Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: 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)

CHOP (GADD153) is a member of the C/EBP family and a stress-induced protein. To investigate the role of CHOP in cellular growth, we expressed CHOP conditionally in M1 myeloblastic leukemia cells that do not express p53 protein. More than 60% of M1 cells died through apoptosis 72 h after CHOP induction. Site-directed mutagenesis revealed that this process requires leucine zipper domain but neither intact basic region nor trans-activation domain. CHOP-mediated apoptosis accompanied downregulation of bcl-2 mRNA and overexpression of Bcl-2 delayed the process. Our results indicate that CHOP can induce apoptosis in a p53-independent manner.
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PMID:Ectopic expression of CHOP (GADD153) induces apoptosis in M1 myeloblastic leukemia cells. 889 82

As a result of deprivation of oxygen (hypoxia) and nutrients, the growth and viability of cells is reduced. Hypoxia-inducible factor (HIF)-1alpha helps to restore oxygen homeostasis by inducing glycolysis, erythropoiesis and angiogenesis. Here we show that hypoxia and hypoglycaemia reduce proliferation and increase apoptosis in wild-type (HIF-1alpha+/+) embryonic stem (ES) cells, but not in ES cells with inactivated HIF-1alpha genes (HIF-1alpha-/-); however, a deficiency of HIF-1alpha does not affect apoptosis induced by cytokines. We find that hypoxia/hypoglycaemia-regulated genes involved in controlling the cell cycle are either HIF-1alpha-dependent (those encoding the proteins p53, p21, Bcl-2) or HIF-1alpha-independent (p27, GADD153), suggesting that there are at least two different adaptive responses to being deprived of oxygen and nutrients. Loss of HIF-1alpha reduces hypoxia-induced expression of vascular endothelial growth factor, prevents formation of large vessels in ES-derived tumours, and impairs vascular function, resulting in hypoxic microenvironments within the tumour mass. However, growth of HIF-1alpha tumours was not retarded but was accelerated, owing to decreased hypoxia-induced apoptosis and increased stress-induced proliferation. As hypoxic stress contributes to many (patho)biological disorders, this new role for HIF-1alpha in hypoxic control of cell growth and death may be of general pathophysiological importance.
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PMID:Role of HIF-1alpha in hypoxia-mediated apoptosis, cell proliferation and tumour angiogenesis. 969 72

In the physiological state, there appears to be a regulatory link between endoplasmic reticulum (ER) Ca(2+) homoeostasis and the initiation of neuronal protein synthesis. Exposing neuronal cell cultures to thapsigargin (Tg), an irreversible inhibitor of sarcoplasmic/ER Ca(2+)-ATPase (SERCA), induced an almost complete suppression of protein synthesis, which recovered to approx. 60% of control 24 h after Tg exposure. This is an experimental model where the regulatory link between the initiation of protein synthesis and ER Ca(2+) homoeostasis recovers, despite an irreversible suppression of SERCA activity [Doutheil, Treiman, Oschlies and Paschen (1999) Cell Calcium 25, 419--428]. The model was used to investigate the relationship between transcription and translation of various stress genes that respond to conditions causing graded suppression of protein synthesis. Expression patterns revealed three groups of genes. The mRNA levels of genes responding to conditions of ER stress (grp78, grp94, gadd34 and gadd153) were increased up to 200-fold after Tg exposure, whereas those coding for ER-resident proteins (SERCA 2b and Bcl-2) were increased up to 6-fold in treated cultures, and those coding for cytoplasmic proteins (heat-shock protein 70 and p67) were increased only 2--4-fold. Analysis of translation of these mRNAs suggests an imbalance in the synthesis of apoptosis-inducing (GADD153) and tolerance-activating (GRP78 and Bcl-2) proteins after blocking of the ER Ca(2+) pump. The observation that the relationship between Tg-induced changes in mRNA and protein levels varied considerably for the various genes studied implies that translation of the respective transcripts is differently regulated under conditions causing graded suppression of global protein synthesis. Detailed analysis of the response of neuronal cells to transient disturbance of ER Ca(2+) homoeostasis may help to elucidate the mechanisms underlying neuronal cell injury in those neurological disorders in which an impairment of ER function is thought to contribute to the pathological process of deterioration.
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PMID:Response of neurons to an irreversible inhibition of endoplasmic reticulum Ca(2+)-ATPase: relationship between global protein synthesis and expression and translation of individual genes. 1138 88

Mutations in the presenilin-1 (PS1) gene cause early onset familial Alzheimer's disease (FAD) by a mechanism believed to involve perturbed endoplasmic reticulum (ER) function and altered proteolytic processing of the amyloid precursor protein. We investigated the molecular mechanisms underlying cell death and ER dysfunction in cultured cells and knock-in mice expressing FAD PS1 mutations. We report that PS1 mutations cause a marked increase in basal protein levels of the pro-apoptotic transcription factor Gadd153. PS1 mutations increase Gadd153 protein translation without affecting mRNA levels, while decreasing levels of the anti-apoptotic protein Bcl-2. Moreover, an exaggerated Gadd153 response to stress induced by ER stress agents was observed in PS1 mutant cells. Cell death in response to ER stress is enhanced by PS1 mutations, and this endangering effect is attenuated by anti-sense-mediated suppression of Gadd153 production. An abnormality in the translational regulation of Gadd153 may sensitize cells to the detrimental effects of ER stress and contribute to the pathogenic actions of PS1 mutations in FAD.
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PMID:Involvement of Gadd153 in the pathogenic action of presenilin-1 mutations. 1239 May 29

The thalamus degenerates following cerebral infarction in the territory supplied by the middle cerebral artery (MCA), and apoptosis is suspected to be the mechanism of this phenomenon. The author studied the role of the growth arrest and DNA damage-inducible gene (GADD) 153 in this thalamic degeneration. The MCA was occluded in stroke-prone spontaneously hypertensive rats. The expression of GADD 153 and Bcl-2, and the release of cytochrome c from the mitochondria to cytosol, were examined in the thalamus until 7 days after ischemia using in situ hybridization, immunoblot, immunohistochemistry and RT-PCR analyses. Gadd153 mRNA expression and GADD153 protein increased transiently at 2, 3, 5 and 7 days, and at 3 and 5 days after ischemia. Bcl-2 mRNA expression and Bcl-2 protein decreased at 3 and 5 days. The release of cytochrome c from the mitochondria was detected at 5 days. These results suggest that increased GADD 153 suppresses Bcl-2 expression, which causes the release of cytochrome c from the mitochondria and leads to thalamic degeneration.
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PMID:Growth arrest and DNA damage-inducible gene 153 increases transiently in the thalamus following focal cerebral infarction. 1583 16

The synthetic retinoid fenretinide [N-(4 hydroxyphenyl)retinamide] induces apoptosis of cancer cells and acts synergistically with chemotherapeutic drugs, thus providing opportunities for novel approaches to cancer therapy. The upstream signaling events induced by fenretinide include an increase in intracellular levels of ceramide, which is subsequently metabolized to GD3. This ganglioside triggers the activation of 12-Lox (12-lipoxygenase) leading to oxidative stress and apoptosis via the induction of the transcription factor Gadd153 and the Bcl-2-family member protein Bak. Increased evidence suggests that the apoptotic pathway activated by fenretinide is p53-independent and this may represent a novel way to treat tumors resistant to DNA-damaging chemotherapeutic agents. Therefore, fenretinide offers increased clinical benefit as a novel agent for cancer therapy, able to complement the action of existing chemotherapeutic treatment regimes. Furthermore, synergy between fenretinide and chemotherapeutic drugs may facilitate the use of chemotherapeutic drugs at lower concentrations, with possible reduction in treatment-associated morbidity.
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PMID:Fenretinide: a p53-independent way to kill cancer cells. 1586 36

This study examined the growth inhibitory effects of the structurally related beta-diketones compounds in human cancer cells. Here, we report that 1-(2-hydroxy-5-methylphenyl)-3-phenyl-1,3-propanedione (HMDB) induces growth inhibition of human cancer cells and induction of apoptosis in A431 cells through modulation of mitochondrial functions regulated by reactive oxygen species (ROS). ROS generation occurs in the early stages of HMDB-induced apoptosis, preceding cytochrome c release, caspase activation, and DNA fragmentation. The changes occurred after single breaks in DNA were detected, suggesting that HMDB induced irreparable DNA damage, which in turn triggered the process of apoptosis. Up-regulation of Bad and p21; down-regulation of Bcl-2, Bcl-XL, Bid, p53, and fatty acid synthase; and cleavage of Bax were found in HMDB-treated A431 cells. Glutathione and N-acetylcysteine (NAC) suppress HMDB-induced apoptosis. HMDB markedly enhanced growth arrest DNA damage inducible gene 153 (GADD153) mRNA and protein in a time- and concentration-dependent manner. NAC prevented up-regulation of GADD153 mRNA expression caused by HMDB. These findings suggest that HMDB creates an oxidative cellular environment that induces DNA damage and GADD153 gene activation, which in turn helps trigger apoptosis in A431 cells.
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PMID:Induction of apoptosis by 1-(2-hydroxy-5-methylphenyl)-3-phenyl-1,3-propanedione through reactive oxygen species production, GADD153 expression, and caspases activation in human epidermoid carcinoma cells. 1627

Unfolded protein response (UPR) is an important genomic response to endoplasmic reticulum (ER) stress. The ER chaperones, GRP78 and Gadd153, play critical roles in cell survival or cell death as part of the UPR, which is regulated by three signaling pathways: PERK/ATF4, IRE1/XBP1 and ATF6. During the UPR, accumulated unfolded protein is either correctly refolded, or unsuccessfully refolded and degraded by the ubiquitin-proteasome pathway. When the unfolded protein exceeds a threshold, damaged cells are committed to cell death, which is mediated by ATF4 and ATF6, as well as activation of the JNK/AP-1/Gadd153-signaling pathway. Gadd153 suppresses activation of Bcl-2 and NF-kappaB. UPR-mediated cell survival or cell death is regulated by the balance of GRP78 and Gadd153 expression, which is coregulated by NF-kappaB in accordance with the magnitude of ER stress. Less susceptibility to cell death upon activation of the UPR may contribute to tumor progression and drug resistance of solid tumors.
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PMID:Role of the unfolded protein response in cell death. 1637 48

Loss of trophic or activity-dependent survival signals is commonly recognized as a stimulus for neuronal apoptosis and may play a significant role in neurodegeneration. Recent data have also implicated endoplasmic reticulum (ER) stress as an important factor in some neurodegenerative conditions. However, whether shared or unique apoptotic cascades are activated by trophic factor withdrawal (TFW) versus ER stress in primary neurons has not previously been investigated. In primary cultures of rat cerebellar granule neurons (CGNs), the ER stressor brefeldin A activated a discrete pathway involving the following: (1) stimulation of the ER resident kinase PERK, (2) enhanced phosphorylation of the translation initiation factor eIF2alpha, and (3) increased expression and nuclear localization of the transcription factor Gadd153/CHOP. ER stress-induced CGN apoptosis was blocked by an antagonist of IP3 receptor-mediated Ca2+ release, 2-aminoethoxydiphenyl borate (2-APB), and by expression of ER-targeted Bcl-2. In contrast, CGN apoptosis elicited by TFW (i.e., removal of serum and depolarizing extracellular potassium) did not display any ER stress component nor was it blocked by either 2-APB or ER-Bcl-2. Despite these apparent differences, both brefeldin A and TFW induced dephosphorylation (activation) of glycogen synthase kinase-3beta (GSK-3beta). Moreover, inhibitors of GSK-3beta (IGF-I, lithium) and caspase-9 (LEHD-fmk) significantly protected CGNs from apoptosis induced by either ER stress or TFW. These data indicate that ER stress and TFW elicit distinct signals that activate GSK-3beta and intrinsic apoptosis in neurons.
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PMID:Endoplasmic reticulum stress and trophic factor withdrawal activate distinct signaling cascades that induce glycogen synthase kinase-3 beta and a caspase-9-dependent apoptosis in cerebellar granule neurons. 1676 55

A recent clinical trial (Chwalisz K, Larsen L, Mattia-Goldberg C, Edmonds A, Elger W, Winkel CA. Fertil Steril 87: 1399-1412, 2007) has demonstrated that the selective progesterone receptor modulator asoprisnil efficiently causes the shrinkage of uterine leiomyoma. The present study was conducted to examine whether asoprisnil elicits endoplasmic reticulum (ER) stress-induced apoptosis in cultured human uterine leiomyoma cells. After subculture in phenol red-free DMEM supplemented with 10% FBS for 120 h, cultured cells were stepped down to serum-free conditions with or without graded concentrations of asoprisnil. ER stress-associated and apoptosis-related proteins were assessed by reverse transcription-PCR analysis or Western blot analysis. RNA interference of growth-arrest- and DNA-damage-inducible gene 153 (GADD153) was performed using small interfering RNA. Terminal deoxynucleotidyl transferase-mediated 2'-deoxyuridine 5'-triphosphate nick end labeling (TUNEL)-positive rates were assessed by TUNEL assay. Compared with untreated control cultures, treatment with 10(-7) M asoprisnil significantly (P < 0.05) increased the protein contents of ubiquitin at 2 h and phospho-double-stranded RNA-activated protein kinase-like ER kinase, phospho-eukaryotic initiation factor 2alpha, activating transcription factor 4, and glucose-regulated protein 78 kDa at 4 h, followed by the significant (P < 0.05) increase in GADD153 protein content at 6 h and cleaved poly(adenosine 5'-diphosphate ribose)polymerase (PARP) at 8 h. RNA interference of GADD153 suppressed protein contents of asoprisnil-induced cleaved PARP, Bax, Bak, GADD34, and tribbles-related protein 3 (TRB3) and TUNEL-positive rate but attenuated asoprisnil-induced reduction in Bcl-2 protein content in cultured leiomyoma cells. These results suggest that asoprisnil elicits ER stress-induced apoptosis in cultured leiomyoma cells and that GADD153 plays a role in asoprisnil-induced apoptosis by modulating the Bcl-2 family of proteins, GADD34, and TRB3.
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PMID:Selective progesterone receptor modulator asoprisnil induces endoplasmic reticulum stress in cultured human uterine leiomyoma cells. 1765 52


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