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)

The transmembrane transport pump P-glycoprotein (P-gp) causes the efflux of chemotherapeutic agents from cells and is an important system that secures multidrug resistance (MDR) of neoplastic cells. In the present study drug sensitive L1210 and multidrug resistant L1210/VCR mouse leukemic cell lines were used as an experimental model. We found that LY 294,002, a specific inhibitor of PI3K/Akt kinase pathway, reduced the degree of vincristine resistance in L1210/VCR cells significantly and in a concentration-dependent manner. This was accompanied by decrease in IC(50) value to vincristine from 3.195+/-0.447 to 1.898+/-0.676 micromol/l for 2 micromol/l, to 0.947+/-0.419 micromol/l for 4 micromol/l, and to 0.478+/-0.202 micromol/l for 8 micromol/l LY294,002. The IC(50) value of sensitive cells for vincristine was about 0.010 micromol/l. FACS analysis of the proportion of cells in apoptosis or necrosis by annexin-V apoptosis kit showed the following: (i) vincristine-induced apoptosis in resistant cell to a much lower extent than in sensitive cells; (ii) LY294,002 alone did not induce apoptosis or necrosis in both sensitive and resistant cells; (iii) LY294,002 applied together with vincristine significantly increased the number of apoptotic cells. Transport activity of P-gp in resistant cells was monitored using calcein/AM as substrate and was depressed by LY294,002 in a concentration dependent manner. Significant differences in calcein retention were not observed when cells were preincubated with LY294,002 at different times from 0.5 to 24h. Sensitive and resistant cells contain similar amounts of uncleaved (i.e., unactivated) caspase-3 but in latter cells the activation of caspase-3 by proteolytic cleavage was decreased. The reversal of vincristine resistance by LY294,002 was associated with marked activation of caspase-3. Western blot analysis revealed that the development of MDR phenotype in L1210/VCR cells was also associated with increased level of Bcl-2 protein. All the above findings point to the possible involvement of PI3K/Akt kinase pathway in modulation of P-gp mediated multidrug resistance in L1210/VCR mouse leukemic cell line. MDR reversal effect of LY294,002 is accompanied with this compound's influence on vincristine-induced apoptosis.
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PMID:LY294,002, a specific inhibitor of PI3K/Akt kinase pathway, antagonizes P-glycoprotein-mediated multidrug resistance. 1701 May 77

Our recent studies aimed to elucidate the molecular and biochemical mechanism of actions of the novel anti-Parkinson's drug, rasagiline, an irreversible and selective monoamine oxidase (MAO)-B inhibitor and its propargyl moiety, propargylamine. In cell death models induced by serum withdrawal in rat PC12 cells and human SH-SY5Y neuroblastoma cells, both rasagiline and propargylamine exerted neuroprotective and neurorescue activities via multiple survival pathways, including: stimulation of protein kinase C (PKC) phosphorylation; up-regulation of protein and gene levels of PKCalpha, PKCepsilon and the anti-apoptotic Bcl-2, Bcl-xL, and Bcl-w; and up-regulation of the neurotrophic factors, BDNF and GDNF mRNAs. Rasagiline and propargylamine inhibited the cleavage and subsequent activation of pro-caspase-3 and poly ADP-ribose polymerase. Additionally, these compounds significantly down-regulated PKCgamma mRNA and decreased the level of the pro-apoptotic proteins, Bax, Bad, Bim and H2A.X. Rasagiline and propargylamine both regulated amyloid precursor protein (APP) processing towards the non-amyloidogenic pathway. These structure-activity studies have provided evidence that propargylamine promoted neuronal survival via neuroprotective/neurorescue pathways similar to that of rasagiline. In addition, recent study demonstrated that chronic low doses of rasagiline administered to mice subsequently to 1 methyl-4 phenyl 1,2,3,6 tetrahydropyridine (MPTP), rescued dopaminergic neurons in the substantia nigra pars compacta via activation of the Ras-PI3K-Akt survival pathway, suggesting that rasagiline may possess a disease modifying activity.
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PMID:Involvement of multiple survival signal transduction pathways in the neuroprotective, neurorescue and APP processing activity of rasagiline and its propargyl moiety. 1701 68

CEACAM1 (also known as CD66a) is a transmembrane glycoprotein that mediates homophilic intercellular interactions that influence cellular growth, immune cell activation, and tissue morphogenesis. Various studies have suggested a link between CEACAM1 and cellular apoptosis, including a recent demonstration that ERK1/2 signaling is triggered downstream of CEACAM1. In this study, we reveal that CEACAM1-long binding confers survival signals to human peripheral blood mononuclear cells. CEACAM-specific antibodies effectively protected peripheral blood mononuclear cells from apoptosis, with this effect being particularly dramatic for primary monocytes that undergo spontaneous apoptosis during in vitro culture. This protective effect was reiterated when using soluble CEACAM1, which binds to cell-surface CEACAM1 via homophilic interactions. Monocyte survival correlated with a CEACAM1-dependent up-regulation of the cellular inhibitor of apoptosis Bcl-2 and the abrogation of caspase-3 activation. CEACAM1 binding triggered a phosphatidylinositol 3-kinase-dependent activation of the protein kinase Akt without influencing the activity of extracellular signal-related kinase ERK, whereas the phosphatidylinositol 3-kinase-specific inhibitor LY294002 effectively blocked the protective effect of CEACAM1. Together, this work indicates that CEACAM1 confers a phosphatidylinositol 3-kinase- and Akt-dependent survival signal that inhibits mitochondrion-dependent apoptosis of monocytes. By controlling both ERK/MEK and PI3K/Akt pathways, CEACAM1 functions as a key regulator of contact-dependent control of cell survival, differentiation, and growth.
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PMID:CEACAM1 (CD66a) promotes human monocyte survival via a phosphatidylinositol 3-kinase- and AKT-dependent pathway. 1707 10

Motoneurons are made in excess throughout development. Initial analysis of the mechanisms that lead to apoptotic cell death during later stages of development and the early postnatal period led to the discovery of neurotrophic factors. These factors comprise different families acting through different tyrosine kinase receptors. Intracellular signalling cascades that lead to the survival of neurons are, on the one hand, the Ras/Raf (Ras-activated factor)/MAPK (mitogen-activated protein kinase) pathway and, on the other, the PI3K (phosphoinositide 3-kinase)/Akt (protein kinase B) pathway. The initial thought of these factors acting as single molecules in separate cascades has been converted into a model in which the dynamics of interaction of these pathways and the subcellular diverse functions of the key regulators have been taken into account. Bag1 (Bcl-2-associated athanogene 1), a molecule that was originally found to act as a co-chaperone of Hsp70 (heat-shock protein 70), also interacts with B-Raf, C-Raf and Akt to phosphorylate Bad (Bcl-2/Bcl-X(L)-antagonist, causing cell death), a pro-apoptotic member of the Bcl-2 family, and leads to specific subcellular distribution of phosphorylated Akt and B-Raf. These functions lead to survival of embryonic neural stem cells and therefore serve as a key event to regulate the viability of these cells.
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PMID:Signalling molecules essential for neuronal survival and differentiation. 1707 3

M1 myeloid leukemic cells were used to dissect the molecular mechanisms of myeloid cell survival and apoptosis. A salient feature of M1 cells is that they respond to the physiological survival factor interleukin-6 (IL-6), yet lack the tumor suppressor gene p53. Functional wild-type activation of temperature-sensitive p53 protein (p53 val) at permissive temperature in M1-t-p53 cells results in rapid apoptosis, which is blocked by IL-6. How p53 induces M1 apoptosis and how IL-6 protects against p53-induced apoptosis are not fully understood. Here it is shown that p53-mediated apoptosis of M1 cells involves rapid activation of the proapoptotic Fas/CD95 death pathway, which activates caspases 8 and 10. Functional p53 also targets the mitochondria, causing upregulation of proapoptotic Bax, downregulation of prosurvival Bcl-2 and activation of caspase 9. IL-6 was found to protect against p53-induced apoptosis via activation of the PI3K/Akt survival pathway, which in turn counters both the Fas/CD95 and mitochondrial apoptotic pathways and activates the prosurvival transcription factor nuclear factor-kappaB (NF-kappaB). Taken together, this work supports a novel model for leukemic progression where cells that acquire the ability to produce an autocrine survival factor, such as IL-6, can bypass normal p53 surveillance function by targeting Akt, which in turn can exert effects on the regulators of apoptosis, such as the Fas/CD95 pathway, the mitochondria and NF-kappaB.
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PMID:Phosphatidylinositol 3-kinase/Akt signaling mediates interleukin-6 protection against p53-induced apoptosis in M1 myeloid leukemic cells. 1709 22

The mechanisms underlying the altered osteoblastogenesis and bone loss in response to disuse are incompletely understood. Using the rat tail suspension model, we studied the effect of skeletal unloading on osteoblast and osteocyte apoptosis. Tail suspension for 2 to 7 days decreased tibial bone mass and induced early apoptotic loss of osteoblasts and delayed apoptotic loss of osteocytes. Surrenal gland weight and plasma corticosterone levels did not differ in loaded and unloaded rats at any time point, indicating that osteoblast/osteocyte apoptosis occurred independently of endogenous glucocorticoids. The mechanistic basis for the disuse-induced osteoblast/osteocyte apoptosis was examined. We found that alpha5beta1 integrin and phosphorylated phosphatidyl-inositol-3 kinase (p-PI3K) protein levels were transiently decreased in unloaded metaphyseal long bone compared to loaded bones. In contrast, p-FAK and p-ERK p42/44 levels were not significantly altered. Interestingly, the reduced p-PI3K levels in unloaded long bone was associated with decreased levels of the survival protein Bcl-2 with unaltered Bax levels, causing increased Bax/Bcl-2 levels. The results indicate that skeletal unloading in rats induces a glucocorticoid-independent, immediate increase in osteoblast apoptosis associated with decreased alpha5beta1-PI3K-Bcl-2 survival pathway in rat bone, which may contribute to the altered osteoblastogenesis and osteopenia induced by unloading.
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PMID:Skeletal unloading induces osteoblast apoptosis and targets alpha5beta1-PI3K-Bcl-2 signaling in rat bone. 1712 9

Previous studies demonstrated that lymphocyte development is impaired in leptin receptor (Ob-R)-deficient db/db mice. However, it remains unclear whether or not leptin signaling plays a physiological role in dendritic cell (DC) development and function. In this study, we first detected Ob-R expression in murine DC. Using db/db mice at a pre-diabetic stage, we demonstrate that the total number of DC generated from bone marrow (BM) cultures is significantly lower than in WT controls. Similarly, selective blockade of leptin with a soluble mouse Ob-R chimera (Ob-R:Fc) inhibited DC generation in wild-type BM cultures. The reduced DC yield in db/db BM culture was attributed to significantly increased apoptosis, which was associated with dysregulated expression of Bcl-2 family genes. Moreover, db/db DC displayed markedly reduced expression of co-stimulatory molecules and a Th2-type cytokine profile, with a poor capacity to stimulate allogeneic T cell proliferation. Consistent with their impaired DC phenotype and function, db/db DC showed significantly down-regulated activities of the PI3K/Akt pathway as well as STAT-3 and IkappaB-alpha. In conclusion, our findings demonstrate the involvement of leptin signaling in DC survival and maturation.
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PMID:Involvement of leptin signaling in the survival and maturation of bone marrow-derived dendritic cells. 1712 43

To investigate whether PTEN can augment doxorubicin-induced apoptosis in PTEN-null Ishikawa cells. We previously demonstrated that Ishikawa cells do not possess functional PTEN protein because of protein truncations. Clones expressing the steady-state level of the PTEN protein from PTEN-null Ishikawa cells have been established and were used in this study. Doxorubicin is a commonly used anticancer drug in endometrial carcinoma. The cytotoxic effect of doxorubicin was evaluated using the methyl thiazoleterazolium (MTT) assay. We used the Hoechst 33258 staining to confirm the induction of apoptosis. Immunoprecipitation and Western blot analysis were performed to evaluate the effects of doxorubicin on phosphorylation of Bcl-2 antagonist of cell death (Bad) and protein kinase B (Akt/PKB). Doxorubicin induced death of all cell lines in a dose-dependent manner, but the death was more significant in PTEN-expressing clones than in parent Ishikawa cells. A low concentration of doxorubicin (0.1 muM) did not affect apoptosis in PTEN-null Ishikawa cells, but it induced apoptosis in PTEN-expressing clones. A high concentration (1 microM) induced apoptosis in all cell lines, but the percentages of apoptotic cells were higher in PTEN-expressing clones than in parent Ishikawa cells. In the clones, phospho-Akt/PKB and phospho-Bad (Ser-136) were downregulated. Doxorubicin reduced the levels of phospho-Akt/PKB and phospho-Bad (Ser-136) in all the cell lines, but the reduction was most significant in the PTEN-expressing clones. Our present results indicate that PTEN transfection significantly enhances doxorubicin chemosensitivity through effective induction of apoptosis by downregulation of the PI3K/Akt/PKB signaling pathway in Ishikawa cells.
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PMID:PTEN augments doxorubicin-induced apoptosis in PTEN-null Ishikawa cells. 1735 93

Apoptosis of granulocytes and the subsequent clearance of apoptotic cells are important processes for the successful resolution of inflammation. Signalling pathways, including those involving NF-kappaB (nuclear factor kappaB), MAPK (mitogen-activated protein kinase) and PI3K (phosphoinositide 3-kinase) have been shown to be key regulators of inflammatory cell survival and apoptosis in vitro. In addition, manipulation of such pathways in vivo has indicated that they also play a role in the resolution of inflammation. Furthermore, manipulation of proteins directly involved in the control of apoptosis, such as Bcl-2 family members and caspases, can be targeted in vivo to influence inflammatory resolution. Recently, it has been shown that CDK (cyclin-dependent kinase) inhibitor drugs induce caspase-dependent human neutrophil apoptosis possibly by altering levels of the anti-apoptotic Bcl-2 family member, Mcl-1. Importantly, CDK inhibitor drugs augment the resolution of established 'neutrophil-dominant' inflammation by promoting apoptosis of neutrophils. Thus manipulation of apoptotic pathways, together with ensuring macrophage clearance of apoptotic cells, appears to be a viable pharmacological target for reducing established inflammation.
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PMID:Modulation of granulocyte apoptosis can influence the resolution of inflammation. 1737 Dec 62

We have found that fibronectin (FN) has a functional cryptic site opposing cell adhesion to extracellular matrix (ECM): a synthetic FN peptide derived from the 14th FN type III-like (FN-III) repeat, termed peptide FNIII14, inhibits cell adhesion to the FN without binding to beta1 integrins. This antiadhesive activity of peptide FNIII14 depends on its C-terminal amino acid sequence YTIYVIAL. A 50-kDa membrane protein (p50) has been detected as a specific binding protein of peptide FNIII14. Here we showed that antiadhesive activity of peptide FNIII14 was depedent upon the presence of p50 on cell surfaces. Furthermore, we found that there exists a sequence, analogous to the YTIYVIAL, in the 10th FN-III repeat of the FN molecule and that a FN peptide containing this analogous sequence, termed peptide FNIII10, inhibited cell adhesion to the FN. Peptide FNIII10 appeared to share p50 with peptide FNIII14 in expressing the antiadhesive activity. As a physiological consequence of decreased adhesion, peptides FNIII10 and FNIII14 accelerated the anoikis-like apoptosis of normal fibroblasts by down-regulating Bcl-2 expression through blocking the FAK/PI3K/Akt signaling pathway. Thus, the YTIYVIAL-related sequences of the FN molecule may be involved in cell regulation by modulating negatively cell adhesion to the ECM, in which p50 probably serves as a membrane receptor.
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PMID:Antiadhesive sites present in the fibronectin type III-like repeats of human plasma fibronectin. 1747 31


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