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

Constitutive activation of phosphatidylinositol 3-kinase (PI3K) confers resistance to apoptotic stimuli induced by chemotherapeutic agents in a variety of cancer cells. Therefore, the comprehension of mechanisms whereby PI3K downregulation interferes with chemotherapy is of major clinical interest for the elaboration of combined anticancer treatment modalities. Here, we examined the molecular mechanisms whereby the PI3K inhibitor LY294002 sensitized p53- and Fas-deficient hepatoma cells to etoposide and camptothecin. LY294002 increased Hep3B cell susceptibility to chemotherapy-induced apoptosis by enhancing the expression of DR4 and DR5 and the activation of caspase-8 and -3. Moreover, LY294002-mediated sensitization to chemotherapy involved mitochondrial Bax translocation and cytosolic cytochrome c accumulation. In Hep3B cells, LY294002 led to the reactivation of glycogen synthase kinase-3beta (GSK-3beta) by promoting its dephosphorylation on the serine 9 residue independently from Akt inhibition. The transient transfection of a constitutively active and non-phosphorylable S9AGSK-3beta mutant sensitized cells to etoposide cytotoxic effects while cell treatment with the small GSK-3beta inhibitor SB-415286 repressed the sensitizing effect of LY294002 on chemotherapy-induced apoptosis and caspase-8 activation. Altogether, our results show that LY294002 sensitizes hepatoma cells to chemotherapy-induced apoptosis via death receptor and mitochondria signalling pathways and that GSK-3beta reactivation is involved in this process. Therefore, PI3K-mediated GSK-3beta inhibition could be a mechanism by which cancer cells escape from chemotherapy-induced apoptosis.
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PMID:GSK-3beta reactivation with LY294002 sensitizes hepatoma cells to chemotherapy-induced apoptosis. 1594 63

The Mdm2 oncoprotein regulates abundance and activity of the p53 tumor suppressor protein. For efficient degradation of p53, Mdm2 needs to be phosphorylated at several contiguous residues within the central conserved domain. We show that glycogen synthase kinase 3 (GSK-3) phosphorylated the Mdm2 protein in vitro and in vivo in the central domain. Inhibition of GSK-3 rescued p53 from degradation in an Mdm2-dependent manner while its association with Mdm2 was not affected. Likewise, inhibition of GSK-3 did not alter localization of p53 and Mdm2 or the interaction of Mdm2 and MdmX. Ionizing radiation, which leads to p53 accumulation, directed phosphorylation of GSK-3 at serine 9, which preceded and overlapped with the increase in p53 levels. Moreover, expression of a GSK-3 mutant where serine 9 was replaced with an alanine reduced the accumulation of p53 and induction of its target p21(WAF-1). We therefore conclude that inhibition of GSK-3 contributes to hypophosphorylation of Mdm2 in response to ionizing rays, and in consequence to p53 stabilization.
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PMID:Glycogen synthase kinase 3-dependent phosphorylation of Mdm2 regulates p53 abundance. 1605 26

Activation of p53 tumor suppressor induces either cell cycle arrest or apoptosis through transcription-dependent and independent pathways; however, their relative roles in apoptosis induction and how these pathways are regulated remains elusive. Here, we report a unique role for glycogen synthesis kinase-3beta (GSK-3beta) in regulating p53 functions in human colorectal cancer cells. Pharmacologic modulation of GSK-3beta markedly impaired p53-dependent transactivation of targets including p21 and Puma but promoted p53-dependent conformational activation of Bax, resulting in cytochrome c release, loss of mitochondrial membrane potential, and caspase-9 processing. Thus, p53-mediated damage response is converted from cell cycle arrest to apoptosis following exposure to a variety of chemotherapeutic agents. We found that this effect is associated with the modulation of inhibitory Ser(9) phosphorylation of GSK-3beta but not with the activating tyrosine phosphorylation. We further show that the induction of apoptosis is through a direct mitochondrial pathway that requires Bax but not Puma. Our results underscore the importance of transcription-independent mechanism in p53-induced apoptosis and indicate that GSK-3beta plays distinct dual roles in regulating p53 pathways: promoting p53 transcriptional activity in the nucleus but suppressing p53-mediated direct apoptotic function at the mitochondria. Importantly, our data suggest that small-molecule inhibition of GSK-3beta might represent a novel approach for modulating chemotherapy.
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PMID:Pharmacologic modulation of glycogen synthase kinase-3beta promotes p53-dependent apoptosis through a direct Bax-mediated mitochondrial pathway in colorectal cancer cells. 1620 75

Beta-catenin is a bi-functional protein. It is not only a major component of the cellular adhesion machinery, but is also a transcription co-activator of the Wnt signaling pathway. The cytosolic levels of the beta-catenin protein, as well as its subcellular localization, are tightly regulated due to its oncogenic potentials. Two independent pathways are found to regulate beta-catenin. The canonical pathway is induced by the Axin/adenomatous polyposis coli (APC)/glycogen synthase kinase-3beta (GSK-3beta) complex which is dependent on GSK-3beta phosphorylation. The non-canonical pathway is mediated by p53-induced Siah-1 which is GSK-3beta phosphorylation-independent. Recently, several studies reported that IkappaB kinase alpha (IKKalpha) could stabilize beta-catenin and stimulate beta-catenin/T cell factor (Tcf)-dependent transcription. Here we report that IKKalpha could inhibit beta-catenin degradation mediated not only by the Axin/APC/GSK-3beta complex, but also by the Siah-1 pathway. Consistently, we found that IKKalpha abolished the inhibition of beta-catenin/Tcf-dependent transcription by Siah-1. Furthermore, we found that IKKalpha interacted with beta-catenin and inhibited beta-catenin ubiquitination. Taken together, our results provide a new insight into IKKalpha-mediated beta-catenin stabilization.
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PMID:IKKalpha stabilizes cytosolic beta-catenin by inhibiting both canonical and non-canonical degradation pathways. 1661 28

Indirubin, an isomer of indigo, is a reported inhibitor of cyclin-dependent kinases (CDKs) and glycogen synthase kinase-3 (GSK-3) as well as an agonist of the aryl hydrocarbon receptor (AhR). Indirubin is the active ingredient of a traditional Chinese medicinal recipe used against chronic myelocytic leukemia. Numerous indirubin analogs have been synthesized to optimize this promising kinase inhibitor scaffold. We report here on the cellular effects of 7-bromoindirubin-3'-oxime (7BIO). In contrast to its 5-bromo- and 6-bromo- isomers, and to indirubin-3'-oxime, 7BIO has only a marginal inhibitory activity towards CDKs and GSK-3. Unexpectedly, 7BIO triggers a rapid cell death process distinct from apoptosis. 7-Bromoindirubin-3'-oxime induces the appearance of large pycnotic nuclei, without classical features of apoptosis such as chromatin condensation and nuclear fragmentation. 7-Bromoindirubin-3'-oxime-induced cell death is not accompanied by cytochrome c release neither by any measurable effector caspase activation. Furthermore, the death process is not altered either by the presence of Q-VD-OPh, a broad-spectrum caspase inhibitor, or the overexpression of Bcl-2 and Bcl-XL proteins. Neither AhR nor p53 is required during 7BIO-induced cell death. Thus, in contrast to previously described indirubins, 7BIO triggers the activation of non-apoptotic cell death, possibly through necroptosis or autophagy. Although their molecular targets remain to be identified, 7-substituted indirubins may constitute a new class of potential antitumor compounds that would retain their activity in cells refractory to apoptosis.
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PMID:7-Bromoindirubin-3'-oxime induces caspase-independent cell death. 1670 56

Latency-associated nuclear antigen (LANA) encoded by open reading frame 73 (ORF73) is the major latent protein expressed in all forms of KSHV-associated malignancies. LANA is a large (222-234 kDa) nuclear protein that interacts with various cellular as well as viral proteins. LANA has been classified as an oncogenic protein as it dysregulates various cellular pathways including tumor suppressor pathways associated with pRb and p53 and can transform primary rat embryo fibroblasts in cooperation with the cellular oncogene Hras. It associates with GSK-3beta, an important modulator of Wnt signaling pathway leading to the accumulation of cytoplasmic beta-catenin, which upregulates Tcf/Lef regulated genes after entering into the nucleus. LANA also blocks the expression of RTA, the reactivation transcriptional activator, which is critical for the latency to lytic switch, and thus helps in maintaining viral latency. LANA tethers the viral episomal DNA to the host chromosomes by directly binding to its cognate binding sequence within the TR region of the genome through its C terminus and to the nucleosomes through the N terminus of the molecule. Tethering to the host chromosomes helps in efficient partitioning of the viral episomes in the dividing cells. Disruptions of LANA expression led to reduction in the episomal copies of the viral DNA, supporting its role in persistence of the viral DNA. The functions known so far suggest that LANA is a key player in KSHV-mediated pathogenesis.
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PMID:Structure and function of latency-associated nuclear antigen. 1708 95

The NSAID activated gene (NAG-1), a member of the TGF-beta superfamily, is involved in tumor progression and development. The over-expression of NAG-1 in cancer cells results in growth arrest and increase in apoptosis, suggesting that NAG-1 has anti-tumorigenic activity. This conclusion is further supported by results of experiments with transgenic mice that ubiquitously express human NAG-1. These transgenic mice are resistant to the development of intestinal tumors following treatment with azoxymethane or by introduction of a mutant APC gene. In contrast, other data suggest a pro-tumorigenic role for NAG-1, for example, high expression of NAG-1 is frequently observed in tumors. NAG-1 may be like other members of the TGF-beta superfamily, acting as a tumor suppressor in the early stages, but acting pro-tumorigenic at the later stages of tumor progression. The expression of NAG-1 can be increased by treatment with drugs and chemicals documented to prevent tumor formation and development. Most notable is the increase in NAG-1 expression by the inhibitors of cyclooxygenases that prevent human colorectal cancer development. The regulation of NAG-1 is complex, but these agents act through either p53 or EGR-1 related pathways. In addition, an increase in NAG-1 is observed in inhibition of the AKT/GSK-3beta pathway, suggesting NAG-1 alters cell survival. Thus, NAG-1 expression is regulated by tumor suppressor pathways and appears to modulate tumor progression.
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PMID:NSAID activated gene (NAG-1), a modulator of tumorigenesis. 1712 98

HIV-1 protease inhibitor (PI), nelfinavir (NFV) induced growth arrest and apoptosis of NCI-H460 and -H520, A549, EBC-1 and ABC-1 non-small-cell lung cancer (NSCLC) cells in association with upregulation of p21waf1, p27kip1 and p53, and downregulation of Bcl-2 and matrix metalloproteinase (MMP)-2 proteins. We found that NFV blocked Akt signalling in these cells as measured by Akt kinase assay with glycogen synthase kinase-3alpha/beta (GSK-3alpha/beta) as a substrate. To explore the role of Akt signalling in NFV-mediated growth inhibition of NSCLC cells, we blocked this signal pathway by transfection of Akt small interfering RNA (siRNA) in these cells; transient transfection of Akt siRNA in NCI-H460 cells decreased the level of Bcl-2 protein and slowed their proliferation compared to the nonspecific siRNA-transfected cells. Conversely, forced-expression of Akt partially reversed NFV-mediated growth inhibition of these cells, suggesting that Akt may be a molecular target of NFV in NSCLC cells. Also, we found that inhibition of Akt signalling by NFV enhanced the ability of docetaxel to inhibit the growth of NCI-H460 and -H520 cells, as measured by MTT assay. Importantly, NFV slowed the proliferation and induced apoptosis of NCI-H460 cells present as tumour xenografts in nude mice without adverse systemic effects. Taken together, this family of compounds might be useful for the treatment of individuals with NSCLC.
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PMID:NFV, an HIV-1 protease inhibitor, induces growth arrest, reduced Akt signalling, apoptosis and docetaxel sensitisation in NSCLC cell lines. 1713 72

Prodigiosin (2-methyl-3-pentyl-6-methoxyprodigiosene) is a bacterial metabolite that has anticancer and antimetastatic properties. However, the molecular mechanisms responsible for these abilities are not fully understood. Gene expression profiling of the human breast cancer cell line MCF-7 treated with prodigiosin was analyzed by cDNA array technology. The majority of the significantly modified genes were related to apoptosis, cell cycle, cellular adhesion, or transcription regulation. The dramatic increase of the nonsteroidal anti-inflammatory drug-activated gene 1 (NAG-1) made this gene an interesting candidate regarding the possible mechanism by which prodigiosin induces cytotoxicity in MCF-7 cells. Our results show that prodigiosin triggers accumulation of the DNA-damage response tumor-suppressor protein p53 but that NAG-1 induction was independent of p53 accumulation. Moreover, prodigiosin caused AKT dephosphorylation and glycogen synthase kinase-3beta (GSK-3beta) activation, which correlated with NAG-1 expression. Prodigiosin-induced apoptosis was recovered by inhibiting GSK-3beta, which might be due, at least in part, to the blockade of the GSK-3beta-dependent up-regulation of death receptors 4 and 5 expression. These findings suggest that prodigiosin-mediated GSK-3beta activation is a key event in regulating the molecular pathways that trigger the apoptosis induced by this anticancer agent.
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PMID:Prodigiosin induces the proapoptotic gene NAG-1 via glycogen synthase kinase-3beta activity in human breast cancer cells. 1723 95

UV irradiation has been reported to induce p21(WAF1/CIP1) protein degradation through a ubiquitin-proteasome pathway, but the underlying biochemical mechanism remains to be elucidated. Here, we show that ser-114 phosphorylation of p21 protein by glycogen synthase kinase 3beta (GSK-3beta) is required for its degradation in response to UV irradiation and that GSK-3beta activation is a downstream event in the ATR signaling pathway triggered by UV. UV transiently increased GSK-3beta activity, and this increase could be blocked by caffeine or by ATR small interfering RNA, indicating ATR-dependent activation of GSK-3beta. ser-114, located within the putative GSK-3beta target sequence, was phosphorylated by GSK-3beta upon UV exposure. The nonphosphorylatable S114A mutant of p21 was protected from UV-induced destabilization. Degradation of p21 protein by UV irradiation was independent of p53 status and prevented by proteasome inhibitors. In contrast to the previous report, the proteasomal degradation of p21 appeared to be ubiquitination independent. These data show that GSK-3beta is activated by UV irradiation through the ATR signaling pathway and phosphorylates p21 at ser-114 for its degradation by the proteasome. To our knowledge, this is the first demonstration of GSK-3beta as the missing link between UV-induced ATR activation and p21 degradation.
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PMID:Glycogen synthase kinase 3beta phosphorylates p21WAF1/CIP1 for proteasomal degradation after UV irradiation. 1728 49


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