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)

Resveratrol, a plant constituent enriched in the skin of grapes, is one of the most promising agents for the prevention of cancer. However, the mechanism of the anti-carcinogenic activity of resveratrol is not well understood. Here we offer a possible explanation of its anti-cancer effect. Resveratrol suppresses tumor promoter-induced cell transformation and markedly induces apoptosis, transactivation of p53 activity and expression of p53 protein in the same cell line and at the same dosage. Also, resveratrol-induced apoptosis occurs only in cells expressing wild-type p53 (p53+/+), but not in p53-deficient (p53-/-) cells, while there is no difference in apoptosis induction between normal lymphoblasts and sphingomyelinase-deficient cell lines. These results demonstrate for the first time that resveratrol induces apoptosis through activation of p53 activity, suggesting that its anti-tumor activity may occur through the induction of apoptosis.
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PMID:Resveratrol suppresses cell transformation and induces apoptosis through a p53-dependent pathway. 1006 59

Resveratrol (3,5,4'-trihydroxy-trans-stilbene), in the concentration range of 20 microM and above, induced arrest in the S-phase and apoptosis in the T cell-derived T-ALL lymphocytic leukemia cell line CEM-C7H2 which is deficient in functional p53 and p16. Expression of transgenic p16/INK4A, which causes arrest in G0/G1, markedly reduced the percentage of apoptotic cells. Antagonist antibodies to Fas or FasL, or constitutive expression of crmA did not diminish the extent of resveratrol-induced apoptosis. Furthermore, a caspase-8-negative, Fas-resistant Jurkat cell line was sensitive to resveratrol-induced apoptosis which could be strongly inhibited in the Jurkat as well as in the CEM cell line by z-VAD-fmk and z-IETD-fmk. The almost complete inhibition by z-IETD-fmk and the lack of inhibition by crmA suggested caspase-6 to be the essential initiator caspase. Western blots revealed the massive conversion of procaspase-6 to its active form, while caspase-3 and caspase-2 were proteolytically activated to a much lesser extent.
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PMID:Resveratrol causes arrest in the S-phase prior to Fas-independent apoptosis in CEM-C7H2 acute leukemia cells. 1104 78

Resveratrol, a trihydroxystilbene found in grapes and other plants, has been shown to be active in inhibiting multistage carcinogenesis. Using resveratrol as a prototype, we have synthesized a number of polyhydroxy- and polymethoxy-stilbenes and tested their anti-proliferative effect in normal and transformed human cells. Here we show that one of the resveratrol analogs, 3,4,5,4'-tetrahydroxystilbene (R-4), specifically inhibited the growth of SV40 virally transformed WI38 cells (WI38VA) at 10 microM, but had no effect on normal WI38 cells at even higher concentrations. R-4 also prominently induced apoptosis in WI38VA cells, but not in WI38 cells. RNase protection assay showed that R-4 significantly induced the expression of p53, GADD45 and Bax genes and concomitantly suppressed the expression of bcl-2 gene in WI38VA, but not in WI38 cells. A large increase in p53 DNA binding activity and the presence of p53 in the Bax promoter binding complex suggested that p53 was responsible for the Bax gene expression induced by R-4 in transformed cells. Within 4 h of treatment with R-4, the Bax to bcl-2 protein ratio in WI38 and WI38VA cells was, respectively, 0.1 and 105, a difference of three orders of magnitude. While R-4 prominently induced the p53/Bax pro-apoptotic genes, it also concomitantly suppressed the expression of Cox-2 in WI38VA cells. Taken together, our study suggests that the induction of p53 gene by R-4 in transformed cells may play a key role in the differential growth inhibition and apoptosis of transformed cells.
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PMID:Resveratrol analog, 3,4,5,4'-tetrahydroxystilbene, differentially induces pro-apoptotic p53/Bax gene expression and inhibits the growth of transformed cells but not their normal counterparts. 1118 55

Resveratrol, a phytoalexin found in grapes, berries, and peanuts, is one of the most promising agents for cancer prevention. Our previous study showed that the antitumor activity of resveratrol occurs through p53-mediated apoptosis. In this study, we have elucidated the potential signaling components underlying resveratrol-induced p53 activation and induction of apoptosis. We found that in a mouse JB6 epidermal cell line, resveratrol activated extracellular-signal-regulated protein kinases (ERKs), c-Jun NH2-terminal kinases (JNKs), and p38 kinase and induced serine 15 phosphorylation of p53. Stable expression of a dominant negative mutant of ERK2 or p38 kinase or their respective inhibitor, PD98059 or SB202190, repressed the phosphorylation of p53 at serine 15. In contrast, overexpression of a dominant negative mutant of JNKI had no effect on the phosphorylation. Most importantly, ERKs and p38 kinase formed a complex with p53 after treatment with resveratrol. Strikingly, resveratrol-activated ERKs and p38 kinase, but not JNKs, phosphorylated p53 at serine 15 in vitro. Furthermore, pretreatment of the cells with PD98059 or SB202190 or stable expression of a dominant negative mutant of ERK2 or p38 kinase impaired resveratrol-induced p53-dependent transcriptional activity and apoptosis, whereas constitutively active MEK1 increased the transcriptional activity of p53. These data strongly suggest that both ERKs and p38 kinase mediate resveratrol-induced activation of p53 and apoptosis through phosphorylation of p53 at serine 15.
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PMID:Resveratrol-induced activation of p53 and apoptosis is mediated by extracellular-signal-regulated protein kinases and p38 kinase. 1124 72

Resveratrol, a polyphenol present in wine and grapes, can inhibit tumor cell growth in vitro and tumorigenesis in vivo. Some of its effects have been linked to activation of the p53 tumor suppressor; however, p53 is frequently mutated in tumors, particularly in the common and often therapy-resistant colon cancers. Using the human wild-type p53-expressing HCT116 colon carcinoma cell line and HCT116 cells with both p53 alleles inactivated by homologous recombination, we show in the current study that resveratrol at concentrations comparable to those found in some foods can induce apoptosis independently of p53. The cell death is primarily mitochondria-mediated and not receptor-mediated. No cells survived in cultures continuously exposed to 100 microM resveratrol for 120 hr. When compared with 5-FU, resveratrol stimulated p53 accumulation and activity only weakly and with delayed kinetics and neither the increased levels nor the activity affected apoptosis detectably. The apoptosis agonist Bax was overproduced in response to resveratrol regardless of p53 status, yet the kinetics of Bax expression were influenced by p53. Remarkably, apoptosis was preceded by mitochondrial proliferation and signs of epithelial differentiation. Thus, resveratrol triggers a p53-independent apoptotic pathway in HCT116 cells that may be linked to differentiation.
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PMID:Resveratrol induces colon tumor cell apoptosis independently of p53 and precede by epithelial differentiation, mitochondrial proliferation and membrane potential collapse. 1174 54

Dietary phenolic substances including resveratrol, a stillbene compound, are found in several fruits and vegetables, and these compounds have been reported to have anti-oxidant, anti-inflammatory and antitumorigenic activities. However, the molecular mechanisms underlying the antitumorigenic or chemopreventive activities of these compounds remain largely unknown. The expression of NAG-1 [non-steroidal anti-inflammatory (NSAID) drug-activated gene-1], a member of the transforming growth factor-beta (TGF-beta) superfamily, has been shown to be associated with pro-apoptotic and antitumorigenic activities. Here, we have demonstrated that resveratrol induces NAG-1 expression and apoptosis in a concentration-dependent manner. Resveratrol increases the expression of p53, tumor suppressor protein, prior to NAG-1 induction, indicating that NAG-1 expression by resveratrol is mediated by p53 expression. We also show that the p53 binding sites within the promoter region of NAG-1 play a pivotal role to control NAG-1 expression by resveratrol. Derivatives of resveratrol were examined for NAG-1 induction, and the data suggest that resveratrol-induced NAG-1 and p53 induction is not dependent on its anti-oxidant activity. The data may provide linkage between p53, NAG-1 and resveratrol, and in part, a new clue to the molecular mechanism of the antitumorigenic activity of natural polyphenolic compounds.
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PMID:Resveratrol enhances the expression of non-steroidal anti-inflammatory drug-activated gene (NAG-1) by increasing the expression of p53. 1189 57

Resveratrol, a constituent of grapes and other foods, is one of the most promising agents for cancer prevention. In a previous study, we showed that the antitumor activity of resveratrol occurs through extracellular signal-regulated protein kinases (ERKs) and p38 kinase-mediated p53 activation. In this study, we also determined that c-jun NH(2)-terminal kinases (JNKs) are involved in resveratrol-induced p53 activation and induction of apoptosis. In the JB6 mouse epidermal cell line, resveratrol activated JNKs dose-dependently within a dose range of 10-40 microM, the same dosage responsible for the inhibition of tumor promoter-induced cell transformation. Stable expression of a dominant negative mutant of JNK1 or disruption of the Jnk1 or Jnk2 gene markedly inhibited resveratrol-induced p53-dependent transcription activity and induction of apoptosis. Furthermore, resveratrol-activated JNKs were shown to phosphorylate p53 in vitro, but this activity was repressed in the cells expressing a dominant negative mutant of JNK1 or in Jnk1 or Jnk2 knockout (Jnk1(-/-) or Jnk2(-/-)) cells. These data suggested that JNKs act as mediators of resveratrol-induced activation of p53 and apoptosis, which may occur partially through p53 phosphorylation.
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PMID:Involvement of c-jun NH(2)-terminal kinases in resveratrol-induced activation of p53 and apoptosis. 1193 78

Resveratrol, a natural phytoalexin, has gained much interest on the basis of its potential chemopreventive activity against human cancer. In this work, using the human breast cancer cell lines MCF-7 and MDA-MB-231, we have analyzed a possible mechanism by which resveratrol could interfere with cell cycle control and induce cell death. Our results show that although resveratrol inhibited cell proliferation and viability in both cell lines, apoptosis was induced in a concentration- and cell-specific manner. In MDA-MB-231, resveratrol (up to 200 microM) lowered the expression and kinase activities of positive G1/S and G2/M cell cycle regulators and inhibited ribonucleotide reductase activity in a concentration dependent manner, without a significant effect on the low expression of tumor suppressors p21, p27, and p53. These cells died by a non-apoptotic process in the absence of a significant change in cell cycle distribution. In MCF-7, resveratrol produced a significant and transient (<50 microM) increase in the expression and kinase activities of positive G1/S and G2/M regulators. Simultaneously, p21 expression was markedly induced in presence of high levels of p27 and p53. These opposing effects resulted in cell cycle blockade at the S-phase and apoptosis induction in MCF-7 cells. Thus, the antiproliferative activity of resveratrol could take place through the differential regulation of the cell cycle leading to apoptosis or necrosis. This could be influenced, among other factors, by the concentration of this molecule and by the characteristics of the target cell.
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PMID:The antiproliferative activity of resveratrol results in apoptosis in MCF-7 but not in MDA-MB-231 human breast cancer cells: cell-specific alteration of the cell cycle. 1239 19

Resveratrol, a phytoalexin found in many plants, has been reported to possess a wide range of pharmacological properties and is one of the promising chemopreventive agents for cancer. Here, we examined the antiproliferation effect of resveratrol in two human liver cancer cell lines, Hep G2 and Hep 3B. Our results showed that resveratrol inhibited cell growth in p53-positive Hep G2 cells only. This anticancer effect was a result of cellular apoptotic death induced by resveratrol via the p53-dependent pathway. Here we demonstrated that the resveratrol-treated cells were arrested in G1 phase and were associated with the increase of p21 expression. In addition, we also illustrated that the resveratrol-treated cells had enhanced Bax expression but they were not involved in Fas/APO-1 apoptotic signal pathway. In contrast, the p53-negative Hep 3B cells treated with resveratrol did not show the antiproliferation effect neither did they show significant changes in p21 nor Fas/APO-1 levels. In summary, our study demonstrated that the resveratrol effectively inhibited cell growth and induced programmed cell death in Hepatoma cells on a molecular basis. Furthermore, these results implied that resveratrol might also be a new potent chemopreventive drug candidate for liver cancer as it played an important role to trigger p53-mediated molecules involved in the mechanism of p53-dependent apoptotic signal pathway.
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PMID:Resveratrol- induced apoptosis is mediated by p53-dependent pathway in Hep G2 cells. 1240 42

Prostate cancer prevention by key elements present in human nutrients derived from plants and fruits has been confirmed in various cell cultures and tumor models. Resveratrol (RE), a phytoalexin, induces remarkable inhibitory effects in prostate carcinogenesis via diverse cellular mechanisms associated with tumor initiation, promotion and progression. Earlier studies have shown that RE alters the expression of genes involved in cell cycle regulation and apoptosis, including cyclins, cdks, p53 and cdk inhibitors. However, most of the p53-controlled effects related to the role of RE in transcription either by activation or repression of a sizable number of primary and secondary target genes have not been investigated. Our study examined whether RE activates a cascade of p53-directed genes that are involved in apoptosis mechanism(s) or whether it modifies the androgen receptor and its co-activators directly or indirectly and induces cell growth inhibition. We demonstrate by DNA microarray, RT-PCR, Western blot and immunofluorescence analyses that treatment of androgen-sensitive prostate cancer cells (LNCaP) with 10(-5) M RE for 48 hr downregulates prostate-specific antigen (PSA), AR co-activator ARA 24 and NF-kB p65. Altered expression of these genes is associated with an activation of p53-responsive genes such as p53, PIG 7, p21(Waf1-Cip1), p300/CBP and Apaf-1. The effect of RE on p300/CBP plays a central role in its cancer preventive mechanisms in LNCaP cells. Our results implicate activation of more than one set of functionally related molecular targets. At this point we have identified some of the key molecular targets associated with AR and p53 target genes. These findings point to the need for further extensive studies on AR co-activators, such as p300, its central role in post-translational modifications such as acetylation of p53 and/or AR by RE in a time- and dose-dependent manner at different stages of prostate cancer that will fully elucidate the role of RE as a chemopreventive agent for prostate cancer in humans.
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PMID:Differential expression of genes induced by resveratrol in LNCaP cells: P53-mediated molecular targets. 2727 1


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