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Stress Induction of HSP regulatiosn

P53 signaling pathway

Ras Signaling Pathway

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Apoptosis signaling in response to

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Cell Survial


J Neurosci Res. 2006 Mar 6; [Epub ahead of print]

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A BAD link to mitochondrial cell death in the cochlea of mice with noise-induced hearing loss.

Vicente-Torres MA, Schacht J.

Kresge Hearing Research Institute,
University of Michigan, Ann Arbor, Michigan.

Acoustic overstimulation induces calcium overload and activation of mitochondria-mediated cell death pathways in outer hair cells (OHC) of the cochlea. However, it is not known whether these events are interrelated or independent. We have recently reported that the calcium-dependent phosphatase calcineurin is activated in OHC following noise exposure and now postulate that calcium overload triggers mitochondria-mediated death pathways through activation of Bcl-2-associated death promoter (BAD) by calcineurin. CBA/J mice were exposed to broadband noise (2-20 kHz), causing a permanent threshold shift of about 40 dB at 12 and 20 kHz, corresponding to damage in the middle and basal turns of the cochlea. Loss of OHC in the basal region was evident in surface preparations. BAD immunostaining in control animals had a cytoplasmic distribution in the cells of the organ of Corti. Five hours after acoustic overstimulation, mitochondria and BAD redistributed to the perinuclear region of OHC in the basal and middle turns but not in the apical turn. The nonapoptotic phospho-BAD (Ser 112) was up-regulated in cells undamaged by noise (supporting cells and inner hair cells) but not in OHC. These data establish a connection between calcium overload and mitochondria-mediated death pathways in OHC and also suggest a dual role for BAD. The translocation of BAD to the mitochondria in degenerating cells is indicative of the activation of its proapoptotic capacity, whereas up-regulation of phospho-BAD is consistent with a nonapoptotic role of BAD in less vulnerable cells. (c) 2006 Wiley-Liss, Inc.

PMID: 16521126 [PubMed - as supplied by publisher]



Invest Ophthalmol Vis Sci. 2006 Apr;47(4):1620-1629.

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Inactivation of the Akt Survival Pathway during Photoreceptor Apoptosis in the Retinal Degeneration Mouse.

Jomary C, Cullen J, Jones SE.

Retinitis Pigmentosa Research Unit, The Rayne Institute, Wolfson Centre for Age-Related Diseases, School of Biomedical and Health Sciences, King's College London, St. Thomas' Hospital, London, United Kingdom.

PURPOSE: Previous work has indicated that the serine-threonine protein kinase Akt is a general mediator of cellular survival signals and that loss of Akt-mediated signaling can lead to the activation of apoptosis. This study was conducted to establish whether regulation of the Akt survival pathway mechanisms is implicated in the induction of apoptosis during photoreceptor cell death in the rd mouse model of retinal degeneration. METHODS: Quantitative Western blot analysis and immunocytochemistry were used to examine the activation status and localization of key components of the Akt signaling cascade (Akt, BAD, Forkhead [FKHR], HSP27, mitogen-activated protein (MAP) kinase kinase-3 and -6 (MKK3/6), the tumor-suppressor phosphatase PTEN, and the cytoplasmic protein-tyrosine kinase cSrc-p60), in the retina of the rd mouse in comparison with the control. The time points examined spanned the period of photoreceptor degeneration. RESULTS: In the period up to the peak of photoreceptor apoptosis at postnatal day 15, dysregulation of the survival pathway was identified at several levels, including deactivation of both Akt itself and its downstream transcription factor target Forkhead (FKHR) and activation of the upstream negative regulator PTEN. CONCLUSIONS: Taken in conjunction with previous studies, the data support a model in which photoreceptor cell death in the rd mouse is the result of combined inactivation of the Akt survival pathway and the activation of the two major apoptotic pathways.

PMID: 16565401 [PubMed - as supplied by publisher]






























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