Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P10415 (Bcl-2)
 33,771 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Cerebellar granule neurons depend on insulin-like growth factor-I (IGF-I) for their survival. However, the mechanism underlying the neuroprotective effects of IGF-I is presently unclear. Here we show that IGF-I protects granule neurons by suppressing key elements of the intrinsic (mitochondrial) death pathway. IGF-I blocked activation of the executioner caspase-3 and the intrinsic initiator caspase-9 in primary cerebellar granule neurons deprived of serum and depolarizing potassium. IGF-I inhibited cytochrome c release from mitochondria and prevented its redistribution to neuronal processes. The effects of IGF-I on cytochrome c release were not mediated by blockade of the mitochondrial permeability transition pore, because IGF-I failed to inhibit mitochondrial swelling or depolarization. In contrast, IGF-I blocked induction of the BH3-only Bcl-2 family member, Bim (Bcl-2 interacting mediator of cell death), a mediator of Bax-dependent cytochrome c release. The suppression of Bim expression by IGF-I did not involve inhibition of the c-Jun transcription factor. Instead, IGF-I prevented activation of the forkhead family member, FKHRL1, another transcriptional regulator of Bim. Finally, adenoviral-mediated expression of dominant-negative AKT activated FKHRL1 and induced expression of Bim. These data suggest that IGF-I signaling via AKT promotes survival of cerebellar granule neurons by blocking the FKHRL1-dependent transcription of Bim, a principal effector of the intrinsic death-signaling cascade.
 ...
PMID:Insulin-like growth factor-I blocks Bcl-2 interacting mediator of cell death (Bim) induction and intrinsic death signaling in cerebellar granule neurons. 1241 54

Survival of antigen-experienced T cells is essential for the generation of adaptive immune responses. Here, we show that the genetic and antibody-mediated inactivation of CD152 (cytotoxic T lymphocyte antigen 4) in T helper (Th) effector cells reduced the frequency of nonapoptotic cells in a completely Fas/Fas ligand (FasL)-dependent manner. CD152 cross-linking together with stimulation of CD3 and CD28 on activated Th2 cells prevented activation-induced cell death (AICD) as a result of reduced Fas and FasL expression. Apoptosis protection conferred by CD152 correlated with the up-regulation of Bcl-2 and was mediated by phosphatidylinositol 3 kinase, which prevented FasL expression through the inhibitory phosphorylation of Forkhead transcription factor FKHRL1. We show that signals induced by CD152 act directly on activated T lymphocytes and, due to its differential surface expression on activated Th1 and Th2 cells, induce resistance to AICD mainly in Th2 cells.
 ...
PMID:CD152 (CTLA-4) determines the unequal resistance of Th1 and Th2 cells against activation-induced cell death by a mechanism requiring PI3 kinase function. 1500 96

Amyloid-beta peptide (Abeta)-induced death in cerebral endothelial cells (CECs) is preceded by mitochondrial dysfunction and signaling events characteristic of apoptosis. Mitochondria-dependent apoptosis engages Bcl-2 family proteins, especially the BH3-only homologues, which play a key role in initiating the apoptotic cascade. Here, we report that the expression of bim, but not other BH3-only members, was selectively increased in cerebral microvessels isolated from 18-month-old APPsw (Tg2576) mice, a model of cerebral amyloid angiopathy (CAA), suggesting a pivotal role for Bim in Abeta-induced cerebrovascular degeneration in vivo. A similar expression profile was observed in Abeta-treated CECs. Furthermore, Abeta induction of bim expression involved a pro-apoptotic transcription factor, FKHRL1. FKHRL1 bound to a consensus sequence in the bim promoter region and was activated by Abeta before bim expression. FKHRL1 activity was negatively regulated by phosphorylation catalyzed by Akt, an anti-apoptotic kinase. Akt upregulation by adenoviral gene transfer inhibited Abeta-induced FKHRL1 activation and bim induction. In addition, Abeta increased the activity of protein phosphatase 2A (PP2A), a ceramide-activated protein phosphatase. Suppression of PP2A activity by RNA interference or a specific inhibitor, okadaic acid, effectively suppressed Abeta-induced Akt inactivation and FKHRL1 activation, leading to an attenuation of bim expression and cell death in CECs. Coimmunoprecipitation experiments revealed that Abeta enhanced the binding of the PP2A regulatory subunit PP2ACalphabeta to Akt. These results implicate PP2A as an early regulator of Abeta-induced bim expression and CEC apoptosis via the Akt/FKHRL1 signaling pathway. We raise the possibility that this pathway may play a role in cerebrovascular degeneration in CAA.
 ...
PMID:Protein phosphatase 2A regulates bim expression via the Akt/FKHRL1 signaling pathway in amyloid-beta peptide-induced cerebrovascular endothelial cell death. 1649 56

Genotoxic stress such as ionizing radiation can induce DNA damage and promote cell-cycle arrest or apoptosis through either a p53-dependent or -independent pathway. Recently, members of the FOXO Forkhead transcription factor family have been implicated in playing a role in both DNA repair and apoptosis in mammalian cells that promoted us to examine the role of FOXO transcription factors in ionizing radiation-induced apoptosis. Here, we show that ionizing radiation can promote FOXO3a (FKHRL1) transcriptional activity and protein expression level, and induce nuclear translocation of FOXO3a in Saos2, a p53-null osteosarcoma cell line. Ionizing radiation stimulates expression of apoptosis-inducing proteins such as Fas ligand and the Bcl-2 interacting mediator of cell death (Bim) leading to cellular apoptosis. The observed upregulation of proapoptotic genes and apoptosis in cells without p53 in response to ionizing radiation suggests a novel p53-independent mechanism underlying ionizing radiation-induced apoptosis in cancer cells.
 ...
PMID:Ionizing radiation activates expression of FOXO3a, Fas ligand, and Bim, and induces cell apoptosis. 1686 80

Given that mutant huntingtin may cause dysregulation of gene expression in striatal neurons leading to the neuronal death, we examined the expression level of Bcl-2 interacting mediator of cell death (Bim) in immortalized wild type STHdh(Q7) and knock-in mutant STHdh(Q111) striatal cell lines to understand the underlying mechanism by which mutant huntingtin causes selective death of striatal neurons. Mutant STHdh(Q111) exhibited significantly increased expression level of Bim compared to STHdh(Q7). Serum deprivation resulted in potentiated apoptotic death in STHdh(Q111) compared to STHdh(Q7). However, the expression level of Bim was not changed with serum deprivation in both cell lines. Activation of pro-survival pathway with IGF-1 significantly attenuated serum deprivation-induced neuronal death in both cell lines and attenuated mutant huntingtin-mediated potentiated apoptotic death in STHdh(Q111). The level of active Akt was significantly elevated in STHdh(Q111) compared to STHdh(Q7) resulting in the phosphorylation of a FKHRL1, a forkhead transcription factor regulating Bim expression in neuronal cells. These data suggest that the presence of mutant huntingtin causes transcriptional dysregulation favoring apoptosis and that Akt pro-survival pathway in STHdh(Q111) is not compromised due to the presence of mutant huntingtin. Therefore, activation of this pathway may contribute to the protection of striatal neurons in Huntington's disease.
 ...
PMID:Increased expression of Bim contributes to the potentiation of serum deprivation-induced apoptotic cell death in Huntington's disease knock-in striatal cell line. 1869 53

Forkhead box transcription factor, class 0 (FOXO) is a mammalian homologue of DAF-16, which is known to regulate the lifespan of Caenorhabditis elegans and includes subfamiies of forkhead transcription factors such as FOXO1 (FKHR). FOXO3 (FKHRL1), FOXO4 (AFX) and FOXO6. All these FOXO members are expressed in the brain with different spatial patterns. FOXO1 is phosphorylated on three sites (Thr-24, Ser-256 and Ser-319) in phosphatidylinositol 3-kinase (PI3-K)/Akt-dependenr manner, thereby inhibiting apoptosis signals. We here documented dephosphorylation of FOXO1, FOXO3 and FOXO4 following transient forebrain ischemia with its concomitant translocation into the nucleus in neurons in the gerbil and mouse brains. The dephosphorylarion of FOXO1 following brain ischemia is in part mediated by constirutively active calcineurin in the mouse hippocampus. The activation of FOXOs preceded delayed neuronal death in the vulnerable hippocampal regions following ischemic brain injury. The FOXOl activation is accompanied by an increase in DNA binding activity for FOXO1-responsive element on the Fas ligand promoter. Thus, downstream targets induced by FOXOl include Fas ligand and Bcl-2-interacting mediator of cell death (Bim) in the brain ischemia. Accumulating evidence documented how FOXO activation is involved in the mechanisms of ischemic cell death. In this chapter, we document the activation mechanism of FOXO factors following brain ischemia and deline their downstream targets underlying neuronal death. The pathophysiological relevance of crosstalk between FOXOs and calcineurmn pathways is also discussed. Finally, we propose therapeutic perspectives to rescue neurons from delayed neuronal death by promoting the Akt signaling. Vanadium compounds, protein tyrosine phosphatase inhibitor, up-regulates Akt activity in the brain and thereby rescues neurons from delayed neuronal death by inhibiting FOXO-dependent and -independent death signals in neurons.
 ...
PMID:Pathophysiological relevance of forkhead transcription factors in brain ischemia. 2042 21