respiration, and ionic channel activity, illustrating the important role of mitochondria protein phosphorylation in cellular signaling.…”

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confidence: 99%

A novel mitochondrial matrix serine/threonine protein phosphatase regulates the mitochondria permeability transition pore and is essential for cellular survival and development

Lü

Ren²,

Kôrge³

et al. 2007

Genes Dev.

132

160

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Mitochondria play a central role in the regulation of programmed cell death signaling. Here, we report the finding of a mitochondrial matrix-targeted protein phosphatase 2C family member (PP2Cm) that regulates mitochondrial membrane permeability transition pore (MPTP) opening and is essential for cell survival, embryonic development, and cardiac function. PP2Cm is highly conserved among vertebrates, with the highest expression levels detected in the heart and brain. Small hairpin RNA (shRNA)-mediated knockdown of PP2Cm resulted in cell death associated with loss of mitochondrial membrane potential in cultured cardiac mycoytes and an induction of hepatocyte apoptosis in vivo. PP2Cm-deficient mitochondria showed elevated susceptibility to calcium-induced MPTP opening, whereas mitochondrial oxidative phosphorylation activities were not affected. Finally, inactivation of PP2Cm in developing zebrafish embryos caused abnormal cardiac and neural development as well as heart failure associated with induced apoptosis. These data suggest that PP2Cm is a novel mitochondrial protein phosphatase that has a critical function in cell death and survival, and may play a role in regulating the MPTP opening.[Keywords: Mitochondrial permeability transition pore; protein phosphatase; cell death; heart failure; developmental defects; zebrafish] Supplemental material is available at http://www.genesdev.org.

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IGF-1 inhibits the mitochondrial apoptosis program in mesangial cells exposed to high glucose

Cited by 69 publications

References 50 publications

PKC-ε-dependent survival signals in diabetic hearts

PKC-ε-dependent survival signals in diabetic hearts

A novel pro-apoptotic function of RACK1: suppression of Src activity in the intrinsic and Akt pathways

A novel mitochondrial matrix serine/threonine protein phosphatase regulates the mitochondria permeability transition pore and is essential for cellular survival and development

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