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)

Focal adhesion kinase (FAK) is up-regulated in a variety of cancers, including breast cancer, in association with poor disease prognosis. In the present study, we examined the role of FAK in the control of anticancer drug-induced apoptosis of mammary adenocarcinoma MTLn3 cells. Doxorubicin caused the formation of well defined focal adhesions and stress fibers early after treatment, which was later followed by their loss in association with the onset of apoptosis. Phosphorylation of FAK on tyrosine 397 decreased only during the onset of doxorubicin-induced apoptosis in a Bcl-2 and caspase-independent manner. Doxorubicin also caused an early activation of protein kinase B (PKB). Expression of the dominant-negative acting focal adhesion kinase-related nonkinase (FRNK) sensitized MTLn3 cells to apoptosis caused by doxorubicin. FRNK inhibited the doxorubicin-induced activation of PKB. In addition, inhibition of phosphatidylinositide-3 (PI-3) kinase with wortmannin inhibited the activation of PKB by doxorubicin. Both wortmannin and transient overexpression of the dual lipid/protein phosphatase and tensin homolog deleted on chromosome 10 enhanced doxorubicin-induced cell death. Altogether, these data fit with a model wherein FAK is involved in the doxorubicin-induced activation of the PI-3 kinase/PKB signaling route, thereby suppressing the onset of apoptosis caused by doxorubicin.
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PMID:Focal adhesion kinase and protein kinase B cooperate to suppress doxorubicin-induced apoptosis of breast tumor cells. 1682 86

The involvement and potential interdependence of inositol trisphosphate (IP3) receptors and Bcl-2 in the regulation of Ca2+ signaling is not clear. Here, we have explored the mechanism(s) of how Bcl-2 suppresses the IP3-sensitive Ca2+ release in MCF-7 cells focusing on the possible role of protein phosphatase 1 (PP1). We found that through influences on protein-protein interaction, Bcl-2 may alter the balance between the effects of phosphatase (PP1) and kinase (PKA) on the IP3 R1 signaling complex. Using various experimental approaches including phosphatase inhibition and RNAi, we show that Bcl-2 by competing with IP3R1 for the binding of PP1 can reduce the IP3-mediated calcium signal and protect cells from mitochondrial dysfunction and cell death.
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PMID:Suppression of IP3-mediated calcium release and apoptosis by Bcl-2 involves the participation of protein phosphatase 1. 1687 61

Visceral leishmaniasis (VL) produced in BALB/c mice through intracardial administration of Leishmania donovani amastigotes was accompanied by hepatosplenomegaly with high organ parasite load and lymphadenopathy when followed up to 4-months or so. To elucidate the mechanism of immunosuppression associated with VL, we report here progressive impairment of the proliferative response of lymph node cells (lymphocytes) from infected animals (I-LNC) to in vitro stimulation with the combination of phorbol 12-myristate 13-acetate (PMA) and ionomycin (Io) that could be related to the downregulation of PKC and MAP kinase (ERK 1/2) activation process. Further, pretreatment of I-LNC with the protein phosphatase inhibitor okadaic acid (OA), but not with calyculin A or sodium orthovanadate, significantly restored their proliferative response as well as PMA-induced activation of PKC. A population of LNC (primarily T-lymphocytes) from chronically infected animals was shown to undergo apoptosis, the number of which increased considerably following PMA+ Io stimulation. The apoptotic pathway, which was followed through binding of cells to Annexin V, activation of caspase-3 and fragmentation of DNA, involved destabilization of mitochondria, probably as a result of downregulation of PKC and Bcl-2. Interestingly, prior incubation of I-LNC with OA reversed the state of cell cycle arrest (anergy) and apoptosis through progression of cells from G0/G1 to S and G2/M phases with transcriptional activation of IL-2 and IL-2R genes. Our results suggest that the cellular (immune) dysfunction in VL could be attributed to dephosphorylation of key molecules in the T-lymphocyte signaling pathway by Ser/Thr phosphatase leading to their inactivation.
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PMID:Lymph node cells from BALB/c mice with chronic visceral leishmaniasis exhibiting cellular anergy and apoptosis: involvement of Ser/Thr phosphatase. 1701 55

FTY720 is an immunosuppressant developed to prevent organ transplant rejection. Recent studies indicate an additional role for FTY720 in inducing cell apoptosis. We demonstrate here that FTY720 mediates toxic effects in cell lines representing different B-cell malignancies and primary B cells from patients with chronic lymphocytic leukemia (CLL). In contrast to previous reports in T-cell lines, FTY720-induced toxicity in the Raji cell line and primary CLL B cells is independent of activation of caspases or poly(ADP-ribose) polymerase processing. Further, pancaspase inhibitor Z-VAD-fmk failed to rescue these cells from apoptosis mediated by FTY720. FTY720 induced down-regulation of Mcl-1 but not Bcl-2 in CLL B cells. Overexpression of Bcl-2 failed to protect transformed B cells from FTY720-induced apoptosis, suggesting a Bcl-2-independent mechanism. Interestingly, FTY720 induced protein phosphatase 2a (PP2a) activation and downstream dephosphorylation of ERK1/2, whereas okadaic acid at concentrations that inhibited the FTY720-induced PP2a activation also resulted in inhibition of FTY720-mediated apoptosis and restoration of baseline ERK1/2 phosphorylation in primary CLL cells, indicating a role for PP2a activation in FTY720-induced cytotoxicity. Further, FTY720 treatment resulted in significant prolonged survival in a xenograft severe combined immunodeficiency (SCID) mouse model of disseminated B-cell lymphoma/leukemia. These results provide the first evidence for the potential use of FTY720 as a therapeutic agent in a variety of B-cell malignancies, including CLL.
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PMID:FTY720 demonstrates promising preclinical activity for chronic lymphocytic leukemia and lymphoblastic leukemia/lymphoma. 1776 20

Exon 2 of the Bcl-x gene undergoes alternative splicing in which the Bcl-xS splice variant promotes apoptosis in contrast to the anti-apoptotic splice variant Bcl-xL. In this study, the regulation of the alternative splicing of pre-mRNA of Bcl-x was examined in response to emetine. Treatment of different types of cancer cells with emetine dihydrochloride downregulated the level of Bcl-xL mRNA with a concomitant increase in the mRNA level of Bcl-xS in a dose- and time-dependent manner. Pretreatment with calyculin A, an inhibitor of protein phosphatase 1 (PP1) and protein phosphatase 2A (PP2A), blocked emetine-induced alternative splicing in contrast to okadaic acid, a specific inhibitor of PP2A in cells, demonstrating a PP1-mediated mechanism. Our finding on the regulation of RNA splicing of members of the Bcl-2 family in response to emetine presents a potential target for cancer treatment.
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PMID:Emetine regulates the alternative splicing of Bcl-x through a protein phosphatase 1-dependent mechanism. 1809 99

Signal transducers and activator of transcription 3 (STAT3) is a transcription factor that has been associated with survival, proliferation, chemoresistance, and angiogenesis of tumor cells. Whether the apoptotic, antiproliferative, and antimetastatic effects of guggulsterone (GS), a farnesoid X receptor antagonist, are linked to its ability to suppress STAT3 activation was investigated. We found that the Z but not the E stereoisomer of GS inhibited both constitutive and interleukin-6-induced STAT3 activation in human multiple myeloma cells. The suppression of STAT3 was mediated through the inhibition of activation of protein tyrosine kinases Janus-activated kinase 2 and c-Src. Vanadate treatment reversed the GS-induced down-regulation of STAT3, suggesting the involvement of a protein tyrosine phosphatase. Indeed, we found that GS induced the expression of both the protein and mRNA for tyrosine protein phosphatase SHP-1 that was not due to demethylation of the SHP-1 promoter previously implicated in the epigenetic silencing of SHP-1. Moreover, knockdown of SHP-1 by small interfering RNA suppressed the effect of GS on induction of SHP-1 and on the inhibition of STAT3 activation, thereby implicating SHP-1 in the action of GS. Finally, GS down-regulated the expression of STAT3-regulated antiapoptotic (Bcl-2, Bcl-xL, and Mcl-1), proliferative (cyclin D1), and angiogenic (VEGF) gene products; and this correlated with suppression of proliferation, the accumulation of cells in sub-G(1) phase of cell cycle, and induction of apoptosis. Overall, these results suggest that GS is a novel blocker of STAT3 activation and thus may have a potential in regulation of growth and metastasis of tumor cells.
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PMID:Guggulsterone, a farnesoid X receptor antagonist, inhibits constitutive and inducible STAT3 activation through induction of a protein tyrosine phosphatase SHP-1. 3018 8

Calcineurin (CaN) is a calcium/calmodulin-dependent protein phosphatase that has an important role in ischemia-induced apoptosis. The serine/threonine kinase, Akt, which is also known as protein kinase B, has an important role in the cell death/survival pathways. Akt is activated by its phosphorylation, which is positively regulated by phosphatidylinositol 3-kinase (PI3K) and negatively regulated by a class of protein phosphatases (PPs) in tissue. However, the relationship between CaN and Akt after transient ischemia remains unclear. In the present study, we investigated whether CaN is involved in neuronal cell apoptosis and Akt dephosphorylation that occur during ischemic injury. We examined the interdependence between CaN and Akt/protein kinase B (PKB) in the rat retina after transient ischemia. After ischemic damage, we detected changes in levels of CaN, Akt and Bad in rats in the presence or absence FK506, CaN inhibitor. Our results show that CaN cleavage reduced Akt phosphorylation at Thr308 and Ser473, and led to apoptosis via dephosphorylation of the proapoptotic Bcl-2 family member Bad. After treatment with FK506, Akt and Bad dephosphorylation was greatly reduced. The total number of TUNEL-positive neurons was reduced by intravitreal injection of FK506 after transient ischemia. These results indicate that CaN cleavage negatively regulates Akt phosphorylation and is involved in retinal cell apoptosis after transient ischemia.
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PMID:Calcineurin mediates AKT dephosphorylation in the ischemic rat retina. 1870 31

Peroxiredoxin II, a cytosolic isoform of the antioxidant enzyme family, has been implicated in cancer-associated cell death and apoptosis, but its functional role in the heart remains to be elucidated. Interestingly, the expression levels of peroxiredoxin II were decreased in mouse hearts upon ischemia-reperfusion, while they were elevated in two genetically modified hyperdynamic hearts with phospholamban ablation or protein phosphatase 1 inhibitor 1 overexpression. To delineate the functional significance of altered peroxiredoxin II expression, adenoviruses encoding sense or antisense peroxiredoxin II were generated; cardiomyocytes were infected, and then subjected to H(2)O(2) treatment to mimic oxidative stress-induced cell death and apoptosis. H(2)O(2) stimulation resulted in a significant decrease of endogenous peroxiredoxin II expression, along with reduced cell viability in control cells. However, overexpression of peroxiredoxin II significantly protected from H(2)O(2)-induced apoptosis and necrosis, while downregulation of this enzyme promoted the detrimental effects of oxidative stress in cardiomyocytes. The beneficial effects of peroxiredoxin II were associated with increased Bcl-2 expression, decreased expression of Bax and attenuated activity of caspases 3, 9 and 12. Furthermore, there were no significant alterations in the expression levels of the other five isoforms of peroxiredoxin, as well as active catalase or glutathione peroxidase-1 after ischemia-reperfusion or H(2)O(2) treatment. These findings suggest that peroxiredoxin II may be a unique antioxidant in the cardiac system and may represent a potential target for cardiac protection from oxidative stress-induced injury.
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PMID:Protection of peroxiredoxin II on oxidative stress-induced cardiomyocyte death and apoptosis. 1903 Sep 11

To build up the structure of human BAD (Bcl-2 antagonist of cell death), subsequently combined with PKAc or PP1c (protein phosphatase 1), to investigate the interaction relationship between BAD and its kinase/PTPese at the molecular level. Additionally, it is concerned with the search for all optimal positions and orientations of a set of amino acid residues of BAD, while its binding sites include N-termini (Glu19, Ala27, and Ser34-Lys35), BH3-located helical domain (Arg98-Lys126), and C-termini (Trp154-Ser163 and Ser167-Gln168). The related sites of PKAc are mainly assembled in C-terminal alpha/beta-domain of PKAc, which comprises the KTL motif (47-49), Glu203 residue, a helical region (Asp241-Arg256), and the span from 328 to 333; while the interaction sites with BAD converge at C-terminal beta-domain of PP1c, which includes the DEK motif (166-168), the stretch from 179 to 197 including a helix (Glu184-Arg188), Glu230-Asp242 segment containing Val232-His237 helix, and Glu287-Leu289 loop. In conclusion, analysis of the complex between BAD and PKAc or PP1c provides a novel viewpoint on the structural origins of molecular recognition. And the complex models suggest that BH3 domain of BAD interact with PKAc or PP1c by electrostatic, van der Waals contacts, hydrogen bond and salt bridge. This is helpful for our development and research of some new drugs, especially mimetic BH3 peptides and inspires scientists with BAD complex and molecular mechanism of its integrating glycolysis and apoptosis.
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PMID:Molecular modeling of human BAD and its interaction with PKAc or PP1c. 1910 7

The immunosuppressant cyclosporine A (CsA) is a specific pharmacological inhibitor of calcineurin, the Ca2+-calmodulin activated phospho-Ser/Thr-specific protein phosphatase. Although calcineurin-inhibiting compounds are applied for local treatment of psoriasis or atopic dermatitis in dermatological practice, little is known about the functions of calcineurin in epidermis-derived malignancies. We investigated the effects of CsA on two human melanoma cell lines, the metastasis forming HT168 and WM35 established from an RGP primary lesion. CsA of 2 microM lowered the enzyme activity by 50% and caused elevation in both mRNA and protein expression of calcineurin. Cell proliferation was diminished, as well as the cellular morphology and the actin organization were altered in both cell lines. CsA increased cell death moderately in both cell lines and reduced the metabolic activity of HT168 cells, but not that of WM35 cells. CsA also elevated the expressions of both Bcl-2 and ERK1/2. Fibronectin guided migration of HT168 cells was stimulated under the effect of CsA, while that of WM35 cells was reduced, moreover, HT168 cells switched from the expression of beta3 to beta1 integrin, but WM35 cells continued to express beta3. Based on our results we propose a multiple, partly malignancy-dependent role of calcineurin in these melanoma cell lines.
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PMID:Inhibition of calcineurin by cyclosporine A exerts multiple effects on human melanoma cell lines HT168 and WM35. 1928 56


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