Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.22.62 (caspase-9)
 7,507 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

p75(NTR) was identified as a tumor and metastasis suppressor that functions in part via induction of apoptosis in tumor cells. To examine p75(NTR)-dependent apoptosis in tumor cells, we demonstrated that a dose-dependent increase in p75(NTR) expression was associated with a concomitant increase in the mitochondrial proapoptotic effector proteins Bad, Bax and Bik and a decrease in the mitochondrial prosurvival effector proteins phospho-Bad, Bcl-2 and Bcl-x(L). Significantly, p75(NTR)-dependent induction of cytochrome c release from the mitochondria occurred during CHX potentiation of apoptosis. Furthermore, p75(NTR) expression largely suppressed expression of IAP-1 and induced cleavage of procaspase-9 and procaspase-7 but not of procaspases 2, 3, 6, 8 and 10. A specific peptide inhibitor of procaspase-9 cleavage also inhibited cleavage of procaspase-7, indicating that caspase-7 is downstream of caspase-9. As end points of apoptosis, we observed p75(NTR)-dependent annexin V binding to the plasma membrane, an indicator of early apoptotic events, and Hoechst staining of DNA nuclear fragmentation, an indicator of late apoptotic events, whereas control tumor cells that lack expression of the p75(NTR) protein did not exhibit either of these apoptotic markers. Together, these results delineate the mitochondria-mediated apoptotic pathway of the p75(NTR) tumor-suppressor gene product.
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PMID:The p75(NTR) tumor suppressor induces caspase-mediated apoptosis in bladder tumor cells. 1267 29

The p75 neurotrophin receptor (p75(NTR)) is a death receptor which belongs to the tumor necrosis factor receptor super-family of membrane proteins. This study shows that p75(NTR) retarded cell cycle progression by induced accumulation of cells in G0/G1 and a reduction in the S phase of the cell cycle. The rescue of tumor cells from cell cycle progression by a death domain deleted (DeltaDD) dominant-negative antagonist of p75(NTR) showed that the death domain transduced anti-proliferative activity in a ligand-independent manner. Conversely, addition of NGF ligand rescued retardation of cell cycle progression with commensurate changes in components of the cyclin/cdk holoenzyme complex. In the absence of ligand, p75(NTR)-dependent cell cycle arrest facilitated an increase in apoptotic nuclear fragmentation of the prostate cancer cells. Apoptosis of p75(NTR) expressing cells occurred via the intrinsic mitochondrial pathway leading to a sequential caspase-9 and -7 cascade. Since the death domain deleted dominant-negative antagonist of p75(NTR) rescued intrinsic caspase associated apoptosis in PC-3 cells, this shows p75(NTR) was integral to ligand independent induction of apoptosis. Moreover, the ability of ligand to ameliorate the p75(NTR)-dependent intrinsic apoptotic cascade indicates that NGF functioned as a survival factor for p75(NTR) expressing prostate cancer cells.
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PMID:The p75(NTR) tumor suppressor induces cell cycle arrest facilitating caspase mediated apoptosis in prostate tumor cells. 1646 Jun 73

The mechanisms initiating post-spinal cord injury (SCI) apoptotic cell death remain incompletely understood. The p75 neurotrophin receptor (p75(NTR)) has been shown to exert both pro-survival and pro-apoptotic effects on neural cells in vitro. While a previous study had shown that there is decreased oligodendrocyte apoptosis distal to a clean partial transection injury of the cord in mice with nonfunctional p75(NTR), most human spinal cord injuries do not involve partial transections but are rather due to compression/contusion injuries with significant perilesional ischemia. Therefore, we sought to examine the role of the p75(NTR) in a clinically relevant clip compression model of SCI in p75 null mice with an exon III mutation. Mice with a functional p75(NTR) had increased caspase-9 activation at 3 days after SCI in comparison to the functionally deficient p75(NTR) mice. However, at 7 days following SCI there was no difference in the activation of the effector caspases (caspase-3 and caspase-6) at the spinal cord lesion. Moreover, at 7 days after injury, there was increased terminal deoxynucleotidyl transferase-mediated dUTP nick-end (TUNEL) positive cell death at the injury site in the functionally deficient p75(NTR) mice. Using double labeling with TUNEL and cell specific markers we showed that the absence of p75(NTR) function increased the extent of neuronal but not oligodendroglial cell death at the injury site. This selective loss of neuronal cells after SCI was confirmed with a decrease in levels of microtubule-associated protein 2 in the p75 null mice. Furthermore, the wild-type animals had dramatically improved survival and enhanced locomotor recovery at 8 weeks after SCI when compared with the p75(NTR) null mice. Also at 8 weeks, there were significantly more neurons present at the injury site of wild-type mice when compared with p75 null mice. We conclude that the p75(NTR) receptor is integral to neuronal cell survival and endogenous reparative mechanisms after compressive/contusive SCI.
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PMID:The p75 neurotrophin receptor is essential for neuronal cell survival and improvement of functional recovery after spinal cord injury. 1770 65

During brain ischemic preconditioning (PC), mild bursts of ischemia render neurons resistant to subsequent strong ischemic injuries. Previously, we reported that zinc plays a key role in PC-induced neuroprotection in vitro and in vivo. Zinc-triggered p75(NTR) induction transiently activates caspase-3, which cleaves poly(ADP-ribose) polymerase-1 (PARP-1). Subsequently, the PARP-1 over-activation-induced depletion of nicotinamide adenine dinucleotide (NAD(+))/adenosine triphosphate (ATP) after exposures to lethal doses of zinc or N-methyl-D-aspartate is significantly attenuated in cortical neuronal cultures. In the present study, zinc-mediated preconditioning (Zn PC) reduced apoptotic neuronal death that was caused by N,N,N',N'-tetrakis(2-pyridylmethyl)ethylenediamine (TPEN), etoposide, or staurosporine in mouse cortical cells. We focused on heat shock protein 70 (HSP70) because NAD(+)/ATP depletion does not directly cause apoptosis, and HSP70 can inhibit the activation of caspase-9 or caspase-3 by preventing apoptosome formation or cytochrome C release. Zn PC-mediated HSP70 induction was required for neuroprotection against neuronal apoptosis, and geldanamycin-induced HSP70 induction sufficiently blocked neuronal apoptotic cell death. Furthermore, Zn PC-mediated HSP70 induction was blocked by chemical inhibitors of extracellular signal-regulated kinase (ERK) or p38 mitogen-activated protein kinase (MAPK) signaling, but not c-Jun N-terminal protein kinase. Similarly, neuroprotection by Zn PC against TPEN-induced apoptosis was almost completely reversed by the blockade of ERK or p38 MAPK signaling. Our findings suggest that the ERK- or p38 MAPK-mediated induction of HSP70 plays a key role in inhibiting caspase-3 activation during Zn PC.
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PMID:Zinc preconditioning protects against neuronal apoptosis through the mitogen-activated protein kinase-mediated induction of heat shock protein 70. 2571 25