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)

The kinesin spindle protein (KSP), a microtubule motor protein, is essential for the formation of bipolar spindles during mitosis. Inhibition of KSP activates the spindle checkpoint and causes apoptosis. It was shown that prolonged inhibition of KSP activates Bax and caspase-3, which requires a competent spindle checkpoint and couples with mitotic slippage. Here we investigated how Bax is activated by KSP inhibition and the roles of Bax and p53 in KSP inhibitor-induced apoptosis. We demonstrate that small interfering RNA-mediated knockdown of Bax greatly attenuates KSP inhibitor-induced apoptosis and that Bax activation is upstream of caspase activation. This indicates that Bax mediates the lethality of KSP inhibitors and that KSP inhibition provokes apoptosis via the intrinsic apoptotic pathway where Bax activation is prior to caspase activation. Although the BH3-only protein Puma is induced after mitotic slippage, suppression of de novo protein synthesis that abrogates Puma induction does not block activation of Bax or caspase-3, indicating that Bax activation is triggered by a posttranslational event. Comparison of KSP inhibitor-induced apoptosis between matched cell lines containing either functional or deficient p53 reveals that inhibition of KSP induces apoptosis independently of p53 and that p53 is dispensable for spindle checkpoint function. Thus, KSP inhibitors should be active in p53-deficient tumors.
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PMID:An inhibitor of the kinesin spindle protein activates the intrinsic apoptotic pathway independently of p53 and de novo protein synthesis. 1710 92

The tumor microenvironment is now recognized as a major factor that influences not only the response to conventional anti-cancer therapies but also helps define the potential for malignant progression and metastasis. In particular, hypoxia is now considered a fundamentally important characteristic of the tumor microenvironment. Furthermore, discovery of the hypoxia inducible factor 1alpha (HIF-1alpha) has led to a rapidly increasing understanding of the molecular mechanisms involved in tumor hypoxia. This in turn has led to the current extensive interest in the signal molecules related to tumor hypoxia as potential molecular targets for cancer therapeutics. In this paper we give an overview of recent advances in hypoxia research, including cancer treatments that target tumor hypoxia. Progress in the development of hypoxia-targeting drugs will be discussed, including antiangiogenic hypoxic cell radiosensitizers and hypoxic cytotoxins, hypoxia targeting boron carriers and p53-inhibiting bifunctional radiosensitizers. We will also review our own recent research results in these areas. For example, we have found that certain of the 2-nitroimidazole radiosensitizers and heterocycle-N-oxide hypoxic cytotoxins we developed have antiangiogenic activity and antimetastatic activity. We propose that these activities are based on the inhibition of signal transduction mediated by HIF-1alpha. The anti-tumor activities of hypoxia response are considered to be cytostatic (tumor dormancy-inducing) effects in contrast to cytotoxic DNA damaging effects. The combination of these cytostatic effects that are related to radiosensitization with the cytotoxic effects of radiation should improve the prognosis and QOL of patients receiving radiation and lead to an overall response to treatment. Based on these considerations, we developed the antiangiogenic hypoxic cell radiosensitizers, TX-1877, TX-1898 and the hypoxic cytotoxin TX-402 that inhibits the HIF-1alpha pathway We will also discuss our research involved with the development of other drugs to exploit tumor hypoxia, including a hypoxia-targeting boron carrier for boron neutron capture therapy (BNCT) and a p53 inhibiting radiosensitizer.
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PMID:Design of hypoxia-targeting drugs as new cancer chemotherapeutics. 1714 59

Regulation of cerebellar neural precursor cell (NPC) death is important for both normal brain development and prevention of brain tumor formation. The tumor suppressor p53 is an important regulator of NPC apoptosis, but the precise mechanism of p53-regulated cerebellar NPC death remains largely unknown. Here, by using primary cerebellar NPCs and a mouse cerebellar NPC line, we compared the molecular regulation of cerebellar NPC death produced by staurosporine (STS), a broad-spectrum kinase inhibitor, with that caused by genotoxic agents. We found that both STS- and genotoxin-induced cerebellar NPC death were markedly inhibited by p53 or Bax deficiency. Genotoxin-induced cerebellar NPC death required new protein synthesis and PUMA, a p53 transcriptionally regulated BH3-only molecule. In contrast, STS caused cerebellar NPC death without requiring new protein synthesis or PUMA expression. In addition, genotoxic agents increased nuclear p53 immunoreactivity, whereas STS produced rapid cytoplasmic p53 accumulation. Interestingly, STS-induced death of cerebellar granule neurons was p53-independent, indicating a differentiation-dependent feature of neuronal apoptotic regulation. These results suggest that STS-induced cerebellar NPC death requires a direct effect of p53 on cytoplasmic apoptotic mediators, whereas genotoxin-induced death requires p53-dependent gene transcription of PUMA. Thus, p53 has multiple death promoting mechanisms in cerebellar NPCs.
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PMID:p53 transcription-dependent and -independent regulation of cerebellar neural precursor cell apoptosis. 1720 38

Fenretinide-induced apoptosis of neuroectodermal tumour cells is mediated through generation of reactive oxygen species (ROS), endoplasmic reticulum (ER) stress, mitochondrial cytochrome c release and caspase activation. The present study describes the requirement of the BH3-domain only protein Noxa for this process and its regulation by p53. Noxa expression was induced by fenretinide in neuroblastoma and melanoma cells, including those with mutated p53, and this induction was abolished by antioxidants. Knockdown of p53 by RNA interference (RNAi) demonstrated upregulation of Noxa protein levels in response to fenretinide was p53-independent, although evidence suggested that Noxa may be transcriptionally regulated by p53. The ER stress-inducing agent thapsigargin also induced p53-independent Noxa expression. Conversely, Noxa transcription in response to the chemotherapeutic agents cisplatin or temozolomide was inhibited by p53 knockdown. Apoptosis in response to cisplatin or temozolomide was also inhibited by abrogation of p53 expression yet apoptosis in response to fenretinide or thapsigargin was unaffected. RNAi-mediated down-regulation of Noxa inhibited apoptosis in response to fenretinide or thapsigargin, whereas apoptosis induced by cisplatin or temozolomide was unaffected. These data demonstrate the importance of Noxa induction in determining the apoptotic response to fenretinide and emphasise the role of Noxa in p53-independent apoptosis.
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PMID:Role of Noxa in p53-independent fenretinide-induced apoptosis of neuroectodermal tumours. 1721 84

p53-upregulated modulator of apoptosis (PUMA) is a BH3-only Bcl-2 family protein and an essential mediator of DNA damage-induced apoptosis. PUMA is localized in the mitochondria and induces apoptosis through the mitochondrial pathway. However, the mechanisms of PUMA-induced apoptosis remain unclear. In this study, we found that second mitochondria-derived activator of caspase (SMAC)/Diablo, a mitochondrial apoptogenic protein, mediates the proapoptotic function of PUMA by regulating PUMA-induced mitochondrial events. SMAC is consistently released into the cytosol in colon cancer cells undergoing PUMA-induced apoptosis. In SMAC-deficient cells, execution of PUMA-induced apoptosis is abrogated, in company with decreases in caspase activation, cytosolic release of cytochrome c and collapse of mitochondrial membrane potential. Reconstituting SMAC expression restored these events in the SMAC-deficient cells. Furthermore, SMAC and agents that mimic the inhibitor of apoptosis proteins (IAPs) inhibition function of SMAC significantly sensitize cells to PUMA-induced apoptosis. These results demonstrate an important role of SMAC in executing DNA damage-induced and PUMA-mediated apoptosis and suggest that SMAC participates in a feedback amplification loop to promote cytochrome c release and other mitochondrial events in apoptosis.
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PMID:SMAC/Diablo mediates the proapoptotic function of PUMA by regulating PUMA-induced mitochondrial events. 1723 24

To identify the mechanisms of ultraviolet radiation (UVR)-induced cell death, for which the tumor suppressor p53 is essential, we have analyzed mouse embryonic fibroblasts (MEFs) and keratinocytes in mouse skin that have specific apoptotic pathways blocked genetically. Blocking the death receptor pathway provided no protection to MEFs, whereas UVR-induced apoptosis was potently inhibited by Bcl-2 overexpression, implicating the mitochondrial pathway. Indeed, Bcl-2 overexpression boosted cell survival more than p53 loss, revealing a p53-independent pathway controlled by the Bcl-2 family. Analysis of primary MEFs lacking individual members of its BH3-only subfamily identified major initiating roles for the p53 targets Noxa and Puma. In the transformed derivatives, where Puma, unexpectedly, was not induced by UVR, Noxa had the dominant role and Bim a minor role. Furthermore, loss of Noxa suppressed the formation of apoptotic keratinocytes in the skin of UV-irradiated mice. Collectively, these results demonstrate that UVR activates the Bcl-2-regulated apoptotic pathway predominantly through activation of Noxa and, depending on cellular context, Puma.
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PMID:Ultraviolet radiation triggers apoptosis of fibroblasts and skin keratinocytes mainly via the BH3-only protein Noxa. 1728 83

The tumor suppressor p53 can induce apoptosis by activating gene expression in the nucleus, or by directly permeabilizing mitochondria in the cytoplasm. It has been shown that PUMA, a downstream target of p53 and a BH3-only Bcl-2 family member, plays an essential role in apoptosis induced by both nuclear and cytoplasmic p53. To understand how PUMA does so, we used homologous recombination to delete the binding sites of p53 in the promoter of PUMA in human colorectal cancer cells. As a result, the induction of PUMA and apoptosis in response to p53 and DNA-damaging agents were abrogated. Transcription coactivator recruitment and histone modifications in the PUMA promoter were suppressed. However, induction of PUMA and apoptosis in response to non-DNA-damaging stimuli were unaffected. These results indicate that the binding of nuclear p53 to the specific sites within the PUMA promoter is essential for its ability to induce apoptosis and is likely to be required for its tumor suppressive capacity.
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PMID:The nuclear function of p53 is required for PUMA-mediated apoptosis induced by DNA damage. 1736 Apr 76

NOXA is a BH3-only protein whose expression is induced by certain p53-depenent or independent apoptotic stimuli. Both NOXA and Bim are avid binders of Mcl-1, but a functional linkage between these BH3-only proteins has not yet been reported. In this study, we demonstrate that Mcl-1 binding of endogenously induced NOXA interferes with the ability of Mcl-1 to efficiently sequester endogenous Bim, as Bim is displaced from its complex with Mcl-1. Induced NOXA significantly enhances the UV sensitivity of cells, and the ensuing mitochondrial depolarization is entirely abrogated by Bim knockdown. These results demonstrate a Mcl-1-mediated cross-talk between endogenous NOXA and Bim that occurs upstream of the Bak/Bax-dependent execution of UV-induced mitochondrial depolarization. The current findings demonstrate that the mitochondrial response to an induced expression of NOXA is executed by endogenous Bim and suggest a plausible mechanism for the observed NOXA-Bim linkage.
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PMID:Functional linkage between NOXA and Bim in mitochondrial apoptotic events. 1737 15

Histone deacetylase inhibitors (HDACi) can elicit a range of biological responses that affect tumor growth and survival, including inhibition of cell cycle progression, induction of tumor cell-selective apoptosis, suppression of angiogenesis, and modulation of immune responses, and show promising activity against hematological malignancies in clinical trials. Using the Emu-myc model of B cell lymphoma, we screened tumors with defined genetic alterations in apoptotic pathways for therapeutic responsiveness to the HDACi vorinostat. We demonstrated a direct correlation between induction of tumor cell apoptosis in vivo and therapeutic efficacy. Vorinostat did not require p53 activity or a functional death receptor pathway to kill Emu-myc lymphomas and mediate a therapeutic response but depended on activation of the intrinsic apoptotic pathway with the proapoptotic BH3-only proteins Bid and Bim playing an important role. Our studies provide important information regarding the mechanisms of action of HDACi that have broad implications regarding stratification of patients receiving HDACi therapy alone or in combination with other anticancer agents.
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PMID:Analysis of the apoptotic and therapeutic activities of histone deacetylase inhibitors by using a mouse model of B cell lymphoma. 1747 Jul 84

Dysfunction of mitochondrial complex I is associated with a wide spectrum of neurodegenerative disorders, including Parkinson's disease (PD). In rodents, inhibition of complex I leads to degeneration of dopaminergic neurons of the substantia nigra pars compacta (SNpc), as seen in PD, through activation of mitochondria-dependent apoptotic molecular pathways. In this scenario, complex I blockade increases the soluble pool of cytochrome c in the mitochondrial intermembrane space through oxidative mechanisms, whereas activation of pro-cell death protein Bax is actually necessary to trigger neuronal death by permeabilizing the outer mitochondrial membrane and releasing cytochrome c into the cytosol. Activation of Bax after complex I inhibition relies on its transcriptional induction and translocation to the mitochondria. How complex I deficiency leads to Bax activation is currently unknown. Using gene-targeted mice, we show that the tumor suppressor p53 mediates Bax transcriptional induction after PD-related complex I blockade in vivo, but it does not participate in Bax mitochondrial translocation in this model, either by a transcription-independent mechanism or through the induction of BH3-only proteins Puma or Noxa. Instead, Bax mitochondrial translocation in this model relies mainly on the JNK-dependent activation of the BH3-only protein Bim. Targeting either Bax transcriptional induction or Bax mitochondrial translocation results in a marked attenuation of SNpc dopaminergic cell death caused by complex I inhibition. These results provide further insight into the pathogenesis of PD neurodegeneration and identify molecular targets of potential therapeutic significance for this disabling neurological illness.
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PMID:Two molecular pathways initiate mitochondria-dependent dopaminergic neurodegeneration in experimental Parkinson's disease. 1748 59


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