Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P04637 (p53)
 77,613 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

TPCK is widely used as an inhibitor of chymotrypsin-like proteases but has recently been identified as an inhibitor of the PDK1/Akt pathway. In this study, we show that TPCK inhibits TRAIL-induced caspase activity but potentiates wortmannin-dependent caspase activity in prostatic carcinoma cell lines. The inhibitory activity of TPCK was found to be death ligand-specific since TPCK inhibits TRAIL-mediated caspase activity but does not affect Fas-induced caspase activity. Our data also show that impaired TRAIL-DISC formation in the presence of TPCK is responsible for caspase inhibition. Further, TPCK induces p53 expression and inhibits the PDK1/Akt pathway resulting in BAD dephosphorylation, and the release of cytochrome c and Smac/DIABLO from mitochondria. TPCK also selectively decreases the levels of androgen receptor and caspase-2 whereas it does not change the levels of other proteins (caspases-3, -7, -8, -9; heat shock proteins 27, 70, 90). Finally, TPCK-induced degradation of caspase-2 is protected by Bcl-2 overexpression, apparently by an adapter protein since direct interaction between caspase-2 and Bcl-2 was not detected. Together, these features suggest that TPCK could be used as a therapeutic agent for treatment of those tumor cells that are resistant to ligand-induced treatment because of aberrant signaling pathways downstream of the DISC.
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PMID:Multiple effects of N-alpha-tosyl-L-phenylalanyl chloromethyl ketone (TPCK) on apoptotic pathways in human prostatic carcinoma cell lines. 1519 50

Phosphoinositide 3-OH kinase (PI 3-kinase) provides cells with a survival signal that allows them to withstand apoptotic stimuli. Many tumour cells display elevated levels of PI 3-kinase products as a result of deletion of the phosphatase PTEN, activation of Ras or expression of autocrine growth factors. As a result they are relatively resistant to apoptosis. The mechanisms for PI 3-kinase survival signalling are becoming clear. The principal mediator is Akt, a PI 3-kinase activated protein kinase. Akt has direct effects on the apoptosis machinery, for example targeting the pro-apoptotic Bcl-2 related protein, BAD. It also affects the transcriptional response to apoptotic stimuli, for example by acting on Forkhead factors and also influence the activity of the p53 family. In addition, novel connections between the metabolic effects of Akt and its control of survival have recently been made.
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PMID:PI 3-kinase, Akt and cell survival. 1520 77

It has been demonstrated that exposure to cocaine increases cell death in the fetal CNS. To examine the molecular mechanisms of this effect, we employed mouse oligo microarrays followed by real-time reverse transcriptase-polymerase chain reaction (real-time RT-PCR) to compare expressions of apoptosis-related genes in the cerebral wall of 18-day-old (E18) fetuses from cocaine-treated (20 mg/kg cocaine, s.c., b.i.d., E8th-E18th) and drug-naive (saline, s.c.) mice. Out of approximately 400 relevant genes in the arrays, 53 showed alterations in expression in cocaine-exposed fetuses. Upregulation was observed in 35 proapoptotic and 8 antiapoptotic genes; 4 proapoptotic and 6 antiapoptotic genes were down-regulated. The affected genes encode a wide range of apoptosis-related proteins, including death receptors (NTF-R1, NTF-R2, DR3, DR5, LTbeta-R, GITR, P57 TR-1) and their adaptor and regulatory proteins (MASGE-D1, TRAF-2, SIVA, MET, FLIP, FAIM, IAP1, ATFA), members of transcription regulatory pathways (JNK, NF-kappaB, P53), members of BCL-2 family of proteins (BID, BAD, BAX, BIK, NIP21, NIP3, NIX, BCL-2), DNA damage sensor (PARP-1), caspases and their substrates and regulatory proteins (caspases 8, 4, 9, and 3, ACINUS, CIDE-A, CIDE-B, GAS2), mitochondrially released factors (cytochrome c, AIF, PRG3), specific endoplasmic reticulum- and oxidative stress-associated factors (BACH2, ABL1, ALG2, CHOP), members of cell survival AKT and HSP70 pathways (PIK3GA, PTEN, HSP70, BAG1, BAG2), and others. This suggests that cocaine affects survival of developing cerebral cells via multiple apoptosis-regulating mechanisms.
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PMID:Cocaine-induced changes in the expression of apoptosis-related genes in the fetal mouse cerebral wall. 1568 Nov 17

Mammalian target of rapamycin (mTOR) inhibitors curtail cap-dependent translation. However, they can also induce post-translational modifications of proteins. We assessed both effects to understand the mechanism by which mTOR inhibitors like rapamycin sensitize multiple myeloma cells to dexamethasone-induced apoptosis. Sensitization was achieved in multiple myeloma cells irrespective of their PTEN or p53 status, enhanced by activation of AKT, and associated with stimulation of both intrinsic and extrinsic pathways of apoptosis. The sensitizing effect was not due to post-translational modifications of the RAFTK kinase, Jun kinase, p38 mitogen-activated protein kinase, or BAD. Sensitization was also not associated with a rapamycin-mediated increase in glucocorticoid receptor reporter expression. However, when cap-dependent translation was prevented by transfection with a mutant 4E-BP1 construct, which is resistant to mTOR-induced phosphorylation, cells responded to dexamethasone with enhanced apoptosis, mirroring the effect of coexposure to rapamycin. Thus, sensitization is mediated by inhibition of cap-dependent translation. A high-throughput screening for translational efficiency identified several antiapoptotic proteins whose translation was inhibited by rapamycin. Immunoblot assay confirmed rapamycin-induced down-regulated expressions of XIAP, CIAP1, HSP-27, and BAG-3, which may play a role in the sensitization to apoptosis. Studies in a xenograft model showed synergistic in vivo antimyeloma effects when dexamethasone was combined with the mTOR inhibitor CCI-779. Synergistic effects were associated with an enhanced multiple myeloma cell apoptosis in vivo. This study supports the strategy of combining dexamethasone with mTOR inhibitors in multiple myeloma and identifies a mechanism by which the synergistic effect is achieved.
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PMID:Mechanism by which mammalian target of rapamycin inhibitors sensitize multiple myeloma cells to dexamethasone-induced apoptosis. 1648 35

We expressed zebrafish p53 protein fused to GFP by a neuron-specific HuC promoter in zebrafish embryos. Instead of displaying neuronal expression patterns, p53-GFP was targeted to zebrafish YSL nuclei. This YSL targeting is p53 sequence-specific because GFP fusion proteins of p63 and p73 displayed neuronal-specific patterns. To dissect the underlying mechanisms, various constructs encoding a series of p53 mutant proteins under the control of different promoters were generated. Our results showed that expression of p53, in early zebrafish embryo, is preferentially targeted to the nuclei of YSL, which is mediated by importin. Similarly, this targeting is abrogated when p53 nuclear localization signal is disrupted. In addition, the transcriptional activity of p53 is required for this targeting. We further showed that fusion of pro-apoptotic BAD protein to p53-GFP led to apoptosis of YSL cells, and subsequent imperfect microtubule formation and abnormal blastomere movements.
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PMID:Requirement of nuclear localization and transcriptional activity of p53 for its targeting to the yolk syncytial layer (YSL) nuclei in zebrafish embryo and its use for apoptosis assay. 1661 5

Individual BCL2 family members couple apoptosis regulation and cell cycle control in unique ways. Antiapoptotic BCL2 and BCL-x(L) are antiproliferative by facilitating G0. BAX is proapoptotic and accelerates S-phase progression. The dual functions in apoptosis and cell cycle are coordinately regulated by the multi-domain BCL2 family members (MCL-1) and suggest that survival is maintained at the expense of proliferation. The role of BH3-only molecules in cell cycle is more variable. BAD antagonizes both the cell cycle and antiapoptotic functions of BCL2 and BCL-x(L) through BH3 binding. BID has biochemically separable functions in apoptosis and S-phase checkpoint, determined by post-translational modification. p53-induced PUMA is known only to have apoptotic function. Inhibition of apoptosis is oncogenic, whereas promotion of cell cycle arrest is tumor suppressive. Paradoxically, selected BCL2 family members can be both oncogenic and tumor suppressive. Which of the dual functions predominates is lineage specific and context dependent.
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PMID:BCL2 family in DNA damage and cell cycle control. 1676 16

The effects of different marine derived agents were studied in A549 cell growth. These drugs induced cell cycle arrest at the G2-M phase associated with the up-regulation of GADD45alpha-gamma and down-regulation of c-Myc. In treated cells, GADD45alpha-gamma and c-Myc were up- and down-regulated, respectively. A cascade of events leading to apoptotic mitochondrial 'intrinsic' pathway was observed in treated cells: (1) dephosphorylation of BAD serine136; (2) BAD dissociation from 14-3-3 followed by its association with BCL-XL; (3) cytochrome c release; (4) caspase-3 activation, and (5) cleavage of vimentin. Caspase(s) inhibitor prevented the formation of cleavage products and, in turn, apoptosis was inhibited through a p53-independent mechanism. Moreover, these compounds did not activate NF-kappaB. Our findings may offer new insights into the mechanisms of action of these agents in A549 cells. The better understanding of their effects might be important to fully exploit the potential of these new drugs.
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PMID:Characterization of apoptosis induced by marine natural products in non small cell lung cancer A549 cells. 1700 27

The phosphoinositide-3-kinase (PI3K)/Akt signaling pathway plays an important role in cell survival and the development of cancer. Macrophage migration inhibitory factor (MIF) is a critical inflammatory cytokine that was recently associated with tumorigenesis and that potently inhibits apoptosis. This may involve inhibition of p53-dependent genes, but the initiating molecular mechanism of how MIF controls survival/apoptosis is unknown. Here, we show that MIF prevents apoptosis and promotes tumor cell survival by directly activating the Akt pathway. MIF enhanced Akt activity in primary and immortalized fibroblasts (MEF and NIH/3T3), HeLa cervix carcinoma cells and various breast cancer cell lines. Activation was abolished by kinase inhibitors Ly294002 and PP2 and in Src/Yes/Fyn(SYF)(-/-) and CD74(-/-)(MEFs), while being enhanced in CD74-overexpressing MEFs, demonstrating that the MIF-induced Akt pathway encompasses signaling through the MIF receptor CD74 and the upstream kinases Src and PI3K. Akt was activated by exogenous rMIF and autocrine MIF action, as revealed by experiments in MIF(-/-)MEFs and antibody blockade. siRNA knockdown of CSN5/JAB1, a tumor marker and MIF-binding protein, showed that JAB1 controls autocrine MIF-mediated Akt signaling by inhibition of MIF secretion. Akt activation by MIF led to phosphorylation of the proapoptotic proteins BAD and Foxo3a. Apoptosis inhibition by MIF was functionally associated with Akt activation as it was abolished by overexpression of the Akt pathway inhibitor PTEN and occurred independently of p53. This was shown by studying DNA damage-induced apoptosis in fibroblasts, the Fas death pathway in HeLa cells that do not express functional p53, and etoposide-induced apoptosis in breast carcinoma cells expressing mutant p53. Importantly, dependence of breast cancer cell survival on MIF correlated with Akt activation and the PTEN status of these cells. Thus, MIF can directly promote cell survival through activation of the PI3K/Akt pathway and this effect is critical for tumor cell survival.
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PMID:Macrophage migration inhibitory factor (MIF) promotes cell survival by activation of the Akt pathway and role for CSN5/JAB1 in the control of autocrine MIF activity. 1731 Sep 86

A novel class of platinum(II) complexes of pyridine sulfide derivatives of triazine was synthesized, characterized, and investigated using the human breast cancer cell line, MDA-MB-468. S-30 was one of the most potent derivatives of its class (IC(50), 0.39 microM) eliciting the greatest biological response. S-30 induced arrest in the G1 phase and apoptosis (TUNEL assay) in a p53/p21(WAF1/CIP1)-consistent manner. Modeling and docking experiments were performed for three known targets for cisplatin, d(GpG), d(ApG), and a protein (Cu/Zn superoxide dismutase, SOD) from bovine origin. A Blast search of bovine SOD was performed to identify analogous human protein targets resulting in about 22 human proteins. A multi-sequence alignment of those targets showed >80% sequence identity and >88% similarity. One of them is SOD1 that is differentially expressed (based on global gene expression pattern) in various forms of cancer and other diseases. SOD1 controls apoptosis via p53/BAD/BAX/BCL2 in the amyotrophic lateral sclerosis (ALS) pathway and is also involved in various other KEGG's pathways. Results suggest that the S-30 is a potential cytotoxic agent.
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PMID:A new platinum complex of triazine demonstrates G1 arrest with novel biological profile in human breast cancer cell line, MDA-MB-468. 1732 43

Several lines of evidence indicate that, together with deregulated growth, alteration of apoptosis plays a pivotal role in tumorigenesis. PUMA, a pro-apoptotic member of Bcl-2 family, mediates p53-dependent and -independent apoptosis. BAD is also a pro-apoptotic Bcl-2 family member and phosphorylation of BAD protein inhibits the pro-apoptosis function of BAD. To see whether the alteration of protein expressions of PUMA and phospho-BAD (p-BAD) are characteristics of human colorectal cancers, we analyzed the expression of these proteins in 103 colorectal carcinomas by immunohistochemistry. Also, we analyzed the mutation of the Bcl-2 homology 3 (BH3) domain of PUMA gene, an important domain in the apoptosis function of PUMA, by single-strand conformation polymorphism (SSCP) in 98 colorectal carcinomas. p-BAD immunostaining was detected in 62 cases (60.1%) of the 103 carcinomas, whereas it was not detected in the normal colonic mucosal epithelial cells. PUMA protein expression was detected in both cancer cells and normal mucosal cells in all of the 103 cases. However, the cancer cells showed higher intensities of PUMA immunostaining than the normal cells of the same patients in 50.4% of the cases. There was no association of the p-BAD expression with the PUMA expression. The mutational analysis revealed no PUMA BH3 domain mutation in the cancers. Our data indicated that expressions of both PUMA and p-BAD were increased in the colorectal cancer cells, and suggested that the increased expression of these proteins in malignant colorectal epithelial cells compared to the normal mucosal epithelial cells may possibly alter the cell death regulation during colorectal tumorigenesis.
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PMID:Pro-apoptotic PUMA and anti-apoptotic phospho-BAD are highly expressed in colorectal carcinomas. 1739 17


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