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)

Detachment of adherent cells from extracellular matrix results in apoptosis, a process termed "anoikis". Resistance to anoikis is implicated in the progression of many malignancies by facilitating the migration and eventual colonization of distant sites. Human kidney epithelial cells 293T, human osteoblast cells hFOB 1.19 and human osteosarcoma cells Saos-2 significantly underwent anoikis when adherence was prevented. But human osteosarcoma MG-63 cells were distinctly anoikis resistant when detached. They formed large aggregates and showed little apoptosis compared to the other cells. When MG-63 cells were in suspension, caspase-8, physically associated with death receptor was activated by cell-matrix detachment, whereas. Caspase-3 and caspase-9 were not activated. Translational level of Bcl-2 significantly increased in a time-dependent manner, but the level of beta-catenin and PI3K did not. Caspase-8 participates in an anoikis-inducing process in MG-63 cells at an early time, and overexpression of Bcl-2 blocks activation of caspase-8 making MG-63 cells anoikis resistant.
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PMID:Bcl-2 and caspase-8 related anoikis resistance in human osteosarcoma MG-63 cells. 1867 69

Previously we showed that end-binding protein 1 (EB1) may promote cellular growth by activating beta-catenin/T-cell factor (TCF) pathway. To further investigate the role of EB1 in regulating cellular growth, we established an EB1-inducible expression system in which the protein level of EB1 was significantly upregulated upon doxycycline induction. We found that EB1 promoted cellular growth and resulted in a significant increase in colony formation. In addition, EB1 could induce tumor formation in nude mice, activate beta-catenin-dependent gene expression and upregulate the transcriptional activity of c-myc. We also showed that EB1 in this manner inhibited apoptosis of 293-T-REx cells upon cisplatin and upregulated expression of Bcl-2, whereas DeltaN TCF4, an inhibitor of beta-catenin/TCF pathway, could completely or partially abolish the effects of EB1 on the promotion of cell growth and the inhibition of apoptosis activity. Moreover, knockdown of c-myc by RNAi could abrogate upregulation of EB1-dependent induction of Bcl-2 expression. Overall, EB1 acts as a potential oncogene via activating beta-catenin/TCF pathway to promote cellular growth and inhibit apoptosis.
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PMID:EB1 acts as an oncogene via activating beta-catenin/TCF pathway to promote cellular growth and inhibit apoptosis. 1868 Jan 7

We examined the effect of melatonin on pro-survival processes in three groups of mice. Untreated senescence-accelerated mice (SAMP8), melatonin-treated SAMP8 and untreated senescence-accelerated resistant mice (SAMR1) of 10 months old were studied. Melatonin (10 mg/kg) or vehicle (ethanol at 0.066%) was supplied in the drinking water from the end of the first month until the end of the ninth month of life. Differences in the Akt/Erk1-2 pathway and downstream targets were examined and no significant changes were observed, except for beta-catenin. However, sirtuin 1 expression was significantly lower in SAMP8 than in SAMR1. In addition, acetylated p53 and NFkappaB expression were lower in SAMP8 than in SAMR1. These changes were prevented by melatonin. Moreover, the concentration/expression of alpha-secretase was lower and that of amyloid beta aggregates (Abeta) was higher in untreated SAMP8 than in SAMR1. Likewise, the levels of Bid were higher, whereas Bcl-2(XL) levels were lower in SAMP8 than in SAMR1. Melatonin reduced all these changes. We conclude that melatonin improves pro-survival signals and reduces pro-death signals in age-related impairments of neural processes.
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PMID:Evaluation of potential pro-survival pathways regulated by melatonin in a murine senescence model. 1870 49

Sphingolipid metabolites are generated throughout the intestinal tract after hydrolysis of orally administered complex sphingolipids and significantly suppress colon cancer in carcinogen-treated CF1 mice. In the present study, the mechanisms of tumor suppression by dietary sphingolipids were investigated. Changes in select genes that are critical in early stages of colon cancer were analyzed in the colonic mucosa of dimethylhydrazine-treated CF1 mice fed AIN76A diet with or without 0.05% sphingomyelin (SM). Supplementation with SM did not significantly alter mRNA levels of most of the selected genes. However, a downregulation of beta-catenin (p = 0.007) and increased protein levels of connexin-43 (p = 0.017) and Bcl-2 (p = 0.033) were observed in SM-fed animals. This suggests that sphingolipids may be regulating specific post-transcriptional events to reverse aberrant expression of individual proteins. Since the dysregulation of beta-catenin metabolism and its transcriptional activity in addition to a decreased intercellular communication has been causally linked to the development of colon cancer while a low Bcl-2 expression is associated with a worse prognosis in colon cancer, the reversal of these early changes may be important events in the prevention of colon cancer by orally administered sphingolipids, and may provide specific molecular biomarkers for sphingolipid efficacy in vivo.
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PMID:Regulation of beta-catenin and connexin-43 expression: targets for sphingolipids in colon cancer prevention. 1883 72

BCL2L12, a newly identified member of Bcl-2 family, contains a BH2 domain and a putative BH3 domain. It was found to be highly expressed in normal breast tissues, and was associated with favorable prognosis in breast cancer patients. Here, we reported that the mRNA levels of BCL2L12 and its transcript variant BCL2L12A could be upregulated upon cisplatin treatment in MDA-MB-231 breast cancer cells. Knockdown of BCL2L12 and BCL2L12A dramatically inhibited cisplatin-induced apoptosis. In contrast, ectopic expressions of each of the proteins promoted cisplatin-induced apoptosis. These results indicated that decreased expressions or loss of BCL2L12 and BCL2L12A may contribute to the cisplatin resistance in breast cancer patients. Furthermore, we found that cisplatin-induced downregulation of beta-catenin was partially suppressed in BCL2L12- and BCL2L12A-knocked down MDA-MB-231 cells, which indicated that knockdown of these two proteins may stabilize beta-catenin in cisplatin-induced apoptosis. In short, we proposed that BCL2L12 and BCL2L12A may play an important role in cisplatin-induced apoptosis in MDA-MB-231 breast cancer cells.
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PMID:Knockdown of BCL2L12 leads to cisplatin resistance in MDA-MB-231 breast cancer cells. 1893 Jan 35

It is known that UV modulates the expression of paracrine factors that regulate melanocyte function in the skin. We investigated the consequences of repetitive UV exposure of human skin in biopsies of 10 subjects with phototypes 2-3.5 taken 1-4 years later. The expression of melanogenic factors (TYR, MART1, MITF), growth factors/receptors (SCF/KIT, bFGF/FGFR1, ET1/EDNRB, HGF, GM-CSF), adhesion molecules (beta-catenin, E-cadherin, N-cadherin), cell cycle proteins (PCNA, cyclins D1, E2) as well as Bcl-2, DKK1, and DKK3, were analyzed by immunohistochemistry. Most of those markers showed no detectable changes at > or = 1 year after the repetitive UV irradiation. Although increased expression of EDNRB protein was detected in 3 of 10 UV-irradiated subjects, there was no detectable change in the expression of ET1 protein or in EDNRB mRNA levels. In summary, only the expression of TYR, MART1, and/or EDNRB, and only in some subjects, was elevated at > or = 1 year after UV irradiation. Thus the long-term effects of repetitive UV irradiation on human skin did not lead to significant changes in skin morphology and there is considerable subject-to-subject variation in responses. The possibility that changes in the expression and function of EDNRB triggers downstream activation of abnormal melanocyte proliferation and differentiation deserves further investigation.
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PMID:Long-lasting molecular changes in human skin after repetitive in situ UV irradiation. 1894 95

The aim of this study was to evaluate the relationship between Folate-binding protein one (Folbp1) and embryonic cardiac proliferation, apoptosis, and differentiation. Folbp1 gene expression and short interference RNA expression vectors were constructed. Morphology of P19 cells during differentiation was observed by inverted microscope. Cell proliferation was tested using the 3-(4,5-Dimethylthiazol-2-yl)-2,5-Diphenyltetrazoliumbromide (MTT) method. Cell apoptosis was evaluated by DNA ladder and flow cytometry methods, and marker gene expression during differentiation, such as atrial natriuretic peptide (ANP) and cardiac troponin I (cTnI), and marker gene expression during apoptosis (Bax/Bcl-2) was measured by RT-PCR. Additionally, the critical genes (Wnt, GSK3beta, and/or beta-catenin) expressed in the Wnt signaling pathway were confirmed by RT-PCR. The Folbp1 expressing vector and the silencing vector were constructed. From day 5 of differentiation, the absorbance of cells overexpressing Folbp1 was notably higher than the controls, whereas the controls were notably higher than Folbp1 gene silenced P19 cells. P19 cell apoptosis with Folbp1 gene silencing was lower than the controls; however, more cells were driven into S phase. No significant morphological difference was observed in any of the groups. RT-PCR results show that ANP, cTnI, Wnt, Bax/Bcl-2, and beta-catenin were elevated whereas GSK3beta depressed in cells which overexpressed Folbp1 and was contradictory in Folbp1 gene silenced P19 cells. Folbp1 may be an important candidate mediator of folic acid deficiency-induced congenital cardiac anomalies which are induced by the dysfunction of proliferation and apoptosis of the myocardial cell, and possibly caused by the dysfunction of the Wnt signaling pathway.
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PMID:Folbp1 promotes embryonic myocardial cell proliferation and apoptosis through the WNT signal transduction pathway. 1921 49

Endostatin is a well-characterized endogenous inhibitor of angiogenesis that affects cell proliferation and migration by inhibiting integrin and Wnt-mediated signalling pathways. Here, we show that endothelial cells treated with native and P125A-endostatin activate autophagy. Because autophagy can either be protective or induce programmed cell death, experiments were carried out to understand the signalling pathways leading to autophagy in endothelial cells. P125A-endostatin treatment increased the levels of Beclin 1, a crucial molecule in vesicle nucleation and autophagy. The treatment also reduced the levels of Bcl-2, Bcl-x(L) and beta-catenin; however, progressively increasing amounts of Bcl-2 and Bcl-x(L) were found to be complexed with Beclin 1. Increased beta-catenin and Wnt-mediated signalling reduced Beclin 1 levels and rescued endothelial cells from endostatin-induced autophagy. Finally, knocking down Beclin 1 levels by RNA interference decreased autophagy and accelerated caspase activation in endostatin-treated cells. These studies suggest that endothelial cells may initiate autophagy as a survival response to limit the effects of angiogenesis inhibitors. Thus, interfering with autophagy can potentiate the effects of endostatin by promoting a switch to apoptosis.
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PMID:Endostatin induces autophagy in endothelial cells by modulating Beclin 1 and beta-catenin levels. 1929 26

Endometriosis is a benign chronic gynecological disease of reproductive-age women characterized by the presence of functional endometrial tissues outside the uterine cavity. It is an estrogen-dependent disease. Current treatment modalities to inhibit biosynthesis and actions of estrogen compromise menstruation, pregnancy, and the reproductive health of women and fail to prevent reoccurrence of disease. There is a critical need to identify new specific signaling modules for non-estrogen-targeted therapies for endometriosis. In our previous study, we reported that selective inhibition of cyclooxygenase-2 prevented survival, migration, and invasion of human endometriotic epithelial and stromal cells, which was due to decreased prostaglandin E(2) (PGE(2)) production. In this study, we determined mechanisms through which PGE(2) promoted survival of human endometriotic cells. Results of the present study indicate that 1) PGE(2) promotes survival of human endometriotic cells through EP2 and EP4 receptors by activating ERK1/2, AKT, nuclear factor-kappaB, and beta-catenin signaling pathways; 2) selective inhibition of EP2 and EP4 suppresses these cell survival pathways and augments interactions between proapoptotic proteins (Bax and Bad) and antiapoptotic proteins (Bcl-2/Bcl-XL), facilitates the release of cytochrome c, and thus activates caspase-3/poly (ADP-ribose) polymerase-mediated intrinsic apoptotic pathways; and 3) these PGE(2) signaling components are more abundantly expressed in ectopic endometriosis tissues compared with eutopic endometrial tissues during the menstrual cycle in women. These novel findings may provide an important molecular framework for further evaluation of selective inhibition of EP2 and EP4 as potential therapy, including nonestrogen target, to expand the spectrum of currently available treatment options for endometriosis in women.
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PMID:Selective inhibition of prostaglandin E2 receptors EP2 and EP4 induces apoptosis of human endometriotic cells through suppression of ERK1/2, AKT, NFkappaB, and beta-catenin pathways and activation of intrinsic apoptotic mechanisms. 1940 22

Neural progenitor cells (NPCs) have the potential to survive brain ischemia and participate in neurogenesis after stroke. However, it is not clear how survival responses are initiated in NPCs. Using embryonic mouse NPCs and the in vitro oxygen and glucose deprivation (OGD) model, we found that angiopoietin-1 (Ang1) could prevent NPCs from OGD-induced apoptosis, as evidenced by terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling and annexin V labeling. Ang1 significantly elevated tunica intima endothelial kinase 2 (Tie2) autophosphorylation level, suggesting the existence of functional Tie2 receptors on NPCs. NPCs under OGD conditions exhibited reduction of Akt phosphorylation, decrease of the Bcl-2/Bax ratio, activation of caspase-3, cleavage of PARP, and downregulation of beta-catenin and nestin. Ang1 reversed the above changes concomitantly with significant rising of survival rates of NPCs under OGD, but all these effects of Ang1 could be blocked by either soluble extracellular domain of Tie2 Fc fusion protein (sTie2Fc) or the phosphoinositide 3-kinase (PI3K) inhibitor 2-(4-morpholinyl)-8-phenyl-1(4H)-benzopyran-4-one (LY294002). Our findings suggest the existence of an Ang1-Tie2-PI3K signaling axis that is essential in initiation of survival responses in NPCs against cerebral ischemia and hypoxia.
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PMID:An Ang1-Tie2-PI3K axis in neural progenitor cells initiates survival responses against oxygen and glucose deprivation. 1940 99


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