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)

Ca(2+)-mobilizing compounds such as the Ca(2+) ionophore A23187 or the endoplasmic reticulum Ca(2+) ATPase inhibitor thapsigargin can suppress or induce apoptosis in the same cells. The use of different calcineurin inhibitors has shown that both suppression and induction of apoptosis by the Ca(2+)-mobilizing compounds were mediated by calcineurin activation. Ca(2+)-mobilizing compounds activated p38 and p44/42 mitogen-activated protein kinases (MAPKs). Induction of apoptosis by the Ca(2+)-mobilizing compounds was suppressed by an inhibitor of p38 MAPK but not by an inhibitor of p44/42 MAPK. These MAPK inhibitors did not suppress apoptosis induction by wild-type p53 or by withdrawal of IL-6 from IL-6-dependent cells that are mediated by calcineurin-independent pathways. These MAPK inhibitors also did not affect the ability of Ca(2+)-mobilizing compounds to suppress apoptosis. The results indicate that (i) Ca(2+)- mobilizing compounds activate different and opposing pathways that diverge downstream from calcineurin activation that can either suppress or induce apoptosis in the same cells; (ii) p38 MAPK but not p44/42 MAPK is involved in induction of apoptosis but not in its suppression by the Ca(2+)-mobilizing compounds; and (iii) neither p38 nor p44/42 MAPKs mediate induction of apoptosis by some calcineurin-independent pathways.
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PMID:Suppression or induction of apoptosis by opposing pathways downstream from calcium-activated calcineurin. 1051 68

Components of the ras signaling pathway contribute to activation of cellular p53. In MCF-7 cells, p38 kinase activated p53 more effectively than other members of the ras pathway. p53 and p38 kinase exist in the same physical complex, and co-expression of p38 stabilized p53 protein. In vitro, p38 kinase phosphorylated p53 at Ser33 and Ser46, a newly identified site. Mutation of these sites decreased p53-mediated and UV-induced apoptosis, and the reduction correlated with total abrogation of UV-induced phosphorylation on Ser37 and a significant decrease in Ser15 phosphorylation in mutant p53 containing alanine at Ser33 and Ser46. Inhibition of p38 activation after UV irradiation decreased phosphorylation of Ser33, Ser37 and Ser15, and also markedly reduced UV-induced apoptosis in a p53-dependent manner. These results suggest that p38 kinase plays a prominent role in an integrated regulation of N-terminal phosphorylation that regulates p53-mediated apoptosis after UV radiation.
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PMID:Phosphorylation of human p53 by p38 kinase coordinates N-terminal phosphorylation and apoptosis in response to UV radiation. 1058 Dec 58

gadd45 is a p53-regulated growth arrest and DNA-damage-inducible gene that is also regulated in a p53-independent manner. Whether Gadd45 plays a direct role in apoptosis remains unclear. Microinjection of the exogenous gadd45 expression vector into human fibroblasts has been shown to cause G2 arrest but not apoptosis. Recent studies suggest that Gadd45 may mediate genotoxic stress or Brca1-induced apoptosis via activation of c-Jun N-terminal kinase (JNK) and/or p38 mitogen-activated protein kinase (MAPK). Analyses of gadd45-deficient mice and cells have revealed that Gadd45 appears to exhibit pleiotropic effects, including cell cycle arrest at G2/M, DNA damage repair, and control of genomic stability, but is not required for radiation-induced apoptosis. Furthermore, stress-induced activation of JNK and p38 MAPK is not altered in gadd45-deficient embryonic fibroblasts, suggesting that the lack of Gadd45 may not affect the JNK and p38 MAPK activity. Thus, although the evidence from gadd45-null cells suggests that Gadd45 probably does not play a direct role in genotoxic stress-induced apoptosis, more in-depth studies are needed to firmly establish this contention.
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PMID:Role of Gadd45 in apoptosis. 1060 33

The s-Myc is similar to c-Myc in its ability to induce apoptosis requiring caspase activation. However, s-Myc is distinct from c-Myc in that it has activity to suppress tumor growth and does not require wild-type p53 to induce apoptosis. These facts suggest differential regulation between s-Myc and c-Myc. Here we showed that s-Myc-mediated apoptosis triggered by UV was not inhibited by the inactive form mutant JNK (APF), though c-Myc-mediated apoptosis was. Moreover, we found that JNK did not affect the transactivation activity of s-Myc, but stimulated that of c-Myc. In contrast, both Myc-mediated apoptosis and caspase-3-like protease activation were suppressed by kinase-negative MKK6 and an inactive form mutant p38(AGF). Our results indicate that s-Myc does not require the JNK signaling unlike c-Myc during UV-triggered apoptosis, but the MKK6/p38MAPK pathway might regulate common apoptotic machinery for both s-Myc and c-Myc upstream of caspase.
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PMID:Differential role of the JNK and p38 MAPK pathway in c-Myc- and s-Myc-mediated apoptosis. 1062 2

Two p53-null T lymphoma cell lines proved to be highly sensitive to inhibition of gene expression. With either actinomycin D or cycloheximide, apoptosis commenced within 2 h, as indicated by loss of membrane integrity, degradation of certain proteins (including the phosphatase calcineurin) and DNA fragmentation. These effects were ablated by co-expression of Bcl-2 or co-incubation with the caspase inhibitor Z-VAD-fmk. These results suggest that the apoptotic machinery is in place in these cells but held in check by an unknown labile protein, which probably acts upstream of Bcl-2. Although cycloheximide can activate the JNK or p38 MAP kinases in some cells, neither was implicated here. However, disruption of phosphoinositide 3-kinase signaling may be involved, because the cells were also sensitive to wortmannin. The high sensitivity of the p53-null lymphoma cells to inhibitors of gene expression suggests that such inhibitors might prove useful in the cytotoxic therapy of certain tumors.
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PMID:Interference with gene expression induces rapid apoptosis in p53-null T lymphoma cells. 1063 38

The c-Jun N-terminal kinases (JNKs, also called stress activated protein kinases. SAPKs) and p38 kinases constitute together with extracellular signal-regulated kinases (ERKs) the family of MAP kinases. Whereas the functions of JNKs under physiological conditions are largely unknown, there is raising evidence that JNKs are potent effectors of apoptosis or degeneration of neurons in vitro and in the brain. The activation of the inducible transcription factor c-Jun by N-terminal phosphorylation is a central event in JNK-mediated degenerative processes that depend on de novo protein synthesis. At the post-translational level, cytoplasmic degenerative actions of JNKs might comprise inhibition of Bcl-2 and steroid hormone-receptor signaling or hyperphosphorylation of tau; and at transcriptional level, JNKs might trigger the induction of the apoptotic effectors p53 and Fas-Ligand by phosphorylation of c-Jun. The role of p38 is the nervous system is poorly understood, but its activation is also considered as part of the neuronal stress response. This review informs about the genetic processing, the regulation of activity and the biochemical actions of JNK and p38 isoforms in general. In the second part, we summarize the findings on expression and activation of JNKs and p38 under neurodegenerative condition. A particular focus is also put on the putative function of JNK under physiological conditions and for neuroprotection.
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PMID:JNK and p38 stresskinases--degenerative effectors of signal-transduction-cascades in the nervous system. 1075 64

Phosphorylation of the p53 tumor suppressor protein is likely to play an important role in regulating its activity. Serine 15 phosphorylation of p53 leads to a stabilization of p53 by reducing its interaction with murine double minute 2, a negative regulatory partner. Recently, p53 was reported to be activated and phosphorylated at serine 15 following UV radiation. However, the signaling pathway that mediates UV-induced phosphorylation is less well characterized. Here, we provide evidence that UVB-induced phosphorylation of p53 at serine 15 is mediated directly by ERKs and p38 kinase. We find that in a mouse JB6 epidermal cell line, ERKs and p38 kinase form a complex with p53 following UVB radiation. Inhibition of ERKs or p38 kinase activity by the use of a dominant negative mutant of ERK2 or p38 kinase or their respective specific inhibitor, PD98059 or SB202190, results in abrogation of UVB-induced phosphorylation of p53 at serine 15. Strikingly, incubation of UVB-activated ERKs or p38 kinase immunoprecipitated complex with exogenous p53 shows serine 15 phosphorylation of both exogenous and co-precipitated endogenous p53 protein. Additionally, active recombinant ERK1/2 and p38 kinase but not JNKs are also able to phosphorylate p53 at serine 15 in vitro. Furthermore, pretreatment of cells with PD98059 or SB202190 blocks p53-dependent transcription activity but increases the level of p53 co-precipitated murine double minute. These results strongly suggest that both ERKs and p38 kinase have a direct role in UVB-induced phosphorylation of p53 at serine 15 in vivo.
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PMID:ERKs and p38 kinase phosphorylate p53 protein at serine 15 in response to UV radiation. 1078 82

The tumor suppressor p53 plays a central role in sensing damaged DNA and orchestrating the consequent cellular responses. However, how DNA damage leads to the activation of p53 is still poorly understood. In this study, we have found that the p38 mitogen-activated protein kinase (MAPK) plays a key role in the activation of p53 by genotoxic stress when provoked by chemotherapeutic agents. Indeed, we found that blockade of p38 prevents stimulation of the transcriptional activity of p53 and that activation of the p38 pathway is sufficient to stimulate p53 function. Furthermore, we observed that p38 does not affect the accumulation of p53 in response to DNA damage or its nuclear localization. In contrast, we observed that p38 associates physically with p53, and we provide evidence that this MAPK phosphorylates the NH2-terminal transactivation domain of p53 in serine 33, thereby stimulating its functional activity. Moreover, inhibition of the p38 MAPK diminished the apoptotic fraction of cells exposed to chemotherapeutic agents and increased cell survival, thus suggesting a role for p38 activation in the apoptotic response to genotoxic stress when elicited by drugs used in cancer therapy.
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PMID:A role for the p38 mitogen-acitvated protein kinase pathway in the transcriptional activation of p53 on genotoxic stress by chemotherapeutic agents. 1081 Nov 25

Photodynamic therapy (PDT) using the silicon phthalocyanine photosensitizer Pc 4 [HOSiPcOSi(CH3)2(CH2)3N-(CH3)2] is an oxidative stress associated with induction of apoptosis in various cell types. We assessed the effectiveness of Pc 4-PDT on SW480 colon cancer xenografts grown in athymic nude mice. Animals bearing xenografts were treated with 1 mg/kg body weight Pc 4 and 48 h later were irradiated with 150 J/cm2 672-nm light from a diode laser delivered at 150 mW/cm2. Biochemical studies were performed in xenografts resected at various time points up to 26 h after Pc 4-PDT treatment, whereas tumor size was evaluated over a 4-week period in parallel experiments. In the tumors resected for biochemical studies, apoptosis was visualized by activation of caspase-9 and caspase-3 and a gradual increase in the cleavage of the nuclear enzyme poly(ADP-ribose) polymerase (PARP) to a maximum of approximately 60% of the total PARP present at approximately 26 h. At that time all Pc 4-PDT-treated tumors had regressed significantly. Two signaling responses that have previously been shown to be associated with Pc 4-PDT-induced apoptosis in cultured cells, p38 mitogen-activated protein kinase and p21/WAF1/Cip1, were examined. A marked increase in phosphorylation of p38 was observed within 1 h after Pc 4-PDT without changes in levels of the p38 protein. Levels of p21 were not altered in the xenografts in correspondence with the presence of mutant p53 in SW480 cells. Evaluation of tumor size showed that tumor growth resumed after a delay of 9-15 days. Our results suggest that: (a) Pc 4-PDT is effective in the treatment of SW480 human colon cancer xenografts independent of p53 status; (b) PARP cleavage may be mediated by caspase-9 and caspase-3 activation in the Pc 4-PDT-treated tumors; and (c) p38 phosphorylation may be a trigger of apoptosis in response to PDT in vivo in this tumor model.
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PMID:Photodynamic therapy with the phthalocyanine photosensitizer Pc 4 of SW480 human colon cancer xenografts in athymic mice. 1081 28

Apoptosis is a normal physiological process which eliminates cells that do not receive adequate extracellular signals. One of the pathways signalling apoptosis is controlled by the small GTPases of the Rho family, also involved in cell proliferation, differentiation and motility. Another major apoptosis signalling pathway involves the p53 tumour suppressor which is activated by a variety of stress and mediates growth arrest or apoptosis in normal cells. We show here that upon detachment from the extracellular matrix, fibroblasts undergo rapid apoptosis that can be rescued by constitutive activation of Rac1 and Cdc42Hs GTPases. Conversely, inhibition of Rac1 and Cdc42Hs efficiently triggers apoptosis in adherent cells. Interestingly, apoptosis is not observed in p53-/- cells either cultured in suspension or inhibited for Rac1 and Cdc42Hs activity. Moreover, Rac1 and Cdc42Hs extinction in normal cells activates endogenous p53. Using specific inhibitors of MAPK pathways, we demonstrate that, in our experimental system, p38 signals survival, while ERK activity is required for apoptosis. Our data constitute the first demonstration that Rac1 and Cdc42Hs control pathways that require simultaneous signalling through MAPK ERK and p53 to induce apoptosis.
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PMID:Extinction of rac1 and Cdc42Hs signalling defines a novel p53-dependent apoptotic pathway. 1082 79


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