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)

Using recombinant baculovirus expressed p53 and Raf proteins, we show that activated Raf-1 kinase can phosphorylate mouse p53 in vitro. We also show that co-expression of vRaf and p53 in NIH3T3 fibroblasts, potentiates the ability of p53 to transactivate a minimal promoter with a p53 cognate DNA binding site. A dominant negative mutant of Raf inhibits the transactivation function of p53 in NIH3T3 fibroblasts. Incubation of Raf-1 kinase with a series of p53 derived synthetic peptides maps the Raf-1 phosphorylation sites to the 27 amino terminal residue region of p53 which coincides with the transactivation domain. Phosphorylation occurs on serines which are phosphorylated in vivo. Our results suggest that the transactivation function of p53 can be regulated by a signaling cascade involving Raf.
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PMID:Raf phosphorylates p53 in vitro and potentiates p53-dependent transcriptional transactivation in vivo. 778 54

DNA damage inducing treatment of cultured mammalian cells triggers the activation of transcription factors and the prolongation of the half life of p53. As the earliest event detectable in the nucleus (5 min), AP-1 (c-Jun/c-Fos) is post-translationally modified. Triggering this early event and triggering subsequent transcription factor dependent processes requires extra-nuclear components of signal transduction such as Src, Ras, Raf-1 and MAP-2 kinase. Recent efforts have concentrated on examining whether DNA damage or other secondary effects of the damaging agent generate the signal then passed on to transcription factors. Further, it has been studied whether a pathway of reverse signalling exists that originates in the nucleus and reaches the cell surface. At the cell surface the UV induced signalling chain can be interrupted experimentally. Beyond this step DNA damage and signal transduction induced by phorbol esters and growth factors merge and reach the nuclear proteins through common components.
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PMID:The mammalian UV response: mechanism of DNA damage induced gene expression. 794 83

Recent studies have shown that paclitaxel leads to activation of Raf-1 kinase and have suggested that this activation is essential for bcl-2 phosphorylation and apoptosis. In the present study, we demonstrate that, in addition to paclitaxel, other agents that interact with tubulin and microtubules also induce Raf-1/bcl-2 phosphorylation, whereas DNA-damaging drugs, antimetabolites, and alkylating agents do not. Activation of Raf-1 kinase by paclitaxel is linked to tubulin polymerization; the effect is blunted in paclitaxel-resistant cells, the tubulin of which does not polymerize following the addition of paclitaxel. In contrast, vincristine and vinblastine, drugs to which the paclitaxel-resistant cells retain sensitivity were able to bring about Raf-1 phosphorylation. The requirement for disruption of microtubules in this signaling cascade was strengthened further using paclitaxel analogues by demonstrating a correlation between tubulin polymerization, Raf-1/bcl-2 phosphorylation, and cytotoxicity. Inhibition of RNA or protein synthesis prevents Raf-1 activation and bcl-2 phosphorylation, suggesting that an intermediate protein(s) acts upstream of Raf-1 in this microtubule damage-activating pathway. A model is proposed that envisions a pathway of Raf-1 activation and bcl-2 phosphorylation following disruption of microtubular architecture, serving a role similar to p53 induction following DNA damage.
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PMID:Raf-1/bcl-2 phosphorylation: a step from microtubule damage to cell death. 898 53

Growth arrest and differentiation of leukemic cells by phorbol 12-myristate 13-acetate (PMA) is accompanied by p53-independent activation of p21WAF1/CIP1 and c-myc down-regulation. We show that despite p21 induction in 7 of 12 human cancer cell lines treated with PMA, growth inhibition was observed only in two cell lines (SKBr3 breast and LNCaP prostate cancer cells). Treatment of SKBr3 and LNCaP cells with PMA was followed by Raf-1 hyperphosphorylation, p21 induction, Rb hypophosphorylation, c-myc down-regulation and growth inhibition. The 10 remaining PMA-resistant cell lines were comprised of 5 that failed to induce p21 and 5 that induced p21 but had defects in steps putatively downstream of this (Rb hypophosphorylation and c-myc down-regulation). Exogenous expression and subsequent failure to down-regulate c-myc protein expression in SKBr3 and LNCaP cells was correlated with acquisition of resistance to the growth inhibitory effect of PMA. Exogenous p21 expression down-regulated c-myc protein in PMA-sensitive cancer cells. Our findings suggest that induction of p21 and down-regulation of c-myc may be necessary steps in a PMA-induced growth-inhibitory pathway in cancer cells.
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PMID:Defects in p21WAF1/CIP1, Rb, and c-myc signaling in phorbol ester-resistant cancer cells. 900 May 76

Intercellular adhesion molecule 1 (ICAM-1) (CD54) is an adhesion molecule of the immunoglobulin superfamily. The interaction between ICAM-1 on B lymphocytes and leukocyte function-associated antigen 1 on T cells plays a major role in several aspects of the immune response, including T-dependent B cell activation. While it was originally believed that ICAM-1 played a purely adhesive role, recent evidence suggests that it can itself transduce biochemical signals. We demonstrate that cross-linking of ICAM-1 results in the up-regulation of class II major histocompatibility complex, and we investigate the biochemical mechanism for the signaling role of ICAM-1. We show that cross-linking of ICAM-1 on the B lymphoma line A20 induces an increase in tyrosine phosphorylation of several cellular proteins, including the Src family kinase p53/p56(lyn). In vitro kinase assays showed that Lyn kinase was activated within 1 min after ICAM-1 cross-linking. In addition, ICAM-1 cross-linking resulted in activation of Raf-1 and mitogen-activated protein kinases, as determined by gel mobility shift. Activation of these kinases may represent important components in the cascade of signals that link ICAM-1 to various ICAM-1-elicited cellular responses. These data confirm the important role of ICAM-1 as a signaling molecule in B cell activation.
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PMID:Signaling through intercellular adhesion molecule 1 (ICAM-1) in a B cell lymphoma line. The activation of Lyn tyrosine kinase and the mitogen-activated protein kinase pathway. 908 38

The radiosensitivity of proliferating crypt epithelial cells makes the gut a major limiting factor in the use of radiotherapy for treatment of abdominal cancers. As post-mitotic epithelial cells migrate from mouse small intestinal crypts to the base of adjacent villi, they rapidly lose their ability to undergo apoptosis in response to ionizing irradiation (IR). To determine whether this radioresistance reflects withdrawal from the cell cycle, we used a lineage-specific promoter to direct expression of wild type Simian virus 40 T antigen (SV40 TAg(Wt)) to villus, but not crypt, enterocytes in FVB/N transgenic mice. SV40 TAg(Wt) induced, pRB-dependent, re-entry into the cell cycle is not associated with the acquisition of IR-stimulated apoptosis 4 h or 24 h after 6 Gy or 12 Gy of gamma-irradiation. Co-expression of SV40 TAg(Wt) and K-ras(val12) produces dysplasia in cycling villus enterocytes but no shift towards apoptotic responsiveness to IR. These findings suggest that the radioresistance of villus enterocytes is not simply due to their cell cycle arrest and may be a reflection of their microenvironment. Remarkably, reentry of villus enterocytes to the cell cycle increases the radiosensitivity of the crypt epithelium without changing Bcl-2, Bcl-xL, Bak, or Bax expression. This effect is only manifest after IR and, based upon results obtained with mutant SV40 TAgs, depends upon reaching a critical level of proliferation in villus enterocytes. Like the normal crypt response to IR, the villus-derived enhancement of IR-stimulated crypt apoptosis is associated with an induction of p53 and Raf-1, and is dependent upon p53. Unlike the normal crypt response to IR, the p53 induction involves cells distributed throughout the crypt and the apoptotic response is not confined to the lower half of the crypt. These results indicate that signals initiated by cycling enterocytes can be transmitted to the crypt epithelium to induce p53 and influence their IR-induced apoptosis. Understanding the underlying signaling pathways may provide clues about how to modify a normal crypt's radiosensitivity for therapeutic benefit.
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PMID:gamma-Ray-induced apoptosis in transgenic mice with proliferative abnormalities in their intestinal epithelium: re-entry of villus enterocytes into the cell cycle does not affect their radioresistance but enhances the radiosensitivity of the crypt by inducing p53. 924 49

Ribonucleotide reductase is a highly regulated, cell cycle-controlled activity that plays an important role in DNA synthesis and repair. Recent studies have shown that elevated expression of the rate-limiting R2 component of ribonucleotide reductase increases Raf-1 protein activation and mitogen-activated protein kinase activity and acts as a novel malignancy determinant in cooperation with activated oncogenes like H-ras. We show that hydroxyurea-resistant mouse L cells with elevated R2 gene expression and increased ribonucleotide reductase activity exhibit significantly decreased sensitivities to the chemotherapeutic compounds N-(phosphonacetyl)-L-aspartate (PALA) and methotrexate (MTX). Furthermore, BALB/c 3T3 cells containing a retroviral expression vector encoding the R2 sequence also showed decreased sensitivity to PALA and MTX when compared to cells containing the same vector but without the R2 coding region. Colonies that developed in the presence of PALA or MTX contained amplifications of the CAD or dihydrofolate reductase genes and exhibited wild-type p53 function as determined in sequence-specific p53 binding activity assays. NIH-3T3 cells containing the R2 retroviral expression vector also showed significantly decreased sensitivity to hydroxyurea and MTX but not to PALA. Furthermore, NIH-3T3 cells transfected with a vector containing the R2 sequence in antisense orientation exhibited increased sensitivity to hydroxyurea, PALA, and MTX. Similarly, mouse 10T1/2 cells that are highly transformed and drug resistant due to alterations in H-ras and a mutant oncogenic form of p53 exhibited significant increases in sensitivity to hydroxyurea, PALA, and MTX when transfected with a vector containing the R2 sequence in antisense orientation and compared to cells containing the same vector without the antisense sequence. These results indicate that altered expression of the R2 component is capable of significantly modifying drug sensitivity properties of tumor cells. We hypothesize that this occurs, at least in part, through a mechanism of increased genetic instability that is independent of direct p53 mutation or loss and involves R2 stimulation of the mitogen-activated protein kinase signal pathway.
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PMID:Ribonucleotide reductase R2 gene expression and changes in drug sensitivity and genome stability. 935 52

This study demonstrates that Ha-rasVal12 oncogene overexpression sensitizes NIH/3T3 fibroblasts to lovastatin (LOV) cytotoxicity. This sensitization is through apoptosis, which was characterized by increasing CPP32 (caspase-3) activity and DNA fragmentation. Bcl-2 overexpression increased the resistance of the Ha-ras transformants to LOV and rescued the cells from apoptosis, further confirming that the LOV-sensitive cells died of apoptosis. Further analysis showed that Ha-ras activity inversely correlated with WAF1 activity. LOV treatment suppressed Ha-ras activity but induced WAF1 activity and disrupted the cell population in G0/G1 and S phases. The Ha-ras transformants expressing either dominant negative RasAsn17 or Raf-1CB4 showed reverted susceptibility to LOV. These data confirm the involvement of Ras and demonstrate that Raf-1 signalling is required for LOV-induced cell death. Taken together, the possible action of LOV-induced apoptosis is through suppressing Ha-ras activity and increasing WAF1 activity, which alters cell cycle progression and finally activates suppressed apoptotic pathway in a Fas/Fas-L- and p53-independent fashion.
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PMID:Ha-rasVal12 oncogene increases susceptibility of NIH/3T3 cells to lovastatin. 967 86

Although the ability of Taxol to stabilize cellular microtubules is well accepted, the mechanisms by which Taxol induces growth arrest and cell death remain unclear. Recent evidence indicates that Taxol alters specific intracellular signal transduction events, such as the activation of Raf-1 kinase, that may be essential for drug-induced apoptosis. To determine whether Raf-1 kinase activation occurs at different concentrations of Taxol and in response to disruption of the normal microtubule cytoskeleton, A549 cells were treated with different concentrations of Taxol after which Raf-1 activation and the microtubule cytoskeleton were analyzed. Raf-1 activation was observed at Taxol concentrations of 9 nM and greater. However, disruption of the normal microtubule cytoskeleton was seen at lower Taxol concentrations (1-7 nM), indicating that this process begins in the absence of Raf-1 activation. Raf-1 activation correlated with the induction of a G2-M block. Depletion of Raf-1 resulted in the accumulation of cells in the G2-M phase of the cell cycle, suggesting that Raf-1 may play an important role in the passage through mitosis. Supporting this idea, Raf-1 was activated in mitotic cells. Low concentrations of Taxol induced cell death in the absence of Raf-1 activation, indicating that Taxol-induced cell death is not dependent on Raf-1 activation. At concentrations of drug lower than the critical concentration required for Raf-1 activation, p53 and p21(WAF-1) were induced independently of Raf-1. These studies suggest that Taxol-mediated cell death may result from two different mechanisms. At low Taxol concentrations (< 9 nM), cell death may occur after an aberrant mitosis by a Raf-1 independent pathway, whereas at higher Taxol concentrations (> or = 9 nM) cell death may be the result of a terminal mitotic arrest occurring by a Raf-1-dependent pathway.
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PMID:Mechanisms of Taxol-induced cell death are concentration dependent. 972 70

The oncogenes RAS and RAF came to view as agents of neoplastic transformation. However, in normal cells, these genes can have effects that run counter to oncogenic transformation, such as arrest of the cell division cycle, induction of cell differentiation, and apoptosis. Recent work has demonstrated that RAS elicits proliferative arrest and senescence in normal mouse and human fibroblasts. Because the Raf/MEK/MAP kinase signaling cascade is a key effector of signaling from Ras proteins, we examined the ability of conditionally active forms of Raf-1 to elicit cell cycle arrest and senescence in human cells. Activation of Raf-1 in nonimmortalized human lung fibroblasts (IMR-90) led to the prompt and irreversible arrest of cellular proliferation and the premature onset of senescence. Concomitant with the onset of cell cycle arrest, we observed the induction of the cyclin-dependent kinase (CDK) inhibitors p21(Cip1) and p16(Ink4a). Ablation of p53 and p21(Cip1) expression by use of the E6 oncoprotein of HPV16 demonstrated that expression of these proteins was not required for Raf-induced cell cycle arrest or senescence. Furthermore, cell cycle arrest and senescence were elicited in IMR-90 cells by the ectopic expression of p16(Ink4a) alone. Pharmacological inhibition of the Raf/MEK/MAP kinase cascade prevented Raf from inducing p16(Ink4a) and also prevented Raf-induced senescence. We conclude that the kinase cascade initiated by Raf can regulate the expression of p16(Ink4a) and the proliferative arrest and senescence that follows. Induction of senescence may provide a defense against neoplastic transformation when the MAP kinase signaling cascade is inappropriately active.
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PMID:Senescence of human fibroblasts induced by oncogenic Raf. 976 2

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