Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P04637 (p53)
 77,613 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The PP2C family serine/threonine phosphatase WIP1 is characterized by distinctive oncogenic properties mediated by inhibitory functions on several tumor suppressor pathways, including ATM, CHK2, p38MAPK and p53. PPM1D, the gene encoding WIP1, is aberrantly amplified in different types of human primary cancers, and its deletion in mice results in a profound tumor-resistant phenotype. Numerous downstream targets of WIP1 have been identified, and genetic studies confirm that some play a part in tumorigenesis. Recent evidence highlights a new role for WIP1 in the regulation of a cell-autonomous decline in proliferation of certain self-renewing cell types, including pancreatic beta-cells, with advancing age. These emerging functions of WIP1 make it a potent therapeutic target against cancer and aging.
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PMID:WIP1 phosphatase at the crossroads of cancer and aging. 1987 49

The present study demonstrates that theaflavins exploit p53 to impede metastasis in human breast cancer cells. Our data suggest that p53-dependent reactive oxygen species (ROS) induce p53-phosphorylation via p38MAPK in a feedback loop to inhibit IkappaBalpha-phosphorylation and NF-kappaB/p65 nuclear translocation, thereby down-regulating the metastatic proteins metalloproteinase (MMP)-2 and MMP-9. When wild-type p53-expressing MCF-7 cells are transfected with p53 short-interfering RNA, or treated with a pharmacological inhibitor of ROS, theaflavins fail to inhibit NF-kappaB-mediated cell migration. On the other hand, NF-kappaB over-expression bestows MCF-7 cells with resistance to the anti-migratory effect of theaflavins. These results indicate that inhibition of NF-kappaB via p53-ROS crosstalk is a pre-requisite for theaflavins to accomplish the anti-migratory effect in breast cancer cells.
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PMID:Theaflavins retard human breast cancer cell migration by inhibiting NF-kappaB via p53-ROS cross-talk. 1988 46

The anthracycline antibiotic doxorubicin (DOX) is a potent cancer chemotherapeutic agent that exerts both acute and chronic cardiotoxicity. Here we show that in adult mouse cardiomyocytes, DOX activates (i) the pro-apoptotic p53, (ii) p38MAPK and JNK, (iii) Bax translocation, (iv) cytochrome c release, and (v) caspase 3. Further, it (vi) inhibits expression of anti-apoptotic Akt, Bcl-2 and Bcl-xL, and (vii) induces internucleosomal degradation and cell death. WNT1-inducible signaling pathway protein-1 (WISP1), a CCN family member and a matricellular protein, inhibits DOX-mediated cardiomyocyte death. WISP1 inhibits DOX-induced p53 activation, p38 MAPK and JNK phosphorylation, Bax translocation to mitochondria, and cytochrome c release into cytoplasm. Additionally, WISP1 reverses DOX-induced suppression of Bcl-2 and Bcl-xL expression and Akt inhibition. The pro-survival effects of WISP1 were recapitulated by the forced expression of mutant p53, wild-type Bcl-2, wild-type Bcl-xL, or constitutively active Akt prior to DOX treatment. WISP1 also induces the pro-survival factor Survivin via PI3K/Akt signaling. Overexpression of wild-type, but not mutant Survivin, blunts DOX cytotoxicity. Further, WISP1 stimulates PI3K-Akt-dependent GSK3beta phosphorylation and beta-catenin nuclear translocation. Importantly, WISP1 induces its own expression. Together, these results provide important insights into the cytoprotective effects of WISP1 in cardiomyocytes, and suggest a potential therapeutic role for WISP1 in DOX-induced cardiotoxicity.
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PMID:WNT1-inducible signaling pathway protein-1 activates diverse cell survival pathways and blocks doxorubicin-induced cardiomyocyte death. 2007 38

In the present study, we investigated the effects of millimeter wave treatment on the activation of the p38MAPK signaling pathway in the process of NO-induced apoptosis in chondrocytes. Cartilage was isolated from the knee joint of SD rats and used to establish cultured primary chondrocytes. After identification using in situ staining of type II collagen, the passage 2 chondrocytes were incubated with or without sodium nitroprussiate (SNP) to induce apoptosis and treated with a millimeter wave for various times. The apoptosis of chondrocytes was detected using immunofluorescence, an MTT assay, and Annexin V-FITC labeling followed by fluorescence-activated cell sorting (FACS). The activity of caspase-3 was measured using colorimeters, and the levels of p38 and p53 were also detected using RT-PCR and Western blotting. After treatment with SNP, the OD values of the experimental groups were significantly lower than the control group (P<0.01). The 24-h interference of a millimeter wave significantly prevented apoptosis (P<0.01) and showed a dose dependency, and an identical trend of apoptosis was noted with normal cell number counting (P<0.01) and FACS (P<0.01). Consistently, the caspase 3 activity showed a reverse trend, with the highest activity in the experimental group receiving no millimeter wave treatment (P<0.01). The mRNA expression of p38 and p53 and the protein levels of phosphorylated p38 and p53 showed a similar trend (P<0.01) to that of caspase 3 activity. In conclusion, millimeter wave treatment inhibits the SNP-induced apoptosis of chondrocytes through the p38MAPK pathway.
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PMID:Millimeter wave treatment inhibits NO-induced apoptosis of chondrocytes through the p38MAPK pathway. 2012 44

Cutaneous and ocular injuries caused by sulfur mustard (SM; bis-(2-chloroethyl) sulfide) are characterized by severe inflammation and death of exposed cells. Given the known roles of p38MAPK and NF-kappaB in inflammatory cytokine production, and the known roles of NF-kappaB and p53 in cell fate, these pathways are of particular interest in the study of SM injury. In this study, we utilized inhibitory RNA (RNAi) targeted against p38 alpha, the p50 subunit of NF-kappaB, or p53 to characterize their role in SM-induced inflammation and cell death in normal human epidermal keratinocytes (NHEK). Analysis of culture supernatant from 200 microM SM-exposed cells showed that inflammatory cytokine production was inhibited by p38 alpha RNAi but not by NF-kappaB p50 RNAi. These findings further support a critical role for p38 in SM-induced inflammatory cytokine production in NHEK and suggest that NF-kappaB may not play a role in the SM-induced inflammatory response of this cell type. Inhibition of NF-kappaB by p50 RNAi did, however, partially inhibit SM-induced cell death, suggesting a role for NF-kappaB in SM-induced apoptosis or necrosis. Interestingly, inhibition of p53 by RNAi potentiated SM-induced cell death, suggesting that the role of p53 in SM injury, may be complex and not simply prodeath.
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PMID:Sulfur mustard induced cytokine production and cell death: investigating the potential roles of the p38, p53, and NF-kappaB signaling pathways with RNA interference. 2014 54

Previous research has shown that muscarinic receptors (MAChRs) show loss of sensitivity in aging and AD and are selectively sensitive to oxidative stress (OS). Thus, COS-7 cells transfected (tn) with MAChR subtype M1 show > OS sensitivity [as reflected in the ability of the cell to extrude or sequester Ca(2+) following depolarization (recovery) by oxotremorine (oxo) and exposure to dopamine (DA) or amyloid beta (Abeta)] than M3-transfected COS-7 cells. Blueberry (BB) extract pretreatment prevented these deficits. Research has also indicated that C2 ceramide (Cer) has several age-related negative cellular effects (e.g., OS). When these cells were treated with Cer, the significant decrements in the ability of both types of tn cells to initially respond to oxo were antagonized by BB treatment. Present experiments assessed signaling mechanisms involved in BB protection in the presence or absence of DA, Abeta, and/or Cer in this model. Thus, control or BB-treated M1 and M3 tn COS-7 cells were exposed to DA or Abeta(42) in the presence or absence of Cer. Primarily, results showed that the effects of DA or Abeta(42) were to increase stress (e.g., PKCgamma, p38MAPK) and protective signals (e.g., pMAPK). Cer also appeared to raise several of the stress and protective signals in the absence of the other stressors, including PKCgamma, pJNK, pNfkappaB, p53, and p38MAPK, while not significantly altering MAPK, or Akt. pArc was, however, increased by Cer in both types of transfected cells. The protective effects of BB when combined with Cer generally showed greater protection when BB extract was applied prior to Cer, except for one protective signal (pArc) where a greater effect was seen in the M3 cells exposed to Abeta(42.) In the absence of the Abeta(42) or DA, for several of the stress signals (e.g., pNfkappaB, p53), BB lowered their Cer-induced increases in M1- and M3-transfected cells. We are exploring these interactions further, but it is clear that increases in ceramide, to the same levels as are seen in aging, can have profound effects on calcium clearance and signaling during oxidative stress.
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PMID:Blueberry treatment antagonizes C-2 ceramide-induced stress signaling in muscarinic receptor-transfected COS-7 cells. 2017 93

The DNA damage response activates several pathways that stall the cell cycle and allow DNA repair. These consist of the well-characterized ATR (Ataxia telangiectasia and Rad-3 related)/CHK1 and ATM (Ataxia telangiectasia mutated)/CHK2 pathways in addition to a newly identified ATM/ATR/p38MAPK/MK2 checkpoint. Crucial to maintaining the integrity of the genome is the S-phase checkpoint that functions to prevent DNA replication until damaged DNA is repaired. Inappropriate expression of the proto-oncogene c-Myc is known to cause DNA damage. One mechanism by which c-Myc induces DNA damage is through binding directly to components of the prereplicative complex thereby promoting DNA synthesis, resulting in replication-associated DNA damage and checkpoint activation due to inappropriate origin firing. Here we show that following etoposide-induced DNA damage translation of c-Myc is repressed by miR-34c via a highly conserved target-site within the 3(') UTR. While miR-34c is induced by p53 following DNA damage, we show that in cells lacking p53 this is achieved by an alternative pathway which involves p38 MAPK signalling to MK2. The data presented here suggest that a major physiological target of miR-34c is c-Myc. Inhibition of miR-34c activity prevents S-phase arrest in response to DNA damage leading to increased DNA synthesis, DNA damage, and checkpoint activation in addition to that induced by etoposide alone, which are all reversed by subsequent c-Myc depletion. These data demonstrate that miR-34c is a critical regulator of the c-Myc expression following DNA damage acting downstream of p38 MAPK/MK2 and suggest that miR-34c serves to remove c-Myc to prevent inappropriate replication which may otherwise lead to genomic instability.
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PMID:p38 MAPK/MK2-mediated induction of miR-34c following DNA damage prevents Myc-dependent DNA replication. 2021 54

Cells' ability to evade cell death and to proliferate post geno-/cell-toxic stresses likely leads to formation of cancer. Activation of p38MAPK and p53 following these stresses helps protect cells against cancer development by initiating apoptosis. The duration of p38MAPK and p53 activation is regulated by the WIP1 phosphatase. BRCA1-IRIS triggers WIP1 expression in a p53-dependent and -independent manner. BRCA1-IRIS triggers the expression and cytoplasmic localization of the mRNA stabilization and translation inducer, HuR, that binds p53 and PPM1D mRNA. Hence, BRCA1-IRIS overexpression inactivates p38MAPK and/or p53 by upregulating WIP1 expression. BRCA1-IRIS abrogation of the homeostatic balance maintained by the p38MAPK-p53-WIP1 pathway suppressed cell death induced by a lethal dose of short-wavelength UV light, and high dosage of etoposide or H(2)O(2), and allowed cells to survive and proliferate post geno-/cell-toxic stresses. This mechanism represents a new link between geno-/cell-toxic stress and aggressive breast cancer formation in p53 wild-type cells.
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PMID:BRCA1-IRIS overexpression abrogates UV-induced p38MAPK/p53 and promotes proliferation of damaged cells. 2062 93

Reactive oxygen species (ROS) are a continuous hazard in eukaroytic cells by their ability to cause damage to biomolecules, in particular to DNA. Previous data indicated that the cytosolic serine peptidase tripeptidyl-peptidase II (TPPII) translocates into the nucleus of most tumor cell lines in response to gamma-irradiation and ROS production; an event that promoted p53 expression as well as caspase-activation. We here observed that nuclear translocation of TPPII was dependent on signaling by MAP kinases, including p38MAPK. Further, this was caused by several types of DNA-damaging drugs, a DNA cross-linker (cisplatinum), an inhibitor of topoisomerase II (etoposide), and to some extent also by nucleoside-analogues (5-fluorouracil, hydroxyurea). In the minority of tumor cell lines where TPPII was not translocated into the nucleus in response to DNA damage we observed reduced intracellular ROS levels, and the expression levels of redox defense systems were increased. Further, treatment with the ROS-inducer gamma-hexa-chloro-cyclohexane (gamma-HCH, lindane), an inhibitor of GAP junctions, restored nuclear translocation of TPPII in these cell lines upon gamma-irradiation. Moreover, blocking nuclear translocation of TPPII in etoposide-treated cells, by using a peptide-derived inhibitor (Z-Gly-Leu-Ala-OH), attenuated expression of gamma-H2AX in gamma-irradiated melanoma cells. Our results indicated a role for TPPII in MAPK-dependent DNA damage signaling.
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PMID:MAP kinase-signaling controls nuclear translocation of tripeptidyl-peptidase II in response to DNA damage and oxidative stress. 2064

Congenital myotonic dystrophy type 1 (CDM1) affects patients from birth and is associated with mental retardation and impaired muscle development. CDM1 patients carry 1000-3000 CTG repeats in the DMPK gene and display defective skeletal muscles differentiation, resulting in reduced size of myotubes and decreased number of satellite cells. In this study, human myoblasts in culture deriving from control and DM1 embryos (3200 CTG repeats) were analyzed using both a biochemical and electron microscopic approach, in order to provide new insights into the molecular mechanisms underlying such alteration. Interestingly, electron microscopy analysis showed not only ultrastructural features of abnormal differentiation but also revealed the presence of autophagic vacuoles in DM1 myoblasts not undergoing differentiation. In accordance with the electron microscopic findings, the autophagic markers LC3 and ATG5, but not apoptotic markers, were significantly up regulated in DM1 myoblasts after differentiating medium addition. The induction of autophagic processes in DM1 myoblasts was concomitant to p53 over-expression and inhibition of the mTOR-S6K1 pathway, causatively involved in autophagy. Moreover biochemical alterations of the two main signal transduction pathways involved in differentiation were observed in DM1 myoblasts, in particular decreased activation of p38MAPK and persistent activation of the MEK-ERK pathway. This work, while demonstrating that major signaling pathways regulating myoblasts differentiation are profoundly deranged in DM1 myoblasts, for the first time provides evidence of autophagy induction, possibly mediated by p53 activation in response to metabolic stress which might contribute to the dystrophic alterations observed in the muscles of congenital DM1 patients.
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PMID:Altered signal transduction pathways and induction of autophagy in human myotonic dystrophy type 1 myoblasts. 2079 47


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