Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: 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)

Breast cancers lacking estrogen and progesterone receptor expression and Her2 amplification exhibit distinct gene expression profiles and clinical features, and they comprise the majority of BRCA1-associated tumors. Here we demonstrated that the p53 family member p63 controls a pathway for p73-dependent cisplatin sensitivity specific to these "triple-negative" tumors. In vivo, DeltaNp63 and TAp73 isoforms were coexpressed exclusively within a subset of triple-negative primary breast cancers that commonly exhibited mutational inactivation of p53. The DeltaNp63alpha isoform promoted survival of breast cancer cells by binding TAp73 and thereby inhibiting its proapoptotic activity. Consequently, inhibition of p63 by RNA interference led to TAp73-dependent induction of proapoptotic Bcl-2 family members and apoptosis. Breast cancer cells expressing DeltaNp63alpha and TAp73 exhibited cisplatin sensitivity that was uniquely dependent on TAp73. Thus, in response to treatment with cisplatin, but not other chemotherapeutic agents, TAp73 underwent c-Abl-dependent phosphorylation, which promoted dissociation of the DeltaNp63alpha/TAp73 protein complex, TAp73-dependent transcription of proapoptotic Bcl-2 family members, and apoptosis. These findings define p63 as a survival factor in a subset of breast cancers; furthermore, they provide what we believe to be a novel mechanism for cisplatin sensitivity in these triple-negative cancers, and they suggest that such cancers may share the cisplatin sensitivity of BRCA1-associated tumors.
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PMID:The p63/p73 network mediates chemosensitivity to cisplatin in a biologically defined subset of primary breast cancers. 1744 29

The proteasome inhibitor bortezomib is an efficacious inducer of apoptosis in the hepatoma HepG2 cell line. This study shows that bortezomib increased in these cells the level of the survival factor Hsp72 in a time- and dose-dependent manner. In a first phase of treatment, Hsp72 rapidly increased so that at 24 h of incubation with 50 nM bortezomib its level was approximately five-fold higher than the control. In this phase Hsp72 seemed to play a role in preventing HepG2 cell death, since it interacted with and sequestered the pro-apoptotic factors p53, AIF, Bax and Apaf-1. During a second day of treatment, although the nuclear levels of Hsp72, p53 and AIF increased, the interaction of Hsp72 with these factors diminished. In addition, bortezomib induced the activation of caspases, which stimulated Hsp72 degradation. In conclusion, in the second day of treatment with bortezomib the protective ability of Hsp72 decreased thus favouring the appearance of apoptosis.
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PMID:Hsp72 controls bortezomib-induced HepG2 cell death via interaction with pro-apoptotic factors. 1761 69

MDMX has been shown to modulate p53 in dividing cells after DNA damage. In this study, we investigated the role of MDMX in primary cultures of neurons undergoing cell death. We found that DNA damage, but also membrane-initiated apoptotic stresses (glutamate receptor; Amyloid beta precursor) or survival factor deprivation downregulated MDMX protein levels. Forced downregulation of murine double minute X (MDMX) by shRNA induced apoptosis suggesting that MDMX is required for survival in neurons. Protease inhibitors prevented the loss of MDMX after neurotoxic treatments, indicating a regulation of protein stability. Some, but not all, neurotoxic stresses induced phosphorylation of MDMX at serine 367, further supporting regulation at the protein level. Interestingly, we found that depending on the stimulus either p53 or E2F1 was induced, but overexpression of MDMX inhibited the transcriptional activity of both proapoptotic factors, and maintained neuronal viability upon neurotoxic stresses. Taken together, our data show that MDMX is an antiapoptotic factor in neurons, whose degradation is induced by various stresses and allows activation of p53 and E2F-1 during neuronal apoptosis.
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PMID:Multiple neurotoxic stresses converge on MDMX proteolysis to cause neuronal apoptosis. 1782 17

Natural (intrinsic) resistance of many tumor types to DNA damaging agents is closely associated with their capacity to undergo robust cell cycle arrest in G(2)/M. G(2) arrest is regulated by the DNA damage checkpoint and by survival signaling, with a potential role of PI3K/Akt in checkpoint function. In this work, we wanted to clarify if inhibition of multiple checkpoint/survival pathways may confer better efficacy in the potentiation of genotoxic agents compared to inhibition of either pathway alone. We compared the influence of UCN-01, which affects both the DNA damage checkpoint and PI3K/Akt-mediated survival signaling, with the PI3K inhibitors wortmannin and LY294002 in p53-deficient M1 acute myeloid leukemia cells treated with the DNA damaging agent cisplatin. Our results show that direct inhibition of PI3K/Akt in G(2)-arrested cells by wortmannin or LY294002 strongly enhanced the cytotoxicity of cisplatin without influencing the G(2) checkpoint. Unexpectedly, dual inhibition of both survival and checkpoint signaling by UCN-01, also increased the cytotoxicity of cisplatin, but to a lesser degree than wortmannin or LY294002. The differences in cytotoxicity were accompanied by differences in cell death pathways: direct inhibition of PI3K/Akt was accompanied by rapid apoptotic cell death during G(2), whereas cells underwent mitotic transit and cell division followed by cell death during G(1) when both checkpoint and survival signaling were inhibited. Our results elucidate a novel function for PI3K/Akt as a survival factor during DNA damage-induced G(2) arrest and could have important pharmacological consequences for the application of response modulators in p53-deficient tumors with strong survival signaling.
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PMID:Dual inhibition of PI3K/Akt signaling and the DNA damage checkpoint in p53-deficient cells with strong survival signaling: implications for cancer therapy. 1789 Sep 6

A fall in circulating levels of cardiac survival factor insulin-like growth factor 1 (IGF-1) contributes to cardiac aging. To better understand the role of IGF-1 in cardiac aging, we examined the influence of cardiac IGF-1 overexpression on lifespan, cardiomyocyte intracellular Ca2+ homeostasis, protein damage, apoptosis and expression of pro- and anti-apoptotic proteins in young and old mice. Mouse survival rate was constructed by the Kaplan-Meier curve. Intracellular Ca2+ was evaluated by fura-2 fluorescence. Protein damage was determined by protein carbonyl formation. Apoptosis was assessed by caspase-8 expression, caspase-3 and TUNEL (terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling) assay. Pro- and anti-apoptotic proteins including Bax, p53, pp53, Bcl2, Omi/HtrA2, apoptosis repressor with caspase recruitment domain (ARC) and X-linked inhibitor of apoptosis protein (XIAP) were assessed by Western blot. Aging decreased plasma in IGF-1 levels, elevated myocyte resting intracellular Ca2+ levels, reduced electrically stimulated rise in intracellular Ca2+ and delayed intracellular Ca2+ decay associated with enhanced protein carbonyl formation, caspase-8 expression and caspase-3 activity in FVB mice, all of which with the exception of elevated resting intracellular Ca2+ were attenuated by IGF-1. Aging up-regulated expression of Bax, Bcl2 and ARC, down-regulated XIAP expression and did not affect p53, pp53 and Omi/HtrA2. The IGF-1 transgene attenuated or nullified aging-induced changes in Bax, Bcl2 and XIAP. Our data suggest a beneficial role for IGF-1 in aging-induced survival, cardiac intracellular Ca2+ homeostasis, protein damage and apoptosis possibly related to pro- and anti-apoptotic proteins.
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PMID:Influence of cardiac-specific overexpression of insulin-like growth factor 1 on lifespan and aging-associated changes in cardiac intracellular Ca2+ homeostasis, protein damage and apoptotic protein expression. 1797 71

The adenoviral E1A-mediated sensitization to a variety of anti-cancer drug-induced apoptosis is a well-established phenomenon on different types of cell systems. However, the mechanisms underlying E1A-mediated chemosensitization are still not fully understood. Recent studies demonstrate that E1A-mediated sensitization to drug-induced apoptosis can occur via multiple pathways; some of which depend on the expression of functional p53 and/or p19ARF proteins, while some are not. In human breast cancer cells with Her-2/neu overexpression, which usually are more resistance to anti-cancer drugs than cells without Her-2/ neu overexpression, may be sensitized through E1A-mediated downregulation of Her-2/neu. Alternatively, E1A can induce sensitization to anticancer drugs in cancer cells or normal diploid fibroblast cells through upregulating the expression of caspase proenzymes, or downregulating the activity of a critical survival factor Akt and/or upregulating the activities of a pro-apoptotic kinase p38 and a protein phosphatase PP2A, etc. This review summarizes these progresses and proposes a plausible feed-forward model for E1A-mediated chemosensitization in human breast cancer cells.
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PMID:Novel approaches for chemosensitization of breast cancer cells: the E1A story. 1799 39

The oncogenic hepatitis B virus X protein (HBx) and cyclooxygenase (COX)-2 are highly co-expressed in chronic hepatitis, cirrhosis and well-differentiated hepatocellular carcinoma (HCC). Although HBx is shown to activate COX-2, the functional consequences of this interaction in hepatocarcinogenesis remain unknown. Using an engineered hepatoma cell system in which the expression of wild-type p53 can be chemically modulated, we show here that COX-2 mediates HBx actions in opposing p53. Enforced expression of HBx sequestrates p53 in the cytoplasm and significantly abolishes p53-induced apoptosis. The anti-apoptotic Mcl-1 protein is suppressed by p53 but reactivated by HBx. The abrogation of apoptosis is completely reversed by specific COX-2 inhibition, suggesting that HBx blocks p53-induced apoptosis via activation of COX-2/PGE(2) pathway. We further show that COX-2 inhibition blocks HBx reactivation of Mcl-1, linking this protein to the anti-apoptotic function of COX-2. These results demonstrate that COX-2 is an important survival factor mediating the oncogenic actions of HBx. Over-expression of HBx and COX-2 may provide a selective clonal advantage for preneoplastic or neoplastic hepatocytes and contribute to the initiation and progression of HCC.
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PMID:COX-2 mediates hepatitis B virus X protein abrogation of p53-induced apoptosis. 1860 5

The saturated fatty acid palmitate alters normal cell function via disruption of cell signaling, and this effect has been implicated in the end-organ damage associated with dyslipidemia. Neuregulin-1beta (NRG-1beta) is a growth and survival factor in cardiac myocytes. We tested the hypothesis that palmitate alters NRG-1beta signaling and biology in isolated neonatal rat cardiac myocytes. Palmitate treatment inhibited NRG-1beta activation of the PI3-kinase/Akt pathway in myocytes. We found that the pro-apoptotic activity of palmitate was increased by NRG-1beta treatment. The effects of palmitate on NRG-1beta signaling and survival were reversed by the mono-unsaturated fatty acid oleate. Under control conditions NRG-1beta decreases p53 expression in myocytes. In the presence of palmitate, NRG-1beta caused an increase in p53 expression, bax multimer formation, concurrent with degradation of mdm2, a negative regulator of p53. Thus in the presence of palmitate NRG-1beta activates pro-apoptotic, rather than pro-survival signaling in cardiac myocytes.
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PMID:Palmitate alters neuregulin signaling and biology in cardiac myocytes. 1907 May 92

The transcriptional regulator TBX2 is genetically amplified in several cancers and has, in addition, important roles in development. In carcinogenesis, TBX2 regulates the cell cycle by suppressing the expression of cyclin-dependent kinase (CDK) inhibitors and destabilizes p53 by suppressing expression of ARF. In embryogenesis, however, TBX2 appears to act independently of the cell cycle or p53 and is regulated by growth factors. Tumorigenic functions of TBX2 that are independent of p53 or cell cycle regulation remain poorly understood. Here we used SW13 carcinoma cells which express inactive p53 and have no detectable p16 or p21 CDK-inhibitors as a model to study these functions. Expression of TBX2 in SW13 cells had no effect on the cell cycle but promoted anchorage-independence and increased resistance to apoptotic stimuli including UV-irradiation, the cytotoxic drug doxorubicin and lethal endoplasmic-reticulum stress. This is a cell type-dependent effect as TBX2 overexpression in PANC1 pancreatic cancer cells which are p53-negative has no effect on colony formation or survival after irradiation. Mechanistically, in SW13 cells, TBX2 overexpression strongly reduced the activation of caspase 3, 8 and 9 following UV-irradiation but without altering the expression of the corresponding procaspases. There were, however, dramatic and specific decreases in the expression of procaspases 1 and 4. The expression of the inhibitor of apoptosis, cIAP2/BIRC3, increased in TBX2-overexpressing cells. TBX2 was upregulated in a PI3K-dependent manner by growth factors that are tumorigenic for SW13. Inhibition of Akt phosphorylation abrogates upregulation of TBX2 by FGF-4. Our findings identify TBX2 as a cell type-dependent survival factor under a p53-negative background, and are indicative of a potentially wider role for TBX2 in carcinogenesis than hitherto described.
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PMID:Expression of TBX2 promotes anchorage-independent growth and survival in the p53-negative SW13 adrenocortical carcinoma. 1921 23

Protein arginine methyltransferases (PRMTs) mediate the transfer of methyl groups to arginines in proteins involved in signal transduction, transcriptional regulation and RNA processing. Tumor suppressor p53 coordinates crucial cellular processes, including cell-cycle arrest and DNA repair, in response to stress signals. Post-translational modifications and interactions with co-factors are important to regulate p53 transcriptional activity. To explore whether PRMTs modulate p53 function, we generated multiple cell lines in which PRMT1, CARM1 and PRMT5 are inducibly knocked down. Here, we showed that PRMT5, but not PRMT1 or CARM1, is essential for cell proliferation and PRMT5 deficiency triggers cell-cycle arrest in G1. In addition, PRMT5 is required for p53 expression and induction of p53 targets MDM2 and p21 upon DNA damage. Importantly, we established that PRMT5 knockdown prevents p53 protein synthesis. Furthermore, we found that PRMT5 regulates the expression of translation initiation factor eIF4E and growth suppression mediated upon PRMT5 knockdown is independent of p53 but is dependent on eIF4E. Taken together, we uncovered that arginine methyltransferase PRMT5 is a major pro-survival factor regulating eIF4E expression and p53 translation.
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PMID:PRMT5 is required for cell-cycle progression and p53 tumor suppressor function. 1952 79


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