Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P10415 (Bcl-2)
 33,771 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Paclitaxel (PTX) is an anticancer drug currently in phase II clinical trials. This study shows for the first time that low doses of PTX (5 nM) potently induce apoptosis in human retinoblastoma Y79 cells. The effect of PTX is accompanied by a potent induction of E2F1 which appears to play a critical role in the effects induced by PTX. PTX induced a dose- and time-dependent effect, with G2/M arrest, cyclines A, E and B1 accumulation and a marked modification in the status of Cdc2-cyclin B1 complex, the major player of the G2/M checkpoint. Apoptosis followed G2/M arrest. An early and prolonged increase in p53 expression with its stabilization by phosphorylation and acetylation and its nuclear translocation occurred. Consistently, PTX increased p21WAF1, bax and MDM2 levels, suggesting that p53 is transcriptionally active. p53 accumulated following both E2F1 up-regulation and increase in the levels of p14ARF which interacts with MDM2 preventing ubiquitination and proteosomal degradation of p53. Both extrinsic (E2F1/Fas/JNK/caspase-2 activation) and intrinsic (Bcl-2 phosphorylation, Bid fragmentation and Bax increase) pathways seemed to be involved. Loss of mitochondrial potential and activation of apoptosome and executive caspase-3,-6 and-7 was shown. Incubation with either the irreversible pan-caspase inhibitors Z-VAD-FMK, or SP600125, a selective inhibitor of JNK, or pifithrin alpha, a potent p53 inhibitor, significantly inhibited the effects induced by PTX.
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PMID:Low doses of paclitaxel potently induce apoptosis in human retinoblastoma Y79 cells by up-regulating E2F1. 1881 80

Pharmacological manipulation of protein acetylation levels by histone deacetylase (HDAC) inhibitors represents a novel therapeutic strategy to treat neurodegeneration as well as cancer. However, the molecular mechanisms that determine how HDAC inhibition exerts a protective effect in neurons as opposed to a cytotoxic action in tumor cells has not been elucidated. We addressed this issue in cultured postnatal mouse cortical neurons whose p53-dependent and p53-independent intrinsic apoptotic programs require the proapoptotic multidomain protein, Bax. Despite promoting nuclear p53 accumulation, Class I/II HDAC inhibitors (HDACIs) protected neurons from p53-dependent cell death induced by camptothecin, etoposide, heterologous p53 expression or the MDM2 inhibitor, nutlin-3a. HDACIs suppressed p53-dependent PUMA expression, a critical signaling intermediate linking p53 to Bax activation, thus preventing postmitochondrial events including cleavage of caspase-9 and caspase-3. In human SH-SY5Y neuroblastoma cells, however, HDACIs were not able to prevent p53-dependent cell death. Moreover, HDACIs also prevented caspase-3 cleavage in postnatal cortical neurons treated with staurosporine, 3-nitropropionic acid and a Bcl-2 inhibitor, all of which require the presence of Bax but not p53 to promote apoptosis. Although these three toxic agents displayed a requirement for Bax, they did not promote PUMA induction. These results demonstrate that HDACIs block Bax-dependent cell death by two distinct mechanisms to prevent neuronal apoptosis, thus identifying for the first time a defined molecular target for their neuroprotective actions.
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PMID:Histone deacetylase inhibitors prevent p53-dependent and p53-independent Bax-mediated neuronal apoptosis through two distinct mechanisms. 1926 78

Structure-based approaches now impact across the whole continuum of drug discovery, from new target selection through the identification of hits to the optimization of lead compounds. Optimal application of structure-based design involves close integration with other discovery technologies, including fragment-based and virtual screening. Here, we illustrate the use of structural information and of structure-based drug design approaches in the discovery of small-molecule inhibitors for cancer drug targets and provide an outlook on the exploitation of structural information in future cancer drug discovery. Examples include high profile protein kinase targets and structurally related PI3 kinases, histone deacetylases, poly(ADP-ribose)polymerase and the molecular chaperone HSP90. Structure-based design approaches have also been successfully applied to the protein-protein interaction targets p53-MDM2 and the Bcl-2 family.
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PMID:Structure-based design of molecular cancer therapeutics. 1933 67

Vitiligo is characterized by a patchy loss of inherited skin color affecting approximately 0.5% of individuals of all races. Despite the absence of the protecting pigment and the overwhelming evidence for hydrogen peroxide (H(2)O(2))-induced oxidative stress in the entire epidermis of these patients, there is neither increased photodamage/skin aging nor a higher incidence for sun-induced nonmelanoma skin cancer. Here we demonstrate for the first time increased DNA damage via 8-oxoguanine in the skin and plasma in association with epidermal up-regulated phosphorylated/acetylated p53 and high levels of the p53 antagonist p76(MDM2). Short-patch base-excision repair via hOgg1, APE1, and polymerasebeta DNA repair is up-regulated. Overexpression of Bcl-2 and low caspase 3 and cytochrome c levels argue against increased apoptosis in this disease. Moreover, we show the presence of high epidermal peroxynitrite (ONOO(-)) levels via nitrotyrosine together with high nitrated p53 levels. We demonstrate by EMSA that nitration of p53 by ONOO(-) (300 x 10(-6) M) abrogates DNA binding, while H(2)O(2)-oxidized p53 (10(-3) M) enhances DNA binding capacity and prevents ONOO(-)-induced abrogation of DNA binding. Taken together, we add a novel reactive oxygen species to the list of oxidative stress inducers in vitiligo. Moreover, we propose up-regulated wild-type p53 together with p76(MDM2) as major players in the control of DNA damage/repair and prevention of photodamage and nonmelanoma skin cancer in vitiligo.
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PMID:Enhanced DNA binding capacity on up-regulated epidermal wild-type p53 in vitiligo by H2O2-mediated oxidation: a possible repair mechanism for DNA damage. 1964 Nov 44

We investigated the downstream mechanisms by which chemotherapeutic drugs elicit apoptosis in hepatocellular carcinoma (HCC). Genomic signatures of HCC cell lines treated with different chemotherapeutic drugs were obtained. Analyses of apoptosis pathways were performed and RNA interference was used to evaluate the role of the p53 family. Endogenous p53, p63 and p73 were upregulated in response to DNA damage by chemotherapeutic drugs. Blocking p53 family function led to chemoresistance in HCC. Stimulation and blocking experiments of the CD95-, the TNF- and the TRAIL-receptor systems revealed that cytotoxic drugs, via the p53 family members as transactivators, can trigger expression of each of these death receptors and consequently sensitize HCC cells toward apoptosis. Furthermore, our findings demonstrate a link between chemotherapy, the p53 family and the mitochondrial apoptosis pathway in HCC. Chemotherapeutic treatment induces expression of proapoptotic Bcl-2 family members like Bax and BCL2L11 and the expression of Apaf1, BNIP1, Pdcd8 and RAD. Thus, upon DNA damage, p53, p63 and p73 promote apoptosis via the extrinsic and the intrinsic signaling pathway. In addition, not only proapoptotic genes were upregulated, but also genes known to exert antiapoptotic functions. Bleomycin-induced upregulation of BCL-XL/BCLXL1 and MDM2 suggests that it is the ratio of proapoptotic and antiapoptotic proteins that regulates the apoptosis response of HCC cells toward chemotherapy, thereby playing a decisive role between treatment sensitivity vs. drug resistance. The clinical importance of these data is evidenced by our finding that the bleomycin target gene signature can predict the prognosis of patients suffering from HCC.
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PMID:Chemotherapy-induced apoptosis in hepatocellular carcinoma involves the p53 family and is mediated via the extrinsic and the intrinsic pathway. 1971 44

The present study was undertaken to evaluate the possibility of using a panel of proteins and single nucleotide polymorphisms (SNPs) involved in apoptosis, growth control, and DNA repair as predictive markers for cisplatin sensitivity. For this purpose the intrinsic cisplatin sensitivity (ICS) was determined in 39 cell lines derived from squamous cell carcinomas of the head and neck using a colony-forming assay. In these cell lines and in normal oral keratinocytes (NOK), the expression of epidermal growth factor receptor (EGFR), Hsp70, Bax, Bcl-2, Bcl-XL, survivin, and COX-2 was determined. Moreover, the p53, MDM2, FGFR4, XPC, XPD, XRCC1, and XRCC3 genes were analyzed for the presence of specific single nucleotide polymorphisms (SNPs). Pearson's correlation test showed that EGFR was the only protein that was significantly correlated to the ICS (r=0.388, p=0.015). The combination of EGFR, Hsp70, Bax, and Bcl-2 gave the strongest correlation (r=0.566, p<or=0.001), whereas Bax alone had the second highest influence on the ICS. Furthermore, all four SNPs within genes involved in DNA repair, i.e. XPC, XPD, XRCC1, and XRCC3, tended to influence the ICS. In order to find the combination of factors, on both protein and gene levels, with the highest correlation to ICS, a multivariate statistical calculation was performed. Our results indicate that SNPs in DNA repair genes (XRCC3241 and XPD751) influence the ICS and together with the expression of EGFR, Hsp70, Bax, and Bcl-2, they could predict the cisplatin sensitivity of head and neck cancer cell lines (r=0.614, p<or=0.001).
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PMID:Proteins and single nucleotide polymorphisms involved in apoptosis, growth control, and DNA repair predict cisplatin sensitivity in head and neck cancer cell lines. 1972 96

While the transcription-dependent mechanism of p53 has been extensively studied, recently the transcription-independent apoptotic activity of p53 has also been described. Bcl-2 and Bcl-X(L) interact with p53 and induce apoptosis. Initially, the p53 DNA-binding domain (p53DBD) was found to bind to Bcl-2 and Bcl-X(L). Later, the p53 N-terminal domain (p53NTD) was reported to be sufficient for inducing the transcription-independent apoptotic activity of p53 and also shown to interact with Bcl-X(L). Here, we further document that the transactivation domain of p53 (p53TAD) in p53NTD alone binds to Bcl-X(L). We demonstrated that the MDM2-binding region (residues S15 to N29, herein referred to as SN15) in p53TAD is the binding site for Bcl-X(L). The binding interface on Bcl-X(L) was identified at the hydrophobic pocket formed by the BH1, BH2, and BH3 domains, which also binds to the Bak/Bad BH3 peptides, suggesting Bcl-X(L) and MDM2 share a common binding motif in p53TAD. Our NMR structural studies have shown that the SN15 peptide undergoes a conformational change upon binding to Bcl-X(L). A Bcl-X(L)/SN15 complex structural model suggests that the SN15 peptide adopts an extended alpha-helical structure to bind to the hydrophobic pocket on the Bcl-X(L), which is similar to the mode of binding between BH3 peptides and Bcl-X(L).
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PMID:The MDM2-binding region in the transactivation domain of p53 also acts as a Bcl-X(L)-binding motif. 1991 59

Loss of p53-dependent apoptosis contributes to the development of hematologic malignancies and failure to respond to treatment. Proapoptotic Bcl-2 family member Puma is essential for apoptosis in HoxB8-immortalized interleukin-3 (IL-3)-dependent myeloid cell lines (FDM cells) provoked by IL-3 deprivation. p53 and FoxO3a can transcriptionally regulate Puma. To investigate which transcriptional regulator is responsible for IL-3 deprivation-induced Puma expression and apoptosis, we generated wild-type (WT), p53(-/-), and FoxO3a(-/-) FDM cells and found that p53(-/-) but not FoxO3a(-/-) cells were protected against IL-3 withdrawal. Loss of p21(cip/waf), which is critical for p53-mediated cell-cycle arrest, afforded no protection against IL-3 deprivation. A survival advantage was also observed in untransformed p53(-/-) hematopoietic progenitor cells cultured in the presence or absence of cytokines. In response to IL-3 deprivation, increased Puma protein levels in p53(-/-) cells were substantially delayed compared with WT cells. Increased p53 transcriptional activity was detected after cytokine deprivation. This was substantially less than that induced by DNA damage and associated not with increased p53 protein levels but with loss of the p53 regulator, MDM2. Thus, we conclude that p53 protein is activated after IL-3 deprivation by loss of MDM2. Activated p53 transcriptionally up-regulates Puma, which initiates apoptosis.
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PMID:Myeloid progenitor cells lacking p53 exhibit delayed up-regulation of Puma and prolonged survival after cytokine deprivation. 1996 65

Docking experiments of multiple compounds typically focus on a single protein. However, other targets provide information about relative binding efficiencies that is otherwise lacking. We developed a docking strategy that normalized results in both the ligand and target dimensions. This was applied to dock 287 approved small drugs with 35 peptide-binding proteins, including 15 true positives. The combined docking score was normalized by drug and protein and by incorporating information on contact similarity to the template protein-peptide contacts. The 20 top ranking hits included 6 true positives, and three matches with suggestive evidence in the literature: the cardiac glycoside digitoxin may inhibit WW domain interactions, the 14-3-3 zeta protein may bind negatively charged ligands, and the nuclear receptor coactivator site may bind nuclear receptor agonists. Additionally, the Bcl-2 antiapoptotic protein is predicted to bind pargyline, and the antiapoptic p53 interacting protein MDM2 is suggested to bind clofazimine. These predictions represent starting points for the experimental development of PPI inhibitors based on an existing database of approved drugs and demonstrate that two-dimensional normalization improves docking efficiency.
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PMID:Discovery of small molecule inhibitors of protein-protein interactions using combined ligand and target score normalization. 1999 47

Prostaglandin F2alpha (PGF2alpha) regulates fibroblast growth factor-2 (FGF-2) and fibroblast growth factor receptor (FGFR) expression in osteoblasts. Here, the role of FGF-2 in PGF2alpha-induced proliferation and the signaling pathway involved, were determined in calvarial osteoblasts (COBs) from Fgf2+/+ and Fgf2-/- mice. The involvement of the exported FGF-2 isoform, was determined using the FGF-2 neutralizing antibody to alter its binding to FGFR1. PGF2alpha increased activity of Ras, and MAP-kinase cascade as well as Bcl-2 and c-Myc levels in Fgf2+/+ but not in Fgf2-/- COBs. Moreover, in Fgf2+/+ COBs, PGF2alpha-enhanced nuclear accumulation and co-localization of Bcl-2/c-Myc. Although up-regulation of multiple proliferative and survival signals were induced by PGF2alpha in Fgf2+/+ COBs, phospho-p53 was unmodified while p53 was increased. Increased phospho-p53 was, instead, found in Fgf2-/- COBs without up-regulation of oncogenic proteins. The lack of p53 activation in wild type osteoblasts could be due in part to the overexpression of MDM2 caused by PGF2alpha via FGF-2. PGF2alpha, also, increased cyclins D and E in Fgf2+/+ COBs and induced an expansion of Fgf2+/+ osteoblasts in G(2)/M phase. These data clearly show that PGF2alpha induces proliferation via endogenous FGF-2 and the exported isoform mediates PGF2alpha effects by acting in autocrine manner. Furthermore, silencing of FGFR1 in Fgf2+/+ COBs blocked PGF2alpha induced increase of phospho-MDM2 and cyclins.
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PMID:Signaling pathways implicated in PGF2alpha effects on Fgf2+/+ and Fgf2-/- osteoblasts. 2043 42


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