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)

Mammalian target of rapamycin (mTOR) inhibitors curtail cap-dependent translation. However, they can also induce post-translational modifications of proteins. We assessed both effects to understand the mechanism by which mTOR inhibitors like rapamycin sensitize multiple myeloma cells to dexamethasone-induced apoptosis. Sensitization was achieved in multiple myeloma cells irrespective of their PTEN or p53 status, enhanced by activation of AKT, and associated with stimulation of both intrinsic and extrinsic pathways of apoptosis. The sensitizing effect was not due to post-translational modifications of the RAFTK kinase, Jun kinase, p38 mitogen-activated protein kinase, or BAD. Sensitization was also not associated with a rapamycin-mediated increase in glucocorticoid receptor reporter expression. However, when cap-dependent translation was prevented by transfection with a mutant 4E-BP1 construct, which is resistant to mTOR-induced phosphorylation, cells responded to dexamethasone with enhanced apoptosis, mirroring the effect of coexposure to rapamycin. Thus, sensitization is mediated by inhibition of cap-dependent translation. A high-throughput screening for translational efficiency identified several antiapoptotic proteins whose translation was inhibited by rapamycin. Immunoblot assay confirmed rapamycin-induced down-regulated expressions of XIAP, CIAP1, HSP-27, and BAG-3, which may play a role in the sensitization to apoptosis. Studies in a xenograft model showed synergistic in vivo antimyeloma effects when dexamethasone was combined with the mTOR inhibitor CCI-779. Synergistic effects were associated with an enhanced multiple myeloma cell apoptosis in vivo. This study supports the strategy of combining dexamethasone with mTOR inhibitors in multiple myeloma and identifies a mechanism by which the synergistic effect is achieved.
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PMID:Mechanism by which mammalian target of rapamycin inhibitors sensitize multiple myeloma cells to dexamethasone-induced apoptosis. 1648 35

Following the induction of DNA damage, a prominent route of cell inactivation is apoptosis. During the last ten years, specific DNA lesions that trigger apoptosis have been identified. These include O6-methylguanine, base N-alkylations, bulky DNA adducts, DNA cross-links and DNA double-strand breaks (DSBs). Repair of these lesions are important in preventing apoptosis. An exception is O6-methylguanine-thymine lesions, which require mismatch repair for triggering apoptosis. Apoptosis induced by many chemical genotoxins is the consequence of blockage of DNA replication, which leads to collapse of replication forks and DSB formation. These DSBs are thought to be crucial downstream apoptosis-triggering lesions. DSBs are detected by ATM (ataxia telangiectasia mutated) and ATR (ataxia telangiectasia and Rad3 related) proteins, which signal downstream to CHK1, CHK2 (checkpoint kinases) and p53. p53 induces transcriptional activation of pro-apoptotic factors such as FAS, PUMA and BAX. Many tumors harbor mutations in p53. There are p53 backup systems that involve CHK1 and/or CHK2-driven E2F1 activation and p73 upregulation, which in turn transcribes BAX, PUMA and NOXA. Another trigger of apoptosis upon DNA damage is the inhibition of RNA synthesis, which leads to a decline in the level of critical gene products such as MKP1 (mitogen-activated protein kinase phosphatase). This causes sustained activation of JNK (Jun kinase) and, finally, AP-1, which stimulates death-receptor activation. DNA damage-triggered signaling and execution of apoptosis is cell-type- and genotoxin-specific depending on the p53 (p63 and p73) status, death-receptor responsiveness, MAP-kinase activation and, most importantly, DNA repair capacity. Because most clinical anti-cancer drugs target DNA, increasing knowledge on DNA damage-triggered signaling leading to cell death is expected to provide new strategies for therapeutic interventions.
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PMID:DNA damage-induced cell death by apoptosis. 1689 8

Active Ras oncogene is expressed in approximately 30% of human cancers. Yet, very little is known about the molecular mechanisms responsible for its transforming potential. Here, we show that H-Ras-mediated transformation requires isoform 2 of the c-Jun-NH(2)-terminal kinase (JNK). H-Ras-transduced JNK2-deficient (Jnk2-/-) murine embryonic fibroblasts (MEFs) were severely inhibited in colony formation and growth in soft agar in vitro as well as in tumor formation in immunodeficient mice as compared with corresponding Jnk1-/- and wild-type MEFs. Accordingly, the RNA interference-based depletion of JNK2 form wild-type MEFs also resulted in defective Ras transformation. The extra barrier against H-Ras transformation in Jnk2-/- MEFs was not due to their inability to inactivate p53 signaling because all JNK2-deficient MEF lines had lost p19(Arf). Furthermore, expression of the E6 protein of the human papilloma virus failed to overcome the transformation defect. It could, however, be overcome by coexpression of H-Ras with the SV40 large T antigen or c-Myc. Surprisingly, the H-Ras-transduced JNK2-deficient MEFs exhibited higher activity of activator protein-1 and higher levels of c-Jun expression compared with H-Ras-transduced JNK1-deficient or wild-type cells, indicating that the key target of JNK2 during Ras transformation was divergent from activator protein-1. These results clearly show that a single kinase, JNK2, could control Ras transformation and thus point out a vulnerable control point that may prove important for the tumor development in general.
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PMID:c-Jun NH2-terminal kinase 2 is required for Ras transformation independently of activator protein 1. 1721 Jun 97

There is growing evidence that, because of the highly significant differences in gene activation/protein expression between animal models of stroke and stroke patients, the current treatment strategies based on animal stroke models have been unsuccessful. Therefore, it is imperative that the pathobiology of human stroke be studied. As a first step here, Western blotting and immunohistochemistry were employed to examine expression and tissue localization of key apoptotic proteins in infarct and peri-infarcted (penumbra) from grey and white matter in human postmortem tissue of 18 patients who died between 2 and 37 d after stroke caused by large vessel disease. The contralateral hemisphere was used as a control. JNK1, JNK2, and p53 were upregulated in the majority of samples, whereas Bcl-2, caspase-3, active caspase-3, phosphorylated p53 (p-p53), phosphorylated JNK1 (p-JNK1), and phosphorylated JNK2 (p-JNK2) were upregulated in approximately half of the samples. JNK1 expression was positively correlated with JNK2 expression in grey and white matter infarct and penumbra, whereas active caspase-3 levels were positively correlated with p-JNK2 levels in grey and white matter infarct. Using indirect immunoperoxidase staining of paraffin-embedded sections, active caspase-3 was found in infarcted neurons that co-localized with TUNEL-positive cells. p-JNK localization in the nuclei of TUNELpositive cells with the morphological appearance of neurons from infarct and penumbra was also demonstrated. The use of Kaplan Meier survival data demonstrated that the presence of Bcl-2 in penumbra of grey matter correlated significantly with shorter survival (p = 0.006). In conclusion, the present study has identified significantly altered expression of apoptotic proteins in human stroke tissue and shown that the presence of Bcl-2 in penumbra of grey matter has prognostic value. It is tempting to suggest that further studies of apoptotic proteins in human stroke may lead to identification of novel targets for drug discovery.
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PMID:Expression of signaling molecules associated with apoptosis in human ischemic stroke tissue. 1740 61

FDH (10-formyltetrahydrofolate dehydrogenase) is strongly downregulated in tumors while its elevation suppresses proliferation of cancer cells and induces p53-dependent apoptosis. We have previously shown that FDH induces phosphorylation of p53 at Ser6, which is a required step in the activation of apoptosis. In the present study, we report that FDH-induced p53 phosphorylation is carried out by JNK1 and JNK2 (c-Jun N-terminal kinases) working in concert. We have demonstrated that FDH induces phosphorylation of JNK1 and JNK2, while treatment of FDH-expressing cells with JNK inhibitor SP600125, as well as knockdown of JNK1 or JNK2 by siRNA, prevents phosphorylation of p53 at Ser6 and protects cells from apoptosis. Interestingly, the knockdown of JNK1 abolished phosphorylation of JNK2 in response to FDH, while knockdown of JNK2 did not prevent JNK1 phosphorylation. Pull-down assay with the p53-specific antibody has shown that JNK2, but not JNK1, is physically associated with p53. Our studies revealed a novel mechanism in which phosphorylation of JNK2 is mediated by JNK1 before phosphorylation of p53, and then p53 is directly phosphorylated by JNK2 at Ser6.
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PMID:Cooperation between JNK1 and JNK2 in activation of p53 apoptotic pathway. 1752 47

The JNK signaling pathway is implicated in the regulation of the AP1 transcription factor and cell proliferation. Here, we examine the role of JNK by using conditional and chemical genetic alleles of the ubiquitously expressed murine genes that encode the isoforms JNK1 and JNK2. Our analysis demonstrates that JNK is not essential for proliferation. However, JNK is required for expression of the cJun and JunD components of the AP1 transcription factor, and JNK-deficient cells exhibit early p53-dependent senescence. These data demonstrate that JNK can act as a negative regulator of the p53 tumor suppressor.
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PMID:Suppression of p53-dependent senescence by the JNK signal transduction pathway. 1789 31

Retinoblastoma-deficient mice show massive neuronal damage and deficits in both CNS and PNS tissue. Previous work in the field has shown that death is regulated through distinct processes where CNS tissue undergoes death regulated by the tumor suppressor p53 and the apoptosome component, APAF1. Death in the PNS, however, is independent of p53 and reliant on the death protease, caspase 3. In the present study, we more carefully delineated the common and distinct mechanisms of death regulation by examining the stress-activated kinases, JNK2 and 3, the conserved Bcl-2 member Bax, and the relationship among these elements including p53. By use of genetic modeling, we show that death in various regions of the CNS and DRGs of the PNS is reliant on Bax. In the CNS, Bax acts downstream of p53. The relevance of the JNKs is more complex, however. Surprisingly, JNK3 deficiency by itself does not inhibit c-Jun phosphorylation and instead, aggravates death in both CNS and PNS tissue. However, JNK2/3 double deficiency blocks death due to Rb loss in both the PNS and CNS. Importantly, the relationships between JNKs, p53, and Bax exhibit regional differences. In the medulla region of the hindbrain in the CNS, JNK2/3 deficiency blocks p53 activation. Moreover, Bax deficiency does not affect c-Jun phosphorylation. This indicates that a JNK-p53-Bax pathway is central in the hindbrain. However, in the diencephalon regions of the forebrain (thalamus), Bax deficiency blocks c-Jun activation, indicating that a Bax-JNK pathway of death is more relevant. In the DRGs of the PNS, a third pathway is present. In this case, a JNK-Bax pathway, independent of p53, regulates damage. Accordingly, our results show that a death regulator Bax is common to death in both PNS and CNS tissue. However, it is regulated by or itself regulates different effectors including the JNKs and p53 depending upon the specific region of the nervous system.
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PMID:Required roles of Bax and JNKs in central and peripheral nervous system death of retinoblastoma-deficient mice. 1798 95

JNK1/2 proteins belong to the family of stress-activated protein kinases. They play a complex role in growth regulation, inducing either cell death or growth support. In this report, we provide evidence that, in human melanoma cells, JNK inhibition with the small molecule inhibitor SP600125 induces either predominantly a G2/M arrest or apoptosis depending on the cell line. In 1205Lu cells, JNK inhibition induced cell cycle arrest through p53-dependent induction of p21 Cip1/Waf1 expression, while in WM983B cells, induction of apoptosis by JNK inhibition was accompanied by p53, Bad and Bax induction, not p21 Cip1/Waf1. JNK inhibition with the small molecule inhibitor SP600125 slowed growth of all cell lines, although the effect was markedly greater in cells exhibiting high phospho- (P-)JNK1 levels. Specific gene knockdown of JNK1 by means of siRNA oligonucleotides inhibited cell growth only in melanoma cell lines exhibiting high P-JNK1 levels. siRNAs directed against JNK2 did not reduce cell growth in any of the cell lines tested. Together, our findings demonstrate that JNK, and in particular the JNK1 isoform, support the growth of melanoma cells, by controlling either cell cycle progression or apoptosis depending on the cellular context.
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PMID:JNK supports survival in melanoma cells by controlling cell cycle arrest and apoptosis. 1854 Oct 8

10-Formyltetrahydrofolate dehydrogenase (FDH) suppresses cancer cell proliferation through p53-dependent apoptosis but also induces strong cytotoxicity in p53-deficient prostate cells. In the present study, we have shown that FDH induces apoptosis in PC-3 prostate cells through simultaneous activation of the c-Jun-NH(2)-kinase (JNK) and extracellular signal-regulated kinase (ERK) pathways with JNK phosphorylating c-Jun and ERK1/2 phosphorylating Elk-1. The JNK1/2 inhibitor SP600125 or ERK1/2 inhibitor PD98059 prevented phosphorylation of c-Jun and Elk-1, correspondingly and partially protected PC-3 cells from FDH-induced cytotoxicity. Combination of the two inhibitors produced an additive effect. The contribution from the JNK cascade to FDH-induced apoptosis was significantly stronger than from the ERK pathway. siRNA knockdown of JNK1/2 or "turning off" the downstream target c-Jun by either siRNA or expression of the dominant-negative c-Jun mutant, TAM67, rescued PC-3 cells from FDH-induced apoptosis. The pull-down assays on immobilized c-Jun showed that c-Jun is directly phosphorylated by JNK2 in FDH-expressing cells. Interestingly, the FDH-induced apoptosis in p53-proficient A549 cells also proceeds through activation of JNK1/2, but the down-stream target for JNK2 is p53 instead of c-Jun. Furthermore, in A549 cells, FDH activates caspase 9, whereas in PC-3 cells, it activates caspase 8. Our studies indicate that the JNK pathways are common downstream mechanisms of FDH-induced cytotoxicity in different cell types, whereas the end point target in the cascade is cell type specific. JNK activation in response to FDH was inhibited by high supplementation of reduced folate leucovorin, further indicating a functional connection between folate metabolism and mitogen-activated protein kinase pathways.
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PMID:10-formyltetrahydrofolate dehydrogenase-induced c-Jun-NH2-kinase pathways diverge at the c-Jun-NH2-kinase substrate level in cells with different p53 status. 1914 41

Hepatocellular carcinoma (HCC) is one of the most prevalent and lethal cancers worldwide. The main HCC-associated diseases are chronic infections with hepatitis B virus (HBV) and hepatitis C virus (HCV), and HBV-associated HCC is still prevalent in Asia. Many studies have suggested that HBV X protein (HBX), which is the most common ORF integrated into the host genome, plays a crucial role in hepatocarcinogenesis. However, the accumulated evidence regarding HBX-mediated signaling pathways is not concordant, and it is difficult to understand the mechanistic nature of HBX-associated hepatocarcinogenesis. For example, HBX was reported to inactivate the early responses to DNA damage via p53-dependent and -independent pathways by interacting with several DNA damage-binding proteins and was also reported to sensitize cells to p53-mediated apoptosis via ataxia-telangiectasia and Rad3-related (ATR)-dependent signaling. HBX also interferes with the centrosome replication process, resulting in rearrangement of chromosomes with micronuclei. Moreover, HBX was found to sensitize protein kinases such as Ras/Raf/mitogen-activated protein kinase (MAPK), extracellular signal-regulated kinase (ERK), stress-activated protein kinase/NH2-terminal-Jun kinase (SAPK/JNK), protein kinase B (PKB/Akt), and Janus kinase/STAT (JAK/STAT), indicating that a variety of signaling pathways may be activated by HBX. In this review, we focus on the roles of HBX in DNA damage repair during HCC development, with a view to achieving a better understanding of the significance of HBX in the early steps of hepatocarcinogenesis.
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PMID:Impact of hepatitis B virus X protein on the DNA damage response during hepatocarcinogenesis. 1978 39


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