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)

Transforming growth factor-beta1 (TGF-beta1) is the most abundant TGF-beta isoform detected in bone and is an important functional modulator of osteoclasts. TGF-beta1 can induce osteoclast apoptosis; however, the apoptotic pathways involved in this process are not known. We show here that human osteoclasts express both type-I and type-II TGF-beta receptors. In the absence of survival factors, TGF-beta1 (1 ng/ml) induced osteoclast apoptosis. The expression of activated caspase-9, but not that of caspase-8, was increased by TGF-beta1 stimulation, and the rate of TGF-beta1-induced apoptosis was significantly lower in the presence of a caspase-9 inhibitor. To study further the mechanisms involved in TGF-beta1-induced osteoclast apoptosis, we investigated TGF-beta1 signaling, which primarily involves the Smad pathway, but also other pathways that may interfere with intracellular modulators of apoptosis, such as mitogen-activated protein (MAP) kinases and Bcl2 family members. We show here that early events consisted of a trend toward increased expression of extracellular signal-regulated kinase (ERK), and then TGF-beta1 significantly induced the activation of p38 and Smad2 in a time-dependent manner. These signaling cascades may activate the intrinsic apoptosis pathway, which involves Bim, the expression of which was increased in the presence of TGF-beta1. Furthermore, the rate of TGF-beta1-induced osteoclast apoptosis was lower when Bim expression was suppressed, and inhibiting the Smad pathway abolished Bim up-regulation following TGF-beta stimulation. This could correspond to a regulatory mechanism involved in the inhibition of osteoclast activity by TGF-beta1.
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PMID:Transforming growth factor-beta1 (TGF-beta1) induces human osteoclast apoptosis by up-regulating Bim. 1957 21

Inhibitors of catalase (such as ascorbate, methyldopa, salicylic acid and neutralizing antibodies) synergize with modulators of nitric oxide (NO) metabolism (such as arginine, arginase inhibitor, NO synthase-inducing interferons and NO dioxygenase inhibitors) in the singlet oxygen-mediated inactivation of tumor cell protective catalase. This is followed by reactive oxygen species (ROS)-dependent apoptosis induction. TGF-beta, NADPH oxidase-1, NO synthase, dual oxidase-1 and caspase-9 are characterized as essential catalysts in this process. The FAS receptor and caspase-8 are required for amplification of ROS signaling triggered by individual compounds, but are dispensable when the synergistic effect is established. Our findings explain the antitumor effects of catalase inhibitors and of compounds that target NO metabolism, as well as their synergy. These data may have an impact on epidemiological studies related to secondary plant compounds and open new perspectives for the establishment of novel antitumor drugs and for the improvement of established chemotherapeutics.
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PMID:Synergistic effects between catalase inhibitors and modulators of nitric oxide metabolism on tumor cell apoptosis. 2527 27

Hydrogen peroxide (H2O2) is both an exogenous and endogenous cytotoxic agent that can reliably induce apoptosis in numerous cell types for studies on apoptosis signaling pathways. However, little is known of these apoptotic processes in myocardial cells of chicken, a species prone to progressive heart failure. Sequencing of mRNA transcripts (RNA-Seq) allows for the identification of differentially expressed genes under various physiological and pathological conditions to elucidate the molecular pathways involved, including cellular responses to exogenous and endogenous toxins. We used RNA-seq to examine genes differentially expressed during H2O2-induced apoptosis in primary cultures of embryonic chicken cardiomyocytes. Following control or H2O2 treatment, RNA was extracted and sequencing performed to identify novel transcripts up- or downregulated in the H2O2 treatment group and construct protein-protein interaction networks. Of the 19,268 known and 2,160 novel transcripts identified in both control and H2O2 treatment groups, 4,650 showed significant differential expression. Among them, 55.63% were upregulated and 44.37% downregulated. Initiation of apoptosis by H2O2 was associated with upregulation of caspase-8, caspase-9, and caspase-3, and downregulation of anti-apoptotic genes API5 and TRIA1. Many other differentially expressed genes were associated with metabolic pathways (including 'Fatty acid metabolism', 'Alanine, aspartate, and glutamate metabolism', and 'Biosynthesis of unsaturated fatty acids') and cell signaling pathways (including 'PPAR signaling pathway', 'Adipocytokine signaling pathway', 'TGF-beta signaling pathway', 'MAPK signaling pathway', and 'p53 signaling pathway'). In chicken cardiomyocytes, H2O2 alters the expression of numerous genes linked to cell signaling and metabolism as well as genes directly associated with apoptosis. In particular, H2O2 also affects the biosynthesis and processing of proteins and unsaturated fatty acids. These results highlight the value of RNA-seq for revealing unexpected molecular contributors to oxidative stress responses, thereby identifying novel potential therapeutic targets.
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PMID:Differential Gene Expression Patterns in Chicken Cardiomyocytes during Hydrogen Peroxide-Induced Apoptosis. 2680 97


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