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

The p53 tumor suppressor is activated in response to various stresses driving the cells into growth arrest or apoptosis. We have addressed the question of how disintegration of microtubule system induces activation of p53. Depolymerization of microtubules by colcemid in rat and human quiescent fibroblasts resulted in accumulation of transcriptionally active p53 that caused cell-cycle arrest at the G1/S boundary. The p53 activation correlated with prominent activation of Erk1/2 MAP kinases that resulted from colcemid-stimulated development of focal adhesions. Inhibition of focal contacts development by plating of cells onto poly-L-lysine abrogated both Erk1/2 and p53 activations in colcemid-treated cells, while plating of cells onto fibronectin caused transient up-regulation of p53 even in the absence of colcemid. Pre-treatment of cells with the specific MEK1 inhibitor PD098059 also attenuated colcemid-induced p53 activation and G1 cell cycle arrest. Cell types which either failed to develop focal adhesions in response to colcemid treatment (human MCF-7 epithelial cells), or lacked colcemid-induced sustained Erk activation (primary mouse embryo fibroblasts and 12(1) cells) showed virtually no p53 up-regulation in response to disruption of microtubules during G0/G1. Our results indicate that p53 activation is not triggered by disintegration of microtubule system by itself, but rather originates from some of the consequences of such disintegration, in particular, from the development of focal adhesions leading to activation of Erk signaling pathway.
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PMID:p53 activation in response to microtubule disruption is mediated by integrin-Erk signaling. 1131 25

We describe two pathways by which the vesicating agent sulfur mustard (HD) may cause basal cell death and detachment: induction of terminal differentiation and apoptosis. Following treatment of normal human epidermal keratinocytes (NHEK) with 10 or 100 microM HD, the differentiation-specific keratin pair K1/K10 was induced and the cornified envelope precursor protein, involucrin, was cross-linked by epidermal transglutaminase. Fibronectin levels were reduced in a time- and dose-dependent manner. The rapid increase in p53 and decrease in Bcl-2 levels was consistent not only with epidermal differentiation but with apoptosis as well. Further examination of biochemical markers of apoptosis following treatment of either NHEK or human papillomavirus (HPV)-immortalized keratinocytes revealed a burst of poly(ADP-ribose) synthesis, specific cleavage of poly(ADP-ribose)polymerase (PARP) in vivo and in vitro into characteristic 89 and 24 kDa fragments, processing of caspase-3 into its active form and the formation of DNA ladders. The intracellular calcium chelator BAPTA suppressed the differentiation markers, whereas antisense oligonucleotides and chemical inhibitors specific for calmodulin blocked both markers of differentiation and apoptosis. Modulation of p53 levels utilizing retroviral constructs expressing the E6, E7 or E6 + E7 genes of HPV-16 revealed that HD-induced apoptosis was partially p53-dependent. Finally, immortalized fibroblasts derived from PARP -/- 'knockout mice' were exquisitely sensitive to HD-induced apoptosis. These cells became HD resistant when wild-type PARP was stably expressed in these cells. These results indicate that HD exerts its effects via calmodulin, 3 and PARP-sensitive pathways.
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PMID:Calmodulin, poly(ADP-ribose)polymerase and p53 are targets for modulating the effects of sulfur mustard. 1142 42

In apoptosis the tumor suppressor p53 and the c-myc proto-oncogene are usually up-regulated. We show a novel alternative pathway of apoptosis in human primary cells that is mediated by transcriptionally dependent decreases in p53 and c-Myc and decreases in p21. This pathway is regulated by the alternatively spliced V region and high-affinity heparin-binding domain of fibronectin. Requirements for c-Myc, p53, and p21 signals in maintaining survival and for their decreases in inducing apoptosis were demonstrated by the ability of p53, c-Myc, and p21 ectopic expression to rescue this apoptotic phenotype, and the ability of p53-deficient and c-myc antisense conditions to trigger a faster rate of apoptosis.
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PMID:The heparin-binding domain and V region of fibronectin regulate apoptosis by suppression of p53 and c-myc in human primary cells. 1175 53

Rheumatoid arthritis (RA) is a chronic inflammatory disease, which is mainly characterized by synovial hyperplasia, pathological immune phenomena and progressive destruction of the affected joints. Various cell types are involved in the pathogenesis of RA including T cells, antigen presenting cells, and endothelial cells. Recent experimental evidence suggests that the CD40/CD154 system might play an important role in the development of RA. Our experimental approach focuses on RA synovial fibroblasts (RA-SF) that are able to destroy articular cartilage independent of inflammation. To elucidate the specific role of those cells in RA pathophysiology the following questions are currently addressed: 1. Which mechanisms do activate the RA-SF? 2. How do the activated RA-SF attach to the cartilage? 3. How do RA-SF destroy cartilage and bone? Which mechanisms do activate the RA-SF? The process of activation is poorly understood. It is unclear, how far the synovial hyperplasia of RA resembles tumor diseases. Along this line some contradictory results exist concerning the role of the tumor suppressor protein p53. Some investigations could show the expression of p53 in the synovial lining including p53 mutations in RA synovium and in RASF, while other research groups could not confirm these data. Our group has demonstrated that the tumor suppressor PTEN was less expressed in the synovial lining of RA than in normal synovium, but no PTEN mutations could be found in the RA-SF. In addition, the in vivo and in vitro expression of the anti-apoptotic molecule sentrin suggests a functional resistance of RA-SF to undergo apoptosis. Although it is still unclear, whether certain viruses or viral elements are involved in the pathogenesis of RA (cause, consequence or coincidence?), certain viruses could play a role in the pathogenesis of RA. The endogenous retroviral element L1 was found to be expressed in the synovial lining, at sites of invasion as well as in RA-SF grown in vitro. Moreover, the data indicate that after the initial activation of L1 downstream molecules such as the SAP kinase 4, the met-protoonocogene and the galectin-3 binding protein are upregulated. How do the activated RA-SF attach to the cartilage? It has been suggested that integrins mediate the attachment of RA-SF to fibronectin rich sites of cartilage. Intriguingly, other adhesion molecules such as the vascular cellular adhesion molecule-1 (VCAM) and CS-1, a splice variant of fibronectin, are synthesized by RA-SF. By binding to these adhesion molecules, lymphocytes that express the integrin VLA-4 could be stimulated and thereby maintain the inflammatory process. Osteopontin is an extracellular matrix protein, which is associated with matrix adhesion and metastasis in tumors. In RA synovium, osteopontin was detectable in the synovial lining and at sites of invasion. How do RA-SF destroy cartilage and bone? The destruction of cartilage and bone in RA is mediated by matrix metalloproteinases (MMPs) and cathepsins. MMPs exist as secreted and as membrane bound forms. In vitro models are being developed to simulate the invasive process of RA-SF. In an in vitro model developed in our laboratory, the treatment of RA-SF with anti-CD44 or anti-interleukin-1 (IL-1) minimized matrix degradation of RA-SF. On the other hand, co-culture of RA-SF and U937 cells as well as application of interleukin-1 beta (IL-1 beta) or tumor necrosis factor alpha (TNF alpha) increased the invasiveness of RA-SF. Gene transfer of bovine pancreas trypsin inhibitor (BPMI) or interleukin-10 (IL-10) reduced the invasion of RA-SF, while transduction of interleukin-1 receptor antagonist (IL-1Ra) was chondroprotective. Double gene transfer of IL-10 and IL-1Ra resulted in both inhibition of invasion and chondroprotection.
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PMID:[Rheumatoid arthritis: new developments in the pathogenesis with special reference to synovial fibroblasts]. 1175 30

Molecular-based diagnosis of thyroid carcinomas can be more easily established by utilizing specific mRNAs that are expressed only in cancer tissues. In a previous study, we introduced a new method of preoperatively diagnosing thyroid carcinomas. This technique, aspiration biopsy-RT-PCR(ABRP), facilitated simultaneous cytological and molecular-based diagnoses by extracting RNA from cells remaining within the needle used for fine needle aspiration biopsies(FNABs). ABRP provides both RNA information and a cytological diagnosis without further invasion to the patient. We proved that by ABRP detection of oncofetal fibronectin(onfFN) mRNA in FNABs, papillary and anaplastic carcinomas are accurately diagnosed preoperatively. Further, by real-time monitoring RT-PCR measuring onfFN mRNA, a fully automated system was established. It is not clarified, however, why cancer-specific mRNAs, especially those overexpressed in fetal tissues, can clearly distinguish benign tissues from carcinomas, while genomic alternation such as mutations in RAS or P53 gene cannot. Further, a widely accepted hypothesis, multi-step carcinogenesis, does not explain some of the clinical and experimental evidence from thyroid carcinomas. Considering these facts, we propose a new concept of thyroid carcinogenesis called "germ-cell carcinogenesis", in which cancer cells are derived from the remnant of fetal thyroid germ cells(thyroblasts) instead of normal thyroid follicular cells.
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PMID:[Aspiration biopsy-RT-PCR(ABRP): lesson from its success]. 1179 96

Many tumors show a mutant or inactive tumor suppressor p53 (TP53) status, and TP53 in the tumor-carrying human papillomavirus (HPV) may be dysfunctional because of inhibition by the viral protein HPV E6. Molecular mechanisms underlying radiation responses and the radiation-induced resistant phenotype in the TP53-inactive tumor have not been well investigated. In the present study, using a human keratinocyte line (HK18) with TP53 inhibited by HPV18 infection, we demonstrated that nuclear factor (NF)-kappaB is responsible for a major portion of the radioresistance observed in a cell population (HK18-IR) derived from HK18 cells by fractionated ionizing radiation (FIR; 2 Gy/fraction; total dose, 60 Gy). HK18-IR cells showed increased clonogenic radioresistance [dose-modifying factor (DMF), 1.47], reduced apoptotic response, and a shortened radiation-induced growth delay. Both DNA-binding and reporter transcriptional activity of NF-kappaB, but not of TP53, were activated in HK18-IR cells compared with the parental HK18 cells; this activation was observed both before and after a single dose of 5 Gy. To determine target genes responsive to NF-kappaB activation, DNA microarray profiles for 588 genes were matched in HK18-IR cells compared with those in HK18 cells; the paired comparisons were made for basal levels before irradiation or for levels 24 h after 5 Gy. For 25 genes, a 2- to 5-fold up-regulation in HK18-IR cells relative to HK18 cells was similar when comparisons were made for basal levels or for levels after irradiation. Included in the approximately 4% of genes activated in HK18-IR cells, were six genes (Cyclin B1, Cyclin D1, HIAP, BAG-1, TTF, and fibronectin) putatively linked to NF-kappaB regulation. We then measured the expression of this group of FIR-regulated genes in HK18-IR cells expressing a dominant-negative mutant IkappaB (mIkappaB) that inhibited NF-kappaB activation. Clonogenic radioresistance was reduced greatly in the mIkappaB transfectants (DMF, 1.18 and 1.10, respectively, at 10% and 1% of isosurvival for mIkappaB transfectants compared with 1.47 and 1.45, respectively, for vector control transfectants). Expressions of Cyclin B1, Cyclin D1, and HIAP were down-regulated by the inhibition of NF-kappaB. These results suggest that transcription of NF-kappaB and a group of NF-kappaB target genes are involved in radioresistance in FIR-treated tumor cells with inactive TP53.
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PMID:Activation of nuclear factor kappaB in radioresistance of TP53-inactive human keratinocytes. 1186 6

This study focuses on the effects of simulated microgravity (0g) on the human follicular thyroid carcinoma cell line ML-1. Cultured on a three-dimensional clinostat, ML-1 cells formed three-dimensional MCTSs (MCTS diameter: 0.3 +/- 0.01 mm). After 24 and 48 h of clinorotation, the cells significantly decreased fT3 and fT4 secretion but up-regulated the thyroid-stimulating hormone-receptor expression as well as the production of vimentin, vinculin, and extracellular matrix proteins (collagen I and III, laminin, fibronectin, chondroitin sulfate) compared with controls. Furthermore, ML-1 cells grown on the clinostat showed elevated amounts of the apoptosis-associated Fas protein, of p53, and of bax but showed reduced quantities of bcl-2. In addition, signs of apoptosis became detectable, as assessed by terminal deoxynucleotidyl transferase-mediated dUTP digoxigenin nick end labeling, 4', 6-diamidino-2-phenylindole staining, DNA laddering, and 85-kDa apoptosis-related cleavage fragments. These fragments resulted from enhanced 116-kDa poly(ADP-ribose)polymerase (PARP) activity and apoptosis. These observations suggest that clinorotation elevates intermediate filaments, cell adhesion molecules, and extracellular matrix proteins and simultaneously induces apoptosis in follicular thyroid cancer cells. In conclusion, our experiments could provide a regulatory basis for the finding that astronauts show low thyroid hormone levels after space flight, which may be explained by the increase of apoptosis in thyrocytes as a result of simulated 0g.
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PMID:Simulated microgravity alters differentiation and increases apoptosis in human follicular thyroid carcinoma cells. 1191 68

The tumour suppressor functions of p53 that are important for its activity depend on its role as a cell cycle arrest mediator and apoptosis inducer. Here we identify a novel function for p53 in regulating cell morphology and movement. We investigated the overall effect of p53 on morphological changes induced by RhoA, Rac1 and Cdc42 GTPases in mouse embryonic fibroblasts (MEFs). Interestingly, p53 exerted a selective effect on Cdc42-mediated cell functions. (i) Both overexpression of wild-type p53 and activation of endogenous p53 counteracted Cdc42-induced filopodia formation. Conversely, p53-deficient MEFs exhibited constitutive membrane filopodia. Mechanistic studies indicate that p53 prevents the initiating steps of filopodia formation downstream of Cdc42. (ii) Over expression of p53 modulates cell spreading of MEFs on fibronectin. (iii) During cell migration, the reorientation of the Golgi apparatus in the direction of movement is abolished by wild-type p53 expression, thus preventing cell polarity. Our data demonstrate a previously uncharacterized role for p53 in regulating Cdc42-dependent cell effects that control actin cytoskeletal dynamics and cell movement. This novel function may contribute to p53 anti-tumour activity.
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PMID:Regulation of Cdc42-mediated morphological effects: a novel function for p53. 1200 90

Death-associated protein kinase (DAP-kinase) is a calcium/calmodulin-dependent serine/threonine kinase, and participates in various apoptosis systems. However, its apoptosis-promoting mechanism is poorly understood. Here, we demonstrate that DAP-kinase suppresses integrin-mediated cell adhesion and signal transduction, whereas dominant-negative interference of this kinase promotes adhesion. This effect of DAP-kinase is neither a consequence of apoptosis nor a result of decreased expression of integrins. Rather, DAP-kinase downregulates integrin activity through an inside-out mechanism. We present evidence indicating that this adhesion-inhibitory effect accounts for a major mechanism of the apoptosis induced by DAP-kinase. First, in growth-arrested fibroblasts, DAP-kinase triggers apoptosis in cells plated on fibronectin, but does not affect the death of cells on poly-l-lysine. Second, in epithelial cells, DAP-kinase induces apoptosis in the anoikis-sensitive MCF10A cells, but not in the anoikis-resistant BT474 cells. Most importantly, the apoptosis-promoting effect of DAP-kinase is completely abolished by enforced activation of integrin-mediated signaling pathways from either integrin itself or its downstream effector, FAK. Finally, we show that integrin or FAK activation blocks the ability of DAP-kinase to upregulate p53. Our results indicate that DAP-kinase exerts apoptotic effects by suppressing integrin functions and integrin-mediated survival signals, thereby activating a p53-dependent apoptotic pathway.
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PMID:DAP-kinase induces apoptosis by suppressing integrin activity and disrupting matrix survival signals. 1237 Feb 43

Activated pancreatic stellate cells (PSCs) have recently been implicated in the pathogenesis of pancreatic fibrosis and inflammation. Primary PSCs can be subcultured only several times because of their limited growth potential. A continuous cell line would be valuable in studying molecular mechanisms of these pancreatic disorders. The aim of this study was to establish an immortalized cell line of rat PSCs. PSCs were isolated from the pancreas of male Wistar rats, and the simian virus 40 T antigen was introduced to PSCs by retrovirus-mediated gene transfer. This procedure yielded an actively growing cell line, designated as SAM-K. This cell line has been passaged repeatedly for almost 2 years, and is thus likely immortalized. SAM-K cells retained morphological characteristics of primary PSCs, and expressed alpha-smooth muscle actin, glial fibrillary acidic protein, type I collagen, fibronectin, and prolyl hydroxylases. The level of p53 expression was very high in SAM-K cells. Proliferation of SAM-K cells was stimulated by serum and platelet-derived growth factor-BB. Interleukin-1beta (IL-1beta) activated nuclear factor-kappaB, activator protein-1, and three classes of mitogen-activated protein (MAP) kinases: extracellular signal-regulated kinase1/2, c-Jun N-terminal kinase, and p38 MAP kinase. IL-1beta induced expression of intercellular adhesion molecule-1 and monocyte chemoattractant protein-1, both of which were abolished in the presence of pyrrolidine dithiocarbamate, a specific inhibitor of nuclear factor-kappaB activation. IL-1beta-induced monocyte chemoattractant protein-1 was partially inhibited by specific inhibitors of MAP kinase kinase (U0126) and of p38 MAP kinase (SB203580) whereas intercellular adhesion molecule-1 expression was not altered by the inhibitors. Thus, SAM-K would be useful for in vitro studies of cell biology and signal transduction of PSCs.
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PMID:Establishment and characterization of a simian virus 40-immortalized rat pancreatic stellate cell line. 1249 15


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