Bifunctional apoptosis inhibitor (BAR) protects neurons from diverse cell death pathways

Roth, Wilfried; Kermer, Pawel; Krajewska, Maryla; Welsh, Kate; Davis, Scott; Krajewski, Stanisław; Reed, John C.

doi:10.1038/sj.cdd.4401287

Cited by 55 publications

(50 citation statements)

References 33 publications

(49 reference statements)

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“…Thus, the Herp-mediated neuronal protective effect is not mediated by up-or down-regulation of proteins known to regulate neuronal survival upon ER stress induction. At present, we cannot rule out the possibility that Herp overexpression may affect the induction of other genes including Bbc/PUMA (22) and BAR (23), or the redistribution of members of the Bcl-2 family of proteins such as Bax and Bak during ER stress (24).…”

Section: Herp Counteracts the Induction Of The Er Stress Apoptotic Simentioning

confidence: 99%

Herp Stabilizes Neuronal Ca2+ Homeostasis and Mitochondrial Function during Endoplasmic Reticulum Stress

Chan

Zhang

et al. 2004

Journal of Biological Chemistry

114

146

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In response to endoplasmic reticulum (ER) stress, cells launch homeostatic and protective responses, but can also activate cell death cascades. A 54 kDa integral ER membrane protein called Herp was identified as a stress-responsive protein in non-neuronal cells. We report that Herp is present in neurons in the developing and adult brain, and that it is regulated in neurons by ER stress; sublethal levels of ER stress increase Herp levels, whereas higher doses decrease Herp levels and induce apoptosis. The endoplasmic reticulum (ER) 1 is a unique cellular compartment simultaneously involved in the processes of protein synthesis and Ca 2ϩ homeostasis. Various conditions, including oxidative and metabolic stress and Ca 2ϩ overload can interfere with ER functions leading to the accumulation of misfolded proteins. Cells sense and respond to such ER stress by activating a signaling cascade termed the unfolded protein response, which results in the transcriptional up-regulation of stress proteins including members of the glucose-regulated protein (grp) family and other protein chaperones (calnexin, calreticulin, ERp72) that enhance the protein folding capability of the ER (1). ER stress has been documented in neurons in a variety of acute pathological conditions including cerebral ischemia and severe epileptic seizures (2). However, despite the fact that disruption of cellular Ca 2ϩ homeostasis contributes to the death of neurons in these conditions, it is not known how molecular responses to ER stress modify cellular Ca 2ϩ homeostasis and the cell death process. Studies of cultured cells suggest that ER stress can stimulate the expression of cytoprotective genes such as protein chaperones (3) but may also trigger a form of programmed cell death called apoptosis (4), which may involve activation of ER-associated caspases and transcription factors such as Gadd153. A better understanding of ER stress and its links to cell survival/death decisions is therefore needed.Recent findings suggest that ER stress is also implicated in several chronic neurodegenerative disorders including Alzheimer's (5, 6), Parkinson's (7), and Huntington's (8) diseases. Alzheimer's disease (AD) results from altered proteolytic processing of the amyloid precursor protein (APP), resulting in aggregation of neurotoxic forms of amyloid ␤-peptide (A␤) (9). Exposure of cultured neurons to A␤-peptide, and metabolic and oxidative insults can induce an ER stress response (6, 10). Moreover, mutations in presenilin-1 (PS1) that cause earlyonset familial AD perturb ER Ca 2ϩ homeostasis (11, 12) and impair the ability of neurons to engage a cytoprotective ER stress response (20). The adverse effects of A␤ and PS1 mutations on ER function may sensitize neurons to excitotoxicity and apoptosis (11).A novel 54 kDa protein called Herp (homocysteine-induced ER protein) was recently identified and characterized as a stress-responsive protein localized in the ER membrane; Herp contains a ubiquitin-like domain and resembles the human DNA excision repair protein hHR23 ...

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Section: Herp Counteracts the Induction Of The Er Stress Apoptotic Simentioning

confidence: 99%

Herp Stabilizes Neuronal Ca2+ Homeostasis and Mitochondrial Function during Endoplasmic Reticulum Stress

Chan

Zhang

et al. 2004

Journal of Biological Chemistry

114

146

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“…When BAP31 is cleaved, a proapoptotic p20 fragment is derived, which, among other effects, induces mitochondrial fission, enhancing cytochrome c release 78 . Conversely, BAR, which is expressed primarily in neurons of the central nervous system, also bridges Bcl-2 and caspase-8 but functions as an antiapoptotic protein 79 .…”

Section: Box 2 | Endoplasmic-reticulum Stress and Cell Deathmentioning

confidence: 99%

Cell death in the nervous system

Bredesen

Rao

Mehlen

2006

Nature

567

413

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Neurodegenerative diseases such as Alzheimer's disease and Parkinson's disease trigger neuronal cell death through endogenous suicide pathways. Surprisingly, although the cell death itself may occur relatively late in the course of the degenerative process, the mediators of the underlying celldeath pathways have shown promise as potential therapeutic targets.Thank Heaven! The crisis -the danger, is past, and the lingering illness, is over at last -and the fever called "Living" is conquered at last. from For Annie, by Edgar Allan Poe Programmed cell death (PCD) has a critical role in the development of the nervous system, and both anti-PCD and pro-PCD modulators feature prominently in the establishment of neural architecture. It has been 100 years since the first description of developmental neuronal-cell death 1 , and more than 50 years since Levi-Montalcini showed that such physiological cell death is inhibited by soluble factors such as nerve growth factor 2 . Dysregulation of cell-death programmes features in developmental and neoplastic disorders of the nervous system, and there is increasing evidence to suggest that such dysregulation may also occur in neurodegenerative, infectious, traumatic, ischaemic, metabolic and demyelinating disorders.In 1964, Lockshin and his colleagues introduced the term programmed cell death to describe the apparently predetermined pattern by which specific cells die during insect development 3 . In 1966, it was shown that this process requires protein synthesis, at least in some cases 2 , indicating that it is the result of an active cellular suicide process. Then, in 1972, John Kerr and his colleagues coined the term apoptosis to describe a morphologically relatively uniform set of cell deaths seen in many different situations, from development to insult response to cell turnover 4 .Although PCD has often been equated with apoptosis, non-apoptotic forms also exist [5][6][7][8][9] , and neurodegenerative conditions such as Huntington's disease, amyotrophic lateral sclerosis (ALS) and ischaemia show cell deaths that do not fulfil the criteria for apoptosis 7 .Classical developmental studies support the view that at least three different forms of PCD are distinguishable (Table 1) 3,5,8 ; and type III, also known as cytoplasmic 5,6,8,10 . These occur reproducibly in specific nuclei and with specific frequencies, at particular times of nervous-system development. But these cell-death pathways may also be activated by various insults, such as DNA damage or the accumulation of misfolded proteins.Neurodegenerative diseases are associated with a number of insults that may trigger PCD: misfolded proteins, reactive oxygen and nitrogen species, mitochondrial-complex inhibition, calcium entry, excitotoxicity, trophic-factor withdrawal, and death-receptor activation to name a few. In some cases, however, deaths occur that do not fit neatly into any of the three classes of PCD, and these more controversial forms of death are also discussed below.Temporal studies of neurodegenerative m...

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“…11 Similarly, by inhibiting DISC formation in the extrinsic pathway 4,5 and by blocking Bax-dependent amplification through the intrinsic pathway, [12][13][14] ARC would be predicted to inhibit TRAIL-mediated killing, a process important in host defences against cancer cells. 15,16 In this regard, it would be interesting to determine whether BAR, another repressor of both central pathways, 17 whose expression is usually neuronrestricted, 18 is also induced in cancer. Apart from its potential role in breast cancer pathogenesis, ARC may be an important factor in determining the response of breast cancers to a variety of therapies.…”

Section: Dear Editormentioning

confidence: 99%

ARC, an apoptosis suppressor limited to terminally differentiated cells, is induced in human breast cancer and confers chemo- and radiation-resistance

et al. 2005

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Bifunctional apoptosis inhibitor (BAR) protects neurons from diverse cell death pathways

Cited by 55 publications

References 33 publications

Herp Stabilizes Neuronal Ca2+ Homeostasis and Mitochondrial Function during Endoplasmic Reticulum Stress

Herp Stabilizes Neuronal Ca2+ Homeostasis and Mitochondrial Function during Endoplasmic Reticulum Stress

Cell death in the nervous system

ARC, an apoptosis suppressor limited to terminally differentiated cells, is induced in human breast cancer and confers chemo- and radiation-resistance

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