UNIPROT:P04637 - FACTA Search

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Query: UNIPROT:P04637 (p53)
77,613 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Persistent activation of c-Jun N-terminal kinases (JNKs) and phosphorylation of c-Jun has been shown in various cell death paradigms. Inhibition of the JNK signal transduction pathway prevented neuronal cell death both in vitro and in vivo. In the present study, nuclear phospho-c-Jun immunoreactivity became apparent selectively in vulnerable hippocampal CA1 neurons at 24 h after transient global cerebral ischemia. A high constitutive expression of phospho-JNK1 was detected by immunoblot analysis of hippocampal extracts. Expression of JNK interacting protein-1 (JIP-1), which facilitates JNK signaling, remained unchanged in post-ischemic hippocampal neurons. By contrast, p53-activated gene 608 (PAG608), which promotes cell death in vitro, was strongly induced in post-ischemic CA1 neurons. Our data suggest that transcription factors p53 and phospho-c-Jun may contribute to programmed CA1 cell death following ischemia.
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PMID:Expression of cell death-associated phospho-c-Jun and p53-activated gene 608 in hippocampal CA1 neurons following global ischemia. 1058 7

c-Jun N-terminal kinase (JNK) plays a critical role in coordinating the cellular response to stress and has been implicated in regulating cell growth and transformation. To investigate the growth-regulatory functions of JNK1 and JNK2, we used specific antisense oligonucleotides (AS) to inhibit their expression. A survey of several human tumor cell lines revealed that JNKAS treatment markedly inhibited the growth of cells with mutant p53 status but not that of cells with normal p53 function. To further examine the influence of p53 on cell sensitivity to JNKAS treatment, we compared the responsiveness of RKO, MCF-7, and HCT116 cells with normal p53 function to that of RKO E6, MCF-7 E6, and HCT116 p53(-/-), which were rendered p53 deficient by different methods. Inhibition of JNK2 (and to a lesser extent JNK1) expression dramatically reduced the growth of p53-deficient cells but not that of their normal counterparts. JNK2AS-induced growth inhibition was correlated with significant apoptosis. JNK2AS treatment induced the expression of the cyclin-dependent kinase inhibitor p21(Cip1/Waf1) in parental MCF-7, RKO, and HCT116 cells but not in the p53-deficient derivatives. That p21(Cip1/Waf1) expression contributes to the survival of JNK2AS-treated cells was supported by additional experiments demonstrating that p21(Cip1/Waf1) deficiency in HCT116 cells also results in heightened sensitivity to JNKAS treatment. Our results indicate that perturbation of JNK2 expression adversely affects the growth of otherwise nonstressed cells. p53 and its downstream effector p21(Cip1/Waf1) are important in counteracting these detrimental effects and promoting cell survival.
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PMID:Inhibition of c-Jun N-terminal kinase 2 expression suppresses growth and induces apoptosis of human tumor cells in a p53-dependent manner. 1066 48

A member of the small G protein family, cdc42, was isolated from a screen undertaken to identify p53-inducible genes during apoptosis in primary baby rat kidney (BRK) cells transformed with E1A and a temperature-sensitive mutant p53 using a PCR-based subtractive hybridization method. Cdc42 is a GTPase that belongs to the Rho/Rac subfamily of Ras-like GTPases. In response to external stimuli, Cdc42 is known to transduce signals to regulate the organization of the actin cytoskeleton, induce DNA synthesis in quiescent fibroblasts, and promote apoptosis in neuronal and immune cells. In this study, we have demonstrated that cdc42 mRNA and protein were up-regulated in the presence of wild-type p53 in BRK cells, followed by cytoplasmic to plasma membrane translocation of Cdc42. Overexpression of Cdc42 in the presence of a dominant-negative mutant p53 induced apoptosis rapidly, indicating that Cdc42 functions downstream of p53. Furthermore, stable expression of a dominant-negative mutant of Cdc42 partially inhibited p53-mediated apoptosis. The Bcl-2 family members Bcl-xL, and the adenovirus protein E1B 19K, inhibited Cdc42-mediated apoptosis, whereas Bcl-2 did not. We provide evidence that PAK1 and JNK1 may play a role downstream of Cdc42 to transduce its apoptotic signal. Cdc42/PAK1 activates JNK1-induced phosphorylation of Bcl-2, thereby inactivating its function, and that a phosphorylation resistant mutant (Bcl-2S70,87A,T56,74A) gains the ability to inhibit Cdc42- and p53-mediated apoptosis. Thus, one mechanism by which p53 promotes apoptosis is through activation of Cdc42 and inactivation of Bcl-2.
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PMID:p53 mediates bcl-2 phosphorylation and apoptosis via activation of the Cdc42/JNK1 pathway. 1107 43

The p53-regulated stress-inducible gene GADD45 has been shown to participate in cellular response to DNA damage, including cell cycle checkpoint, apoptosis, and DNA repair. However, the regulation of GADD45 expression is complex and may involve both p53-dependent and -independent pathways. Recent findings have demonstrated that the p53-independent induction of GADD45 is mainly regulated by the transcription factors Oct-1 and NF-YA, which directly bind to their consensus motifs located at the GADD45 promoter region. Here, we report that mitogen-activated protein (MAP) kinases are involved in the induction of the GADD45 promoter after DNA damage. Inhibition of JNK1 and ERK kinase activities either by expression of the dominant negative mutant JNK1 or by treatment with a selective chemical inhibitor of ERK (PD098059) substantially abrogates the UV induction of the GADD45 promoter. In contrast, a p38 kinase inhibitor (SB203580) has little effect on GADD45 induction by UV. In addition, the GADD45 promoter is strongly activated following expression of JNK1; Raf-1, which is an upstream activator of the ERK pathway; or MEK1, an upstream activator of both the ERK and the JNK pathways. Activation of the GADD45 promoter by MAP kinases does not require normal p53 function. Interestingly, the MAP kinase-regulatory effect appears to be mediated via OCT-1 and CAAT motifs since disruption of these sites abrogates activation of the GADD45 promoter by MAP kinases. Therefore, these findings indicate that the MAP kinase pathways are involved in the regulation of the p53-independent induction of the GADD45 promoter, probably via interaction with transcription factors that directly bind to OCT-1 and CAAT motifs.
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PMID:Involvement of the MAP kinase pathways in induction of GADD45 following UV radiation. 1152 40

Phosphorylation of the p53 tumor suppressor protein is one of the key regulatory steps in its activation process. Serine 20 phosphorylation of p53 has been shown to be required for the activation of p53 following UV radiation, but the signaling pathway mediating UV-induced phosphorylation is unknown. Here, we determined the role of MAP kinases in UVB-induced phosphorylation and found that JNKs are directly involved in the phosphorylation of p53 at serine 20. In a mouse JB6 epidermal cell line, dominant negative JNK1 abrogated UVB-induced phosphorylation of p53 at serine 20, whereas dominant negative p38 kinase or its inhibitor, SB202190, partially attenuated the phosphorylation. In contrast, dominant negative ERK2 or the MEK1 inhibitor, PD98059, had no effect on p53 phosphorylation at serine 20. Importantly, UVB-activated or active recombinant JNK1/2, or the p38 kinase downstream target, MAPKAPK-2, but not ERKs or p38 kinase, phosphorylated p53 at serine 20 in vitro. Furthermore, phosphorylation of p53 at serine 20 by UVB-activated JNKs and UVB-induced p53-dependent transcriptional activity were suppressed in Jnk1 or Jnk2 knockout (Jnk1(-/-) or Jnk2(-/-)) cells. Additionally, Jnk1(-/-), Jnk2(-/-), and p53-deficient (p53(-/-)) cells, as well as re-introduction of a p53 mutant with substitution of serine 20 to alanine into p53(-/-) cells, were defective for UVB-induced apoptosis. These findings strongly suggest that JNKs are the major direct signaling mediators of UVB-induced p53 phosphorylation at serine 20.
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PMID:Role of MAP kinases in UVB-induced phosphorylation of p53 at serine 20. 1189 87

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

Paclitaxel is able to cause cell death through the induction of apoptosis. Cell death characteristics for docetaxel have not yet been described in detail. We investigated four unselected human ovarian cancer cell lines for the sensitivity to a 1hr exposure to docetaxel and calculated the concentrations inhibiting 50% (IC(50)) and 90% (IC(90)) of cell growth. Of the cell lines A2780, H134, IGROV-1 (all wild-type p53) and OVCAR-3 (mutant, mt p53) A2780 was most sensitive and OVCAR-3 least sensitive. Equitoxic drug concentrations representing IC(90) values (25-510nM) were applied for 1hr to measure cell cycle distribution, DNA degradation, and to count apoptotic cell bodies and cells with multifragmented nuclei at various time-points after drug exposure. H134, IGROV-1 and OVCAR-3 showed a continued mitotic block up to at least 72hr and prolonged presence of cells with multifragmented nuclei. High percentages of apoptosis were calculated at 48hr and at later time-points. In contrast, A2780 cells accumulated in the S-phase of the cell cycle and apoptosis was hardly present. The changes in the expression levels of p53, p21/WAF1, Bax and Bcl-2, were not predictive for docetaxel-induced apoptosis. Caspase-3 activation occurred only in cells with accumulation in the G2/M phase starting as early as 8hr in OVCAR-3. Prolonged Bcl-2 phosphorylation was evident in OVCAR-3, visible at 24hr in H134 and IGROV-1, while this phenomenon did not occur in A2780. The mitogen-activated protein kinase pathway (JNKs/SAPKs or c-Jun N-terminal kinases/stress-activated protein kinases, JNK1/2; extracellular response kinase, ERK1/2; p38) did not seem to be directly involved in Bcl-2 phosphorylation or apoptosis. We conclude that docetaxel is able to activate caspase-3, induce Bcl-2 phosphorylation and apoptosis in cells that show a prolonged G2/M arrest, but cells may also die by a caspase-3-independent cell death mechanism.
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PMID:Variation in the kinetics of caspase-3 activation, Bcl-2 phosphorylation and apoptotic morphology in unselected human ovarian cancer cell lines as a response to docetaxel. 1199 42

Microtubule-interfering agents are widely used in cancer chemotherapy, and prognostic results vary significantly from tumor to tumor, depending on the p53 status. In preliminary experiments, we compared the expression and phosphorylation profiles of more than 100 protein kinases and protein phosphatases in human colorectal carcinoma cell line HCT116 between p53+/+ and p53-/- cells in response to short term nocodazole treatment through application of Kinetworks immunoblotting screens. Among the proteins tracked, the regulation of the phosphorylation of c-Jun N-terminal kinase (JNK)1/2 at Thr-183/Tyr-185 was the major difference between p53+/+ and p53-/- cells. With the loss of the p53 gene, the levels of phosphorylation of Ser-63 of c-Jun and Thr-183/Tyr-185 of JNK1/2 in p53-/- cells did not increase as markedly as in p53+/+ cells in response to a 1-h treatment with nocodazole or other microtubule-disrupting drugs such as vinblastine and colchicine. Similar observations were also made in MCF-7 and A549 tumor cells, which were rendered p53-deficient by E6 oncoprotein expression. However, arsenate-induced JNK activation in p53-/- cells was preserved. Inhibition of p53 expression by its antisense oligonucleotide also attenuated nocodazole-induced JNK activation in p53+/+ cells. Surprisingly, cotransfection of p53+/+ cells with dominant negative mutants of JNK isoforms and treatment of p53+/+ cells with the JNK inhibitor SP600125 actually further enhanced apoptosis in p53+/+ cells by up to 2-fold in response to nocodazole. These findings indicate that inhibition of p53-mediated JNK1/2 activity in certain tumor cells could serve to enhance the apoptosis-inducing actions of cancer chemotherapeutic agents that disrupt mitotic spindle function.
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PMID:Nocodazole-induced p53-dependent c-Jun N-terminal kinase activation reduces apoptosis in human colon carcinoma HCT116 cells. 1222 Oct 76

Arsenic is a well-documented human carcinogen associated with cancers of the skin, lung, liver, and bladder. Interestingly, arsenic has also been used as an effective chemotherapeutic agent in the treatment of certain human cancers. However, the mechanisms by which arsenic induces proliferation of cancer cells or cancer cell death are not well understood. We found that exposure of JB6 P+ cells to low concentrations of arsenic induces cell transformation, whereas higher concentrations of arsenic induce cell apoptosis. Arsenite induces phosphorylation of extracellular signal-regulated protein kinases (Erks) and c-Jun NH(2)-terminal kinases (JNKs). Arsenite-induced Erk activation was markedly inhibited by introduction of dominant-negative Erk2 into cells, whereas expression of dominant-negative Erk2 did not inhibit JNKs or mitogen-activated protein kinase Erk kinase 1/2. Furthermore, arsenite-induced cell transformation was blocked in cells expressing dominant-negative Erk2. In contrast, overexpression of dominant-negative JNK1 increased cell transformation even though it inhibited arsenite-induced JNK activation. Arsenic also induced AP-1 and nuclear factor kappa B (NF-kappaB) activation. Blocking NF-kappaB activation by dominant-negative inhibitory kappa Balpha inhibited arsenic-induced apoptosis and enhanced arsenic-induced cell transformation. Arsenic induced activation of JNKs at a similar dose range that was effective for induction of apoptosis in JB6 cells. In addition, we found that arsenic did not induce p53-dependent transactivation. Similarly, apoptosis induction was not different between p53 wild-type (p53(+/+)) or p53-deficient (p53(-/-)) cells. In contrast, arsenic-induced apoptosis was almost totally blocked by expression of a dominant-negative mutant of JNK. Taken together with previous findings that p53 mutations are involved in approximately 50% of all human cancers and nearly all chemotherapeutic agents kill cancer cells mainly by apoptotic induction, we suggest that arsenic may be a useful agent for the treatment of cancers with p53 mutations. These results suggest that the activation of Erks is required for arsenic-induced cell transformation, whereas the activation of JNKs and NF-kappaB is involved in arsenic-induced apoptosis of JB6 cells.
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PMID:The molecular mechanisms of arsenic-induced cell transformation and apoptosis. 1242 27

Exposure of mammalian cells to genotoxic stress results in activation of the c-jun amino-terminal kinase (JNK)-stress-activated protein kinase (SAPK) pathway and induction of DNA repair enzymes and cell cycle-regulatory proteins such as p53 and p21waf1. The p53 tumor suppressor protein transmits signals that activate p21waf1 gene expression. The p21waf1 protein then restricts cell-cycle progression, thereby allowing time for DNA repair to occur. In this study, we investigated the effects of modulation of the level of wild-type and mutant p53 protein on basal JNK1 activity in the A1-5 rat fibroblast cell line. This cell line contains a p53 gene coding for a temperature-sensitive p53 protein, which allows us to regulate the relative level of wild-type and mutant p53 protein produced in cells. Using the immune complex kinase assay to measure JNK1 activity, we demonstrated that cells expressing the wild-type-conformation p53 protein (when grown at 32.5 degrees C) exhibited a very low level of JNK1 activity. When cells were grown at 37 degrees C or 39 degrees C to express predominantly mutant p53 protein, basal level of JNK1 activity was significantly higher than at 32.5 degrees C. We also demonstrated protein-protein interactions between the p53, p21waf1, and JNK1 proteins in this cell line. Both wild-type p53 protein (expressed at 32.5 degrees C) and mutant p53(val135) protein (expressed at 37 degrees C and 39 degrees C) were present in immunocomplexes of JNK1 protein. Under conditions where wild-type p53 protein was present to induce p21waf1 expression (at 32.5 degrees C), a higher level of p21waf1 protein was also detected in the JNK1 immunocomplexes than in those at 37 degrees C and 39 degrees C. We next investigated the effect that co-association of p53 protein and p21waf1 protein would have on JNK1 activity. We measured basal levels of JNK1 activity in cells expressing wild-type p53 and p21waf1, or in p21waf1-null cells, and demonstrated that cells expressing both p53 and p21waf1 proteins exhibited an approximately threefold lower basal level of JNK1 activity when compared with p21waf1-null cells. To confirm that p21waf1 protein expression in cells resulted in reduced JNK1 activity, we transfected p21waf1-/- cells with a p21waf1 expression vector. We observed that JNK1 activity was inhibited after exogenous p21waf1 protein was expressed in these cells. Our results provide evidence for modulation of the JNK1 pathway by p53 and p21waf1 proteins and support the hypothesis that modulation of JNK1 activity occurred through protein-protein interactions between JNK1, p53, and p21waf1 proteins.
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PMID:Association of JNK1 with p21waf1 and p53: modulation of JNK1 activity. 1250 78

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