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 p53 tumor suppressor controls a cell cycle arrest and apoptosis pathway that is central to tumor suppression and often disrupted in cancer. The accumulation and activity of p53 are positively controlled by the p14/ARF tumor suppressor and full restoration of the pathway in cancer cells may require that both p53 and p14ARF be supplied [corrected]. To address this issue, we have constructed a bicistronic adenoviral vector encoding the two proteins (Adp14/p53) and compared its tumor suppressor activity with that of a single gene vector for p53 (Adp53). We find that tumor cells treated with Adp14/p53 undergo a much sharper decrease in viability with increasing multiplicities of infection than do cells treated with Adp53, even when cells express endogenous p14ARF. Adp14/p53 is also more effective than is a combination of single gene vectors for p14 and p53. The sharper decrease in cell viability after treatment of cells with Adp14/p53 correlates with an increased rate of p53 protein synthesis and a decreased rate of p53 protein turnover, leading to increased steady-state levels of p53 protein and increased levels of p53 downstream targets mdm2, p21waf1, and bax. Adp14/p53 treatment leads to an elevated bax:bcl2 ratio and induction of apoptosis in vitro and in vivo, coupled with a failure of the tumor cells to induce neovascularization in vivo. The results indicate that endogenous p14ARF expression may be insufficient to ensure efficient accumulation of ectopic p53 after gene transfer and demonstrate that for tumor suppression, bicistronic coexpression of p14ARF and p53 is superior to p53 alone. The results show that in this setting, p14ARF promotes p53 accumulation by increasing p53 protein synthesis, in addition to its well-characterized ability to oppose mdm2-mediated degradation of p53.
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PMID:Enhanced tumor suppression by a p14ARF/p53 bicistronic adenovirus through increased p53 protein translation and stability. 1283 54

Ubiquitin inhibitors act at many levels to enhance apoptosis signaling. For TNF-related apoptosis-inducing ligand (TRAIL)-mediated apoptosis signaling, there are at least five mechanisms by which apoptosis are regulated by the ubiquitin-proteasome pathway. First, proteasome inhibitors can decrease Fas-like inhibitor protein (FLIP) protein levels in tumors, resulting in increased apoptosis signaling due to increased caspase-8 activation. This appears to involve the ubiquitin ligase TNF receptor activation factor-2 (TRAF2) and acts indirectly by causing cell-cycle arrest at a stage where there is high degradation of the FLIP-TRAF2 complex. Second, the regulation of the proapoptotic Bcl-2 family member BAX occurs indirectly. Apoptosis signaling and caspase activation results in a confirmation change in the normally monomeric BAX, which exposes the BH3 domain of BAX, leading to dimerization and resistance to ubiquitin degradation. BAX then translocates into the mitochondria, resulting in the release of proapoptotic mitochondrial factors such as cytochrome c and second mitochondria-derived activator of caspase (SMAC). This results in the activation of caspase-9 and formation of the apoptosome and efficient apoptosis signaling. A third mechanism of the regulation of TRAIL signaling in the ubiquitin-proteasome pathway is mediated by the inhibitor of apoptosis proteins (IAP) E3 ligases. These IAPs can directly bind to caspases but also can act as ubiquitin ligases for caspases, resulting in the degradation of these caspases. IAP binding to caspases can be inhibited by SMAC, which exhibits a caspase-9 homology domain. The fourth mechanism for apoptosis activation by proteasome inhibitors is through the stabilization of the inhibitor of the kappaB (IkappaB)/NF-kappaB complex and prevention of nuclear translocation of the antiapoptosis transcription factor NF-kappaB. During TRAIL-DR4, DR5 signaling, this pathway is activated by interactions of activated Fas-associated death domain with activated receptor-interacting protein (RIP), which in turn activates NF-kappaB-inducing kinase and phosphorylates IkappaB. Therefore, the inhibition of IkappaB degradation blocks this RIP-mediated antiapoptosis signaling event. Last, p53 protein levels, and susceptibility to apoptosis, can be deregulated by the human homolog Hdm2 (Mdm2) E3 ligase. This process is inhibited by p53 phosphorylation and by sequestration of Mdm2 by ARF. Better mechanisms to inhibit the ubiquitin-proteasome pathway targeted at the ubiquitin-proteasome degradation process itself, or more specifically at the E3 ligases known to modulate and downregulate proapoptosis pathways will lead to the enhancement of TRAIL apoptosis signaling and better cancer therapeutic outcomes act through this pathway.
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PMID:Regulation of apoptosis proteins in cancer cells by ubiquitin. 1502 88

The peripheral benzodiazepine receptor (PBR) is a critical component of the mitochondrial permeability transition pore, which is involved in the regulation of cell death. In the present study we investigated the role of PBR in the regulation of signaling pathways leading to apoptotic and necrotic damage and renal dysfunction in a rat model of ischemia-reperfusion. Renal ischemia-reperfusion led to extended tubular apoptosis and necrosis that were associated with peroxidative damage, high levels of proapoptotic Bax expression, and low levels of antiapoptotic Bcl-2 expression, cleavage of death substrate, poly(ADP-ribose) polymerase (PARP), and activation of a key effector of apoptosis, caspase-3. Rat pretreatment with a novel PBR antagonist, SSR180575, significantly decreased postreperfusion oxidative stress and tubular apoptosis and necrosis. This effect was associated with inhibition of caspase-3 activation and PARP cleavage, upregulation of Bcl-2, and downregulation of Bax. Furthermore, inhibition of PBR accelerated the recovery of normal renal function, as assessed by measurement of levels of plasma creatinine and blood urea nitrogen. These findings reveal a role for PBR as a modulator of necrotic and apoptotic cell death induced by ischemia-reperfusion and suggest that regulation of PBR may provide new therapeutic implications for the prevention of acute renal failure.
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PMID:Involvement of peripheral benzodiazepine receptor in the oxidative stress, death-signaling pathways, and renal injury induced by ischemia-reperfusion. 1528

We have investigated the effect of estrogen on p53 cellular location and its influence on tumor cell susceptibility to tumor necrosis factor (TNF)-mediated cytotoxic action. For this purpose, we have used the TNF-sensitive human breast adenocarcinoma MCF-7 and its derivative, the TNF-resistant 1001 clone. Our data indicate that although estrogen receptor (ER)alpha is present in both cell lines, estrogen treatment (1x10(-8) M) has an influence only on the MCF-7 cells and protects these cells from the TNF cytotoxicity. This protective effect is associated with translocation of p53 from the nucleus to the cytoplasm in p53 wild-type MCF-7 and not in p53-mutated 1001 cells. The translocation of p53 in MCF-7 cells results in a decrease in its transcriptional activity, as revealed by diminished p21(WAF1/CIP1) induction and an altered ratio of Bax and Bcl-2 proteins. The estrogen-induced effects are reversed by the selective estrogen inhibitor 182, 780 (1x10(-6) M). Interestingly, transient transfection of MCF-7 cells with ERbeta but not ERalpha cDNA encoding plasmid results in retention of p53 in the nucleus, a subsequent potentiation of its transcriptional activity, and in an increased MCF-7 sensitivity to TNF. The estrogen effects on p53 location and transcriptional activity may involve the mdm2 protein since both events were reversed following MCF-7 transfection with plasmid encoding the ARF cDNA. These studies suggest that estrogen-induced MCF-7 cell survival in the presence of TNF requires a transcriptionally active p53 and, more importantly, indicate that introduction of ERbeta can attenuate the estrogen effects on the p53 protein location, its transcriptional activity and also results in a potentiation of cell sensitivity to TNF-mediated cell death.
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PMID:Opposite effects of estrogen receptors alpha and beta on MCF-7 sensitivity to the cytotoxic action of TNF and p53 activity. 1587 Jul 4

Increased wild-type MYC expression occurs frequently in human cancers, except in Burkitt's lymphoma, where the translocated MYC allele is frequently mutated at several hotspots, including a major one at threonine-58. Acute MYC expression increases p53 or ARF levels and induces apoptosis, and previous transgenic animal studies revealed frequent inactivating mutations of p53 or p19ARF in transgenic Myc-induced lymphomas. Lowe and coworkers (Hemann et al., 2005) demonstrate that wild-type MYC can also trigger apoptosis by inducing Bim, which neutralizes Bcl-2. In contrast, the MYC point mutants failed to induce Bim, promoting murine lymphomas that escaped both wild-type p53 and p19ARF, and in doing so, evaded apoptosis.
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PMID:The great MYC escape in tumorigenesis. 1616 62

ARF, often localized in the nucleolus, controls the p53 pathway and ribosomal biogenesis. In a recent issue of Molecular Cell, Kimchi and colleagues describe a short mitochondrial form of ARF (smARF), produced by internal initiation of translation, that dissipates mitochondrial membrane potential independently of p53 and Bcl-2 family members and triggers caspase-independent cell death. The prodeath function of smARF is dependent on the induction of autophagy.
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PMID:Autophagy and caspase-independent cell death: p19ARF enters the game. 1671 77

One of the primary objectives in the design of protein inhibitors is to shape the three-dimensional structures of small molecules to be complementary to the binding site of a target protein. In the course of our efforts to discover potent inhibitors of Bcl-2 family proteins, we found a unique folded conformation adopted by tethered aromatic groups in the ligand that significantly enhanced binding affinity to Bcl-XL. This finding led us to design compounds that were biased by nonbonding interactions present in a urea tether to adopt this bioactive, folded motif. To characterize the key interactions that induce the desired conformational bias, a series of substituted N,N'-diarylureas were prepared and analyzed using X-ray crystallography and quantum mechanical calculations. Stabilizing pi-stacking interactions and destabilizing steric interactions were predicted to work in concert in two of the substitution patterns to promote the bioactive conformation as a global energy minimum and result in a high target binding affinity. Conversely, intramolecular hydrogen bonding present in the third substitution motif promotes a less active, extended conformer as the energetically favored geometry. These findings were corroborated when the inhibition constant of binding to Bcl-XL was determined for fully elaborated analogues bearing these structural motifs. Finally, we obtained the NMR solution structure of the disubstituted N,N'-diarylurea bound to Bcl-XL demonstrating the folded conformation of the urea motif engaged in extensive pi-interactions with the protein.
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PMID:Design, synthesis, and computational studies of inhibitors of Bcl-XL. 1716 73

The aim of this study was to compare the roles of dihydropyridine calcium antagonists nifedipine, nitrendipine, amlodipine on doxorubicin (DXR)-induced nephrotoxicity in rats using biochemical, histopathological and immunohistochemical approaches. Male Sprague-Dawley rats were randomly divided into five experimental groups: control; DXR; DXR+nifedipine (15 mg/kg); DXR+nitrendipine (10 mg/kg); DXR+amlodipine (5 mg/kg). Results showed that treatment with DXR alone caused significant changes in the levels of urinary protein, serum creatinine (SCr), and blood urea nitrogen (BUN). Co-administration with amlodipine effectively reversed the effect of DXR on these parameters. In contrast, nifedipine and nitrendipine either had no effect or worsened DXR induced changes in the levels of urinary protein, SCr and BUN. Furthermore, DXR treatment caused significant increases in the levels of malondialdehyde (MDA), nitric oxide (NO), nitric oxide synthase (NOS) and significant decreases in the levels of reduced glutathione (GSH), glutathione-S-transferase (GST), and superoxide dismutase (SOD). These effects were significantly reduced by co-administration with amlodipine but not affected by nifedipine and worsened by nitrendipine. In addition to the biochemical changes, histopathological studies showed that DXR caused significant structural damages in the kidneys. Glomerular cell apoptosis, a decrease in Bcl-2 expression and an increase in Bax expression were observed in all rats treated with DXR. Co-administration with amlodipine effectively reversed the effect of DXR while nifedipine and nitrendipine had no effect. In conclusion, this study clearly indicated that amlodipine protected against DXR-induced nephrotoxicity while nifedipine and nitrendipine had no effect.
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PMID:Differential effects of dihydropyridine calcium antagonists on doxorubicin-induced nephrotoxicity in rats. 1723 20

NF-kappaB/Rel transcription factors are central to controlling programmed cell death (PCD). Activation of NF-kappaB blocks PCD induced by numerous triggers, including ligand engagement of tumor necrosis factor receptor (TNF-R) family receptors. The protective activity of NF-kappaB is also crucial for oncogenesis and cancer chemoresistance. Downstream of TNF-Rs, this activity of NF-kappaB has been linked to the suppression of reactive oxygen species and the c-Jun-N-terminal-kinase (JNK) cascade. The mechanism by which NF-kappaB inhibits PCD triggered by chemotherapeutic drugs, however, remains poorly understood. To understand this mechanism, we sought to identify unrecognized protective genes that are regulated by NF-kappaB. Using an unbiased screen, we identified the basic-helix-loop-helix factor Twist-1 as a new mediator of the protective function of NF-kappaB. Twist-1 is an evolutionarily conserved target of NF-kappaB, blocks PCD induced by chemotherapeutic drugs and TNF-alpha in NF-kappaB-deficient cells, and is essential to counter this PCD in cancer cells. The protective activity of Twist-1 seemingly halts PCD independently of interference with cytotoxic JNK, p53, and p19(ARF) signaling, suggesting that it mediates a novel protective mechanism activated by NF-kappaB. Indeed, our data indicate that this activity involves a control of inhibitory Bcl-2 phosphorylation. The data also suggest that Twist-1 and -2 play an important role in NF-kappaB-dependent chemoresistance.
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PMID:Upregulation of Twist-1 by NF-kappaB blocks cytotoxicity induced by chemotherapeutic drugs. 1740 2

Understanding factors subserving pituitary cell proliferation enables understanding mechanisms underlying uniquely benign pituitary tumors. Pituitary tumor-transforming gene (Pttg) deletion results in pituitary hypoplasia, low pituitary cell proliferation rates, and rescue of pituitary tumor development in Rb(+/-) mice. Pttg(-/-) pituitary glands exhibit ARF/p53/p21-dependent senescence pathway activation evidenced by up-regulated p19, cyclin D1, and Bcl-2 protein levels and p53 stabilization. High pituitary p21 levels in the absence of PTTG were associated with suppressed cyclin-dependent kinase 2 activity, Rb phosphorylation, and cyclin A expression, all required for cell cycle progression. Although senescence-associated beta-galactosidase was enhanced in Pttg-deficient pituitary glands, telomere lengths were increased. DNA damage signaling pathways were activated and aneuploidy was evident in the Pttg-deficient pituitary, triggering senescence-associated genes. To confirm the p21 dependency of decreased proliferation and senescence in the Pttg-null pituitary, mouse embryonic fibroblast (MEF) colony formation was tested in wild-type, Pttg(-/-), Rb(+/-), Rb(+/-)Pttg(-/-), and Rb(+/-)Pttg(-/-)p21(-/-) cells. Rb(+/-)Pttg(-/-) MEFs, unlike Rb(+/-) cells, failed to produce colonies and exhibited high levels of senescence. p21 deletion from Rb(+/-)Pttg(-/-) MEFs enhanced anchorage-independent cell growth, accompanied by a marked decrease in senescence. As cell proliferation assessed by bromodeoxyuridine incorporation was higher in Rb(+/-)Pttg(-/-)p21(-/-) relative to Rb(+/-)Pttg(-/-) pituitary glands, p21-dependent senescence provoked by Pttg deletion may underlie pituitary hypoplasia and decreased tumor development in Rb(+/-)Pttg(-/-) mice.
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PMID:Senescence mediates pituitary hypoplasia and restrains pituitary tumor growth. 1797 1


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