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)

Malignant transformation of cells is associated with changes in gene expression. Gross alterations in chromatin organization may be involved in such gene dysregulation, as well as the involvement of specific transcription factors. Specialized genomic DNA segments that exhibit high affinity to the nuclear matrix in vitro have been designated as matrix/scaffold attachment regions (MARs/SARs). MARs are postulated to anchor chromatin onto the nuclear matrix, thereby organizing genomic DNA into topologically distinct loop domains that are important in replication and transcription. In support of this notion, MARs often colocalize or exist in close proximity to regulatory sequences including enhancers. Base unpairing regions (BURs) are typically 100-150 bp regions within MARs, possess an intrinsic propensity to unwind under negative superhelical strain, and are considered to be hallmark of MARs. To investigate a potential mechanism that could lead to significant alterations in gene expression in cancer cells, this review focuses on a group of chromatin-associated proteins that specifically recognize double stranded BURs. Several important proteins have been identified from cancer cells as BUR-binding proteins, including poly (ADP-ribose) polymerase (PARP-1), Ku autoantigen, SAF-A, HMG-I(Y), nucleolin and p53. Many of these proteins are dramatically upregulated in malignancy of the breast. Increase in the amount of these BUR-binding proteins, some of which are known to interact with each other, may not only provide an architectural core but also recruit functional multi-molecular complexes at the base of chromatin loops to affect multiple distant genes. Experimental strategies by which these proteins can be exploited as carcinoma-specific diagnostic markers and as targets for antineoplastic therapy are discussed.
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PMID:Chromatin (dis)organization and cancer: BUR-binding proteins as biomarkers for cancer. 1218 16

In previous studies with mice the oxygen radical generating neurotoxin tertiary butylhydroperoxide (t-BuOOH) was used to mimic the oxidative injury that has been implicated in neurodegenerative diseases. In addition, previous studies have shown that the poly (ADP-ribose) polymerase (PARP) inhibitor nicotinamide is able to prevent DNA fragmentation and apoptosis that is induced by t-BuOOH in mouse brain. However, the molecular mechanism(s) by which nicotinamide is able to protect human brain cells at the cellular level is not clear. Therefore in this study a cell culture model system with human cortical neuronal cells (HCN2 cells) has been employed where the molecular mechanism(s) of nicotinamide action, both in the presence and absence of t-BuOOH has been studied. Human cortical neurons (HCN2 cells) have been shown to differentiate to a neuron-like morphology. In this study, exposure of HCN2 cells to t-BuOOH resulted in altered morphology and disruption of neuronal differentiation leading to cell death. However, in neurons, which were treated with nicotinamide before being exposed to t-BuOOH, neuronal differentiation was preserved; morphological disruption was prevented and cell death was reduced significantly. Moreover, our studies indicate that nicotinamide is able to prevent the up-regulation of the pro-apoptotic proteins p53 and p21/WAF-1, and the down-regulation of the anti-apoptotic protein bcl-2 that is induced by t-BuOOH in HCN2 cells. Thus this study indicates that nicotinamide protects human brain cells from the toxic effects of free radical generating toxins by regulating the levels of various pro- and anti-apoptotic proteins.
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PMID:Nicotinamide protects HCN2 cells from the free radical generating toxin, tertiary butylhydroperoxide (t-BuOOH). 1270 97

Although damage to white matter occurs in the brains of patients with Alzheimer's disease (AD), the underlying mechanisms are unknown. Recent findings suggest that individuals with elevated levels of homocysteine are at increased risk of AD. Here we show that oligodendrocytes from mice expressing a mutant form of presenilin-1 (PS1) that causes familial AD exhibit increased sensitivity to death induced by homocysteine compared to oligodendrocytes from wild-type control mice. Homocysteine also sensitized oligodendrocytes to the cytotoxicity of amyloid beta-peptide. Folate deficiency, which is known to result in elevated levels of homocysteine in vivo, also sensitized oligodendrocytes to the cell-death-promoting actions of mutant PS1 and amyloid beta-peptide. Inhibitors of poly (ADP-ribose) polymerase and p53 protected oligodendrocytes against cell death induced by homocysteine and amyloid beta-peptide, consistent with a role for a DNA-damage response in the cell death process. These findings demonstrate an adverse effect of homocysteine on oligodendrocytes, and suggest roles for homocysteine and folate deficiency in the white matter damage in AD and related neurodegenerative disorders.
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PMID:Homocysteine and folate deficiency sensitize oligodendrocytes to the cell death-promoting effects of a presenilin-1 mutation and amyloid beta-peptide. 1272 94

We have recently shown that oral consumption of green tea polyphenols inhibits prostate carcinogenesis in transgenic mouse model of prostate cancer and suggested that induction of apoptosis in prostate cancer cells is responsible for these effects. Much of the chemopreventive effects of green tea are attributed to its major polyphenolic constituent (-) epigallocatechin-3-gallate (EGCG). In the present study, we report that EGCG-induced apoptosis in human prostate carcinoma LNCaP cells is mediated via modulation of two related pathways: (a) stabilization of p53 by phosphorylation on critical serine residues and p14ARF-mediated downregulation of murine double minute 2(MDM2) protein, and (b) negative regulation of NF-kappaB activity, thereby decreasing the expression of the proapoptotic protein Bcl-2. EGCG-induced stabilization of p53 caused an upregulation in its transcriptional activity, thereby resulting in activation of its downstream targets p21/WAF1 and Bax. Thus, EGCG had a concurrent effect on two important transcription factors p53 and NF-kappaB, causing a change in the ratio of Bax/Bcl-2 in a manner that favors apoptosis. This altered expression of Bcl-2 family members triggered the activation of initiator capsases 9 and 8 followed by activation of effector caspase 3. Activation of the caspases was followed by poly (ADP-ribose) polymerase cleavage and induction of apoptosis. Taken together, the data indicate that EGCG induces apoptosis in human prostate carcinoma cells by shifting the balance between pro- and antiapoptotic proteins in favor of apoptosis.
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PMID:Role of p53 and NF-kappaB in epigallocatechin-3-gallate-induced apoptosis of LNCaP cells. 1289 26

In this study, we examined the effects of isoform-specific functional inhibitors of lysophosphatidic acid acyltransferase (LPAAT), which converts lysophosphatidic acid to phosphatidic acid, on multiple myeloma (MM) cell growth and survival. The LPAAT-beta inhibitors CT-32176, CT-32458, and CT-32615 induced >95% growth inhibition (P < 0.01) in MM.1S, U266, and RPMI8226 MM cell lines, as well as MM cells from patients (IC(50), 50-200 nM). We further characterized this LPAAT-beta inhibitory effect using CT-32615, the most potent inhibitor of MM cell growth. CT-32615 triggered apoptosis in MM cells via caspase-8, caspase-3, caspase-7, and poly (ADP-ribose) polymerase cleavage. Neither interleukin 6 nor insulin-like growth factor I inhibited CT-32615-induced apoptosis. Dexamethasone and immunomodulatory derivatives of thalidomide (IMiDs), but not proteasome inhibitor PS-341, augmented MM cell apoptosis triggered by LPAAT-beta inhibitors. CT-32615-induced apoptosis was associated with phosphorylation of p53 and c-Jun NH(2)-terminal kinase (JNK); conversely, JNK inhibitor SP600125 and dominant-negative JNK inhibited CT-32615-induced apoptosis. Importantly, CT-32615 inhibited tumor necrosis factor-alpha-triggered nuclear factor-kappaB activation but did not affect either tumor necrosis factor-alpha-induced p38 mitogen-activated protein kinase phosphorylation or interleukin 6-triggered signal transducers and activators of transcription 3 phosphorylation. Finally, although binding of MM cells to bone marrow stromal cells augments MM cell growth and protects against dexamethasone-induced apoptosis, CT-32615 induced apoptosis even of adherent MM cells. Our data therefore demonstrate for the first time that inhibiting LPAAT-beta induces cytotoxicity in MM cells in the bone marrow milieu, providing the framework for clinical trials of these novel agents in MM.
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PMID:Antitumor activity of lysophosphatidic acid acyltransferase-beta inhibitors, a novel class of agents, in multiple myeloma. 1467 6

Previously, we demonstrated that a plant steroid, diosgenin, altered cell cycle distribution and induced apoptosis in the human osteosarcoma 1547 cell line. The objective of this study was to investigate if the antiproliferative effect of diosgenin was similar for different human cancer cell lines such as laryngocarcinoma HEp-2 and melanoma M4Beu cells. Moreover, this work essentially focused on the mitochondrial pathway. We found that diosgenin had an important and similar antiproliferative effect on different types of cancer cells. In addition, our new results show that diosgenin-induced apoptosis is caspase-3 dependent with a fall of mitochondrial membrane potential, nuclear localization of AIF and poly (ADP-ribose) polymerase cleavage. Diosgenin treatment also induces p53 activation and cell cycle arrest in the different cell lines studied.
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PMID:Induction of antiproliferative effect by diosgenin through activation of p53, release of apoptosis-inducing factor (AIF) and modulation of caspase-3 activity in different human cancer cells. 1522 12

There is persuasive epidemiological and experimental evidence that dietary polyphenolic plant-derived compounds have anticancer activity. Many laboratories, including ours, have reported such an effect in cancers of the gastrointestinal tract, lung, skin, prostate and breast. The catechins are a group of polyphenols found in green tea, which is one of the most commonly consumed beverages in the world. While the preponderance of the data strongly indicates significant antitumorigenic benefits from the green tea catechins, the potential molecular mechanisms involved remain obscure. We found that green tea components induce apoptosis via a TGF-beta superfamily protein, NAG-1 (Non-steroidal anti-inflammatory drug Activated Gene). In this report, we show that ECG is the strongest NAG-1 inducer among the tested catechins and that treatment of HCT-116 cells results in an increasing G(1) sub-population, and cleavage of poly (ADP-ribose) polymerase (PARP), consistent with apoptosis. In contrast, other catechins do not significantly induce NAG-1 expression, PARP cleavage or morphological changes at up to a 50-microM concentration. Furthermore, we provide evidence that ECG induces the ATF3 transcription factor, followed by NAG-1 induction at the transcriptional level in a p53-independent manner. The data generated by this study will help elucidate mechanisms of action for components in green tea and this information may lead to the design of more effective anticancer agents and informed clinical trials.
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PMID:Epicatechin gallate-induced expression of NAG-1 is associated with growth inhibition and apoptosis in colon cancer cells. 1530 87

The present study examines the effects of ionizing radiation in combination with rituximab (RTX), a chimeric human anti-CD20 monoclonal antibody, on proliferation, cell cycle distribution and apoptosis in B-lymphoma RL and Raji cells. Exposure to ionizing radiation (9 Gy) induced cell growth delay and apoptosis in RL cells, whereas Raji cells showed moderate radio-resistance. The simultaneous exposure of lymphoma cells to ionizing radiation and RTX (10 microg/mL) markedly enhanced apoptosis and cell growth delay in RL and Raji cells. Cooperative antiproliferative and apoptotic effects of RTX and radiation were achieved through the inhibition of c-myc and bcl-XL expression. Furthermore, RTX-modulated expression of cell cycle regulating proteins, such as p53, p21/WAF1, p27/KIP1, contributed to the development of radiation-induced cell killing and growth arrest. Each NHL cell line that underwent apoptosis induced by combination treatment revealed enhanced caspase-3 and poly (ADP-ribose) polymerase (PARP) cleavage as compared to only irradiated cells. These findings show that rituximab synergistically enhances radiation-induced apoptosis and cell growth delay through the expression of proteins involved in the programmed cell death and cell cycle regulation pathways.
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PMID:Pretreatment with rituximab enhances radiosensitivity of non-Hodgkin's lymphoma cells. 1598 43

Drug resistance has been a major limitation to chemotherapy. There are many mechanisms that contribute to such resistance. In our study, we subcloned oridonin-sensitive and low sensitive L929 cells and both types of cells grew at almost the same growth rate. The acquired low sensitivity to oridonin-induced apoptosis was associated with Bcl-2 up-regulation and down-regulation of p53 phosphorylation. The p38 inhibitor SB203580 decreased Bcl-2 expression in the low sensitive L929 cells and made the cells more sensitive to oridonin. Moreover, a higher dose of oridonin promoted p53 phosphorylation, increased Bax expression and subsequently induced death of low sensitive L929 cells, however, it had no effect on Bcl-2 expression. The increased Bcl-2/Bax ratio in oridonin low sensitive L929 cells did not inhibit caspase-9 or -3 activation, but suppressed the cleavage of poly (ADP-ribose) polymerase (PARP), indicating the existence of caspase-9 or -3 independent PARP activation. These results indicated that in L929 cells, there was a relationship among the low sensitivity to oridonin, down-regulation of p53 phosphorylation and Bcl-2 up-regulation.
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PMID:Bcl-2 up-regulation and P-p53 down-regulation account for the low sensitivity of murine L929 fibrosarcoma cells to oridonin-induced apoptosis. 1627 91

In a search for new anticancer agents, we have identified serratamolide (AT514), a cyclodepsipeptide from Serratia marcescens 2170 that induces cell cycle arrest and apoptosis in various cancer cell lines. A cell viability assay showed that the concentrations that cause 50% inhibition (IC50) in human cancer cell lines range from 5.6 to 11.5 microM depending on the cell line. Flow cytometry analysis revealed that AT514 caused cell cycle arrest in G0/G1 or cell death, depending on the cell type and the length of time for which the cells were exposed to the drug. Subsequent studies revealed that AT514-induced cell death is caused by apoptosis, as indicated by caspases activation (8, 9, 2 and 3) and cleavage of poly (ADP-ribose) polymerase (PARP), release of cytochrome c and apoptosis inducing factor (AIF) from mitochondria, and the appearance of apoptotic bodies and DNA laddering. Alterations in protein levels of Bcl-2 family members might be involved in the mitochondrial disruption observed. AT514 induced p53 accumulation in wild-type p53 cells but cell death was observed in both deficient and wild-type p53 cells. Our results indicate that AT514 induces cell cycle arrest and apoptosis in breast cancer cells irrespectively of p53 status, suggesting that it might represent a potential new chemotherapeutic agent.
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PMID:Cell cycle arrest and proapoptotic effects of the anticancer cyclodepsipeptide serratamolide (AT514) are independent of p53 status in breast cancer cells. 1629 46


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