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

Na,K-ATPase is a ubiquitous transmembrane protein that regulates and maintains the intracellular Na(+) and K(+) gradient necessary for cell homeostasis. Recently, the importance of this pump in external stimuli-induced leukemia cell apoptosis has been increasingly appreciated, however, the exact role of Na,K-ATPase in mitochondrial apoptotic pathway still remains little understood. In this study, we found mitochondrial toxin rotenone caused a rapid mitochondrial membrane potential (MMP) collapse in Jurkat cells followed by plasma membrane depolarization (PMP). Similar results were also obtained in human U937 cells and non-cancerous mouse primary T cells. Rotenone-induced PMP depolarization occurred before apoptosis and well correlated with Na,K-ATPase impairment. To understand the mechanisms, Jurkat cells with mtDNA depletion and catalase overexpression were used. The results demonstrated that both PMP depolarization and Na,K-ATPase impairment induced by rotenone were regulated by mitochondrial H(2)O(2) and Bcl-2. Finally, Na,K-ATPase suppression by ouabain greatly accelerated and enhanced mitochondrial toxins-induced cells apoptosis in Jurkat, U937 and primary T cells. In sum, by using leukemia cells and mouse primary T cells, we confirmed that mitochondria-to-Na,K-ATPase and PMP depolarization might represent a novel mechanism for mitochondria to amplify death signals in the initiation stage of cells apoptosis induced by mitochondrial toxins.
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PMID:Plasma membrane depolarization and Na,K-ATPase impairment induced by mitochondrial toxins augment leukemia cell apoptosis via a novel mitochondrial amplification mechanism. 1944 64

Because tumor necrosis factor-alpha (TNF-alpha) is well-known to induce inflammatory responses, thus its clinical use is limited in cancer treatment. Rosmarinic acid (RA), a naturally occurring polyphenol flavonoid, has been reported to inhibit TNF-alpha-induced NF-kappaB activation in human dermal fibroblasts. However, the precise mechanisms of RA have not been well elucidated in TNF-alpha-mediated anti-cancer therapy. In this study, we found that RA treatment significantly sensitizes TNF-alpha-induced apoptosis in human leukemia U937 cells through the suppression of nuclear transcription factor-kappaB (NF-kappaB) and reactive oxygen species (ROS). Activation of caspases in response to TNF-alpha was markedly increased by RA treatment. However, pretreatment with the caspase-3 inhibitor, z-DEVD-fmk, was capable of significantly restoring cell viability in response to combined treatment. RA also suppressed NF-kappaB activation through inhibition of phosphorylation and degradation of IkappaBalpha, and nuclear translocation of p50 and p65. This inhibition was correlated with suppression of NF-kappaB-dependent anti-apoptotic proteins (IAP-1, IAP-2, and XIAP). RA treatment also normalized TNF-alpha-induced ROS generation. Additionally, ectopic Bcl-2 expressing U937 reversed combined treatment-induced cell death, cytochrome c release into cytosol, and collapse of mitochondrial potential. These results demonstrated that RA inhibits TNF-alpha-induced ROS generation and NF-kappaB activation, and enhances TNF-alpha-induced apoptosis.
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PMID:Rosmarinic acid sensitizes cell death through suppression of TNF-alpha-induced NF-kappaB activation and ROS generation in human leukemia U937 cells. 1961 38

Eccentric contractions (ECC) induce myofibrillar collapse, edema, and inflammation in muscle cells. Although apoptosis of myonuclei following ECC is activated during the inflammatory phase, the apoptosis response of the regenerative phase remains to be elucidated. The aim of the present study was to determine the inflammatory and regenerative phase of the apoptosis responses induced by ECC. In anesthetized rats, the tibialis anterior muscles were subjected to ECC repeated 40 times, evoked by surface electric stimulation (100 Hz, 10 V) with mechanical muscle stretch. Apoptosis was examined in the control group and in groups 1, 3, 7, and 14 days after ECC (each group, n = 4-6). Terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling (TUNEL)-positive myonuclei were assessed by further labeling with dystrophin staining and DAPI. The expression of proteins related to apoptosis (Bcl-2 and Bax) was examined by Western blot assay. At 1 and 3 days, focal edema and necrotic myofibers invaded by mononuclear phagocytes were present, whereas regenerated myofibers with central nuclei were detected at 7 and 14 days. The occurrence of TUNEL-positive myonuclei increased significantly at 7 (7.0 +/- 1.5%) and 14 days (5.6 +/- 0.6%) compared with control (0.9 +/- 0.5%). Further we found that myonuclear apoptosis was restricted to the subsarcolemmal space at 7 and 14 days and markedly absent from the central nucleus. The Bax/Bcl-2 ratio was significantly higher at 3 (4.5 +/- 0.9) and 7 days (3.4 +/- 0.5) after ECC. In conclusion, myofiber apoptotic responses following ECC are present not only in the inflammatory phase but also persist during the regenerative phase.
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PMID:Myofiber apoptosis occurs in the inflammation and regeneration phase following eccentric contractions in rats. 1963 70

We identified a sequence homologous to the Bcl-2 homology 3 (BH3) domain of Bcl-2 proteins in SOUL. Tissues expressed the protein to different extents. It was predominantly located in the cytoplasm, although a fraction of SOUL was associated with the mitochondria that increased upon oxidative stress. Recombinant SOUL protein facilitated mitochondrial permeability transition and collapse of mitochondrial membrane potential (MMP) and facilitated the release of proapoptotic mitochondrial intermembrane proteins (PMIP) at low calcium and phosphate concentrations in a cyclosporine A-dependent manner in vitro in isolated mitochondria. Suppression of endogenous SOUL by diced small interfering RNA in HeLa cells increased their viability in oxidative stress. Overexpression of SOUL in NIH3T3 cells promoted hydrogen peroxide-induced cell death and stimulated the release of PMIP but did not enhance caspase-3 activation. Despite the release of PMIP, SOUL facilitated predominantly necrotic cell death, as revealed by annexin V and propidium iodide staining. This necrotic death could be the result of SOUL-facilitated collapse of MMP demonstrated by JC-1 fluorescence. Deletion of the putative BH3 domain sequence prevented all of these effects of SOUL. Suppression of cyclophilin D prevented these effects too, indicating that SOUL facilitated mitochondrial permeability transition in vivo. Overexpression of Bcl-2 and Bcl-x(L), which can counteract the mitochondria-permeabilizing effect of BH3 domain proteins, also prevented SOUL-facilitated collapse of MMP and cell death. These data indicate that SOUL can be a novel member of the BH3 domain-only proteins that cannot induce cell death alone but can facilitate both outer and inner mitochondrial membrane permeabilization and predominantly necrotic cell death in oxidative stress.
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PMID:Facilitation of mitochondrial outer and inner membrane permeabilization and cell death in oxidative stress by a novel Bcl-2 homology 3 domain protein. 1990 Oct 22

A central issue regarding vertebrate apoptosis is whether caspase activity is essential, particularly for its crucial biological outcome: non-inflammatory clearance of the dying cell. Caspase-9 is required for the proteolytic cascade unleashed by the mitochondrial outer membrane permeabilization (MOMP) regulated by the Bcl-2 protein family. However, despite the severely blunted apoptosis in cells from Casp9(-/-) mice, some organs with copious apoptosis, such as the thymus, appear unaffected. To address this paradox, we investigated how caspase-9 loss affects apoptosis and clearance of mouse fibroblasts and thymocytes. Although Casp9(-/-) cells were initially refractory to apoptotic insults, they eventually succumbed to slower caspase-independent cell death. Furthermore, in gamma-irradiated mice, the dying Casp9(-/-) thymocytes were efficiently cleared, without apparent inflammation. Notably, MOMP proceeded normally, and the impaired mitochondrial function, revealed by diminished mitochondrial membrane potential (DeltaPsi(m)), committed cells to die, as judged by loss of clonogenicity. Upon the eventual full collapse of DeltaPsi(m), presumably reflecting failure of respiration, intact dying Casp9(-/-) cells unexpectedly exposed the prototypic 'eat-me' signal phosphatidylserine, which allowed their recognition and engulfment by phagocytes without overt inflammation. Hence, caspase-9-induced proteolysis accelerates apoptosis, but impaired mitochondrial integrity apparently triggers a default caspase-independent program of cell death and non-inflammatory clearance. Thus, caspases appear dispensable for some essential biological functions of apoptosis.
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PMID:Apoptosis and non-inflammatory phagocytosis can be induced by mitochondrial damage without caspases. 1991 Oct 5

B-cell chronic lymphocytic leukemia (CLL) expresses CD160, a glycosylphosphatidylinositol-linked receptor found on normal natural killer (NK) and T cells, but not B cells. CD160 is a multifunctional molecule in normal lymphocytes, but its role in CLL biology is unknown. In vitro, CLL cells undergo rapid spontaneous apoptosis, which CD160 activation protected against-mean cell viability increased from 67% to 79% (P < .001). This was associated with up-regulation of Bcl-2, Bcl-xL, and Mcl-1, but not Bax. As expected from these changes in Bcl-2/Bax and Bcl-xL/Bax ratios, CD160 triggering reduced mitochondrial membrane potential collapse and cytochrome c release. CD160 stimulation also induced DNA synthesis, cell cycle progression, and proliferation. B-cell antigen receptor (BCR)-induced CLL proliferation was generally greater than with CD160, but marked variation was seen. Both BCR and CD160 signaling led to CLL secretion of interleukin-6 (IL-6) and IL-8, although CD160 induced greater increases of IL-6 (51-fold) and IL-8 (15-fold). Survival and activation signals mediated by CD160 showed dose-dependent suppression by phosphoinositide-3 kinase (PI3K) inhibitors. Thus, in vitro, CLL cells can use the CD160 pathway for survival and activation, mimicking CD160 signaling in normal NK and CD8(+) T cells. Establishing the pathophysiologic relevance of these findings may reveal new therapeutic targets.
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PMID:CD160 signaling mediates PI3K-dependent survival and growth signals in chronic lymphocytic leukemia. 2016 68

Curcumin (1), a natural polyphenolic compound, has shown strong antioxidant and anticancer activities. Several molecular mechanisms have been attributed to its inhibitory effects on a wide range of tumor cells. In this study, the response of the chronic myeloid leukemia cell line K562 cells to 1 is investigated. Curcumin inhibited the viability of K562 cells in a dose- and time-dependent manner. Furthermore, curcumin-induced cell death was associated with the formation of the apoptosome complex, the collapse of the mitochondrial membrane potential, and caspase-3 activation. Curcumin treatment also induced Bid cleavage and downregulated the expression of Bcl-2 protein. Surprisingly, even with these molecular features of apoptosis, we showed that 1 stimulated autophagy, which was evidenced by microtubule-associated protein light chain 3 (LC3) immunoreactivty. Curcumin also increased the protein levels of beclin 1 and membrane form LC3 (LC3-II). Autophagy inhibitor bafilomycin A1 and the pan-caspase inhibitor Z-VAD-fmk suppressed curcumin-induced K562 cell death. Overall, these results suggest that curcumin induces autophagic and apoptotic death of K562 cells. These findings suggest that both apoptotic and autophagic mechanisms contribute to the curcumin-induced K562 cell death.
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PMID:Autophagic and apoptotic mechanisms of curcumin-induced death in K562 cells. 2018 54

Hedyotis Diffusa Willd has been used as a major component in several Chinese medicine formulations for the clinical treatment of colorectal cancer. However, the molecular mechanism of the anti-cancer activity of Hedyotis Diffusa Willd remains unclear. In the present study, we investigated the cellular effects of the ethanol extract of Hedyotis Diffusa Willd (EEHDW) in the HT-29 human colon carcinoma cell line. We found that EEHDW inhibited the growth of HT-29 cells demonstrating EEHDW-induced cell morphological changes and reduced cell viability in a dose- and time-dependent manner. Furthermore, we observed that EEHDW treatment resulted in DNA fragmentation, loss of plasma membrane asymmetry, collapse of mitochondrial membrane potential, activation of caspase-9 and caspase-3, and increase of the ratio of pro-apoptotic Bax to anti-apoptotic Bcl-2, suggesting that the HT-29 cell growth inhibitory activity of EEHDW was due to mitochondrion-mediated apoptosis, which may partly explain the anti-cancer activity of Hedyotis Diffusa Willd.
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PMID:Hedyotis Diffusa Willd extract induces apoptosis via activation of the mitochondrion-dependent pathway in human colon carcinoma cells. 2087 81

Rosmarinic acid (RA) is a naturally occurring polyphenolic compound found in various plant families. We previously reported that RA exerted protective effects against 6-hydroxydopamine (6-OHDA)-induced neurotoxicity through antioxidative properties. In this study, we investigated whether RA could prevent effects of 1-methyl-4-phenylpyridinium (MPP(+))-induced insult in MES23.5 dopamineric cells. 1-Methyl-4-phenylpyridinium treatment decreased cell viability and dopamine content, as well as caused apoptotic morphological changes. 1-Methyl-4-phenylpyridinium-induced mitochondrial dysfunction, indicated by inhibition of activity associated with mitochondrial respiratory chain complex I, suggested mitochondrial transmembrane potential collapse and generation of reactive oxygen species. Decreased Bcl-2/Bax ratio and caspase 3 activation were also observed. Rosmarinic acid pretreatment restored the complex I activity of the mitochondrial respiratory chain and partially reversed the other damaging effects of MPP(+). Our results indicate that RA plays a neuroprotective role by ameliorating mitochondrial dysfunction against MPP(+)-induced cell apoptosis and suggest that RA has the potential to be considered an aid for prevention of Parkinson's disease.
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PMID:Rosmarinic acid antagonized 1-methyl-4-phenylpyridinium (MPP+)-induced neurotoxicity in MES23.5 dopaminergic cells. 2096 13

The mitochondrial inner membrane permeability transition (MPT) plays an important role in the pathophysiology of acute disorders of the central nervous systems, including ischemic and traumatic brain injury, and possibly in neurodegenerative diseases. Opening of the permeability transition pore (PTP) by a combination of abnormally elevated intramitochondrial Ca2+ and oxidative stress induces the collapse of transmembrane ion gradients, resulting in membrane depolarization and uncoupling of oxidative phosphorylation. This loss of ATP synthesis eventually results in cellular metabolic failure and necrotic cell death. Drugs, e.g., cyclosporin A, can inhibit the permeability transition through their interaction with the mitochondria-specific protein, cyclophilin D, and demonstrate neuroprotection in several animal models. These characteristics of the MPT were developed almost exclusively from experiments performed with young, mature rodents whereas the neuropathologies associated with the MPT are most prevalent in the elderly population. Some evidence indicates that the sensitivity of mitochondria to Ca2+-induced PTP opening is greater in the aged compared to the young mature brain; however, the basis for this difference is unknown. Based on knowledge of factors that regulate the MPT and on other comparisons between cells and mitochondria from young and old animals, several features may be important. These aging-related features include impaired neuronal Ca2+ homeostasis, increased oxidative stress, increased cyclophilin D protein levels, oxidative modification of the adenine nucleotide translocase and of cardiolipin, and changes in the levels of anti-death mitochondrial proteins, e.g., Bcl-2. The influence of aging on both the contribution of the MPT to neuropathology and the neuroprotective efficacy of MPT inhibitors is a substantial knowledge gap that requires extensive research at the subcellular, cellular, and animal model levels.
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PMID:Influence of aging on membrane permeability transition in brain mitochondria. 2131 61


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