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)

We have recently reported that two Rho family GTPases, Rac1 and Cdc42, are intimately involved in the control of cell survival of murine fibroblasts linked to adherence to the extracellular matrix. Inhibition of either Rac1 or Cdc42 signaling in adherent cells mimics the loss of anchorage and efficiently induces apoptosis in both immortalized and primary cells. In both cases cell death is dependent on the wild-type p53 tumor suppressor and is accompanied by activation of endogenous p53. Here, we describe that the inhibition of Rac1 or Cdc42 signaling leads to MAPK ERK activation via a pathway involving PI(3)K, Akt, Raf, and MEK, but not Ras. The moderate level of ERK activation that accompanies anoikis is an essential component of proapoptotic signaling; whereas sustained, high-intensity ERK signaling promotes survival in the same experimental system.
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PMID:Activation of ERK, controlled by Rac1 and Cdc42 via Akt, is required for anoikis. 1248 52

We investigated the signal transduction pathway to low-dose radiation-induced apoptosis in vitro in the human peripheral primitive neuroectodermal tumor (pPNET) cell line with wild-type p53 established in our laboratory. Apoptosis was induced by 2Gy irradiation in an almost p53-dependent manner in this model except for a deficiency of the cleavage of caspase-9. It was detected 3 hours after irradiation by fragmentation assay. The expressions of p53, p21WAF-1 and Bax increased, in contrast to the gradually decreasing expression of Bcl-2, as observed by immunoblotting. Following this, cleavages of caspase-3 and PARP reached peak levels. There were no detectable increases in ERK expression and caspase-9 cleavage. In respect of the probability of other pathways to apoptosis, this cell line will provide a useful model both for investigating low-dose radiation-induced signal transduction pathway and for analyzing the biological characteristics of pPNET.
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PMID:Signal transduction pathway to low-dose radiation-induced apoptosis in peripheral PNET cells. 1252 90

To analyse individual factors that may contribute to leukemic transformation in vivo, we have developed a murine model of leukemogenesis based on the early hematopoietic precursor cell FL5.12. FL5.12 cells are interleukin-3 (IL-3) dependent for growth, proliferation, and survival. Relative resistance to cell death following IL-3 withdrawal can be conferred by either overexpression of the Bcl-x(L) apoptotic inhibitor, or constitutive activation of the serine/threonine kinase Akt. The ability of Bcl-x(L) or a constitutively active myristylated Akt to promote leukemic transformation of FL5.12 cells was compared in athymic nu(+)/nu(+) mice. Bcl-x(L) alone could not promote leukemic transformation, but mice injected with FL5.12 cells overexpressing Bcl-x(L) and a dominant-negative p53 construct developed leukocytosis and blastic infiltration of lymph nodes, spleen, and liver with features of a high-grade lymphoid malignancy. In contrast to the cells injected into these animals, cell lines derived from the mice were able to proliferate in the absence of IL-3, and were found to have constitutively activated Akt. This constitutive activation was associated with a variety of alterations of the signaling pathway regulating Akt activity, including alterations of PTEN mRNA and protein expression. In addition, some of these leukemic clones demonstrated concurrent constitutive upregulation of ERK activity. A constitutively active Akt construct introduced into FL5.12 cells promoted similar clonal expansion in vivo, with emergence of clonal IL-3-independent proliferation. Bcl-x(L) and Akt appeared to function cooperatively in this model, enhancing rapid clonal outgrowth in vivo relative to Akt alone. These results implicate activated Akt and growth-factor independence in leukemogenic transformation, and demonstrate the potential for in vivo analysis of genetic determinants of leukemogenesis.
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PMID:Bcl-x(L) and Akt cooperate to promote leukemogenesis in vivo. 1256 61

This work examined the importance of radiation-induced and ligand-induced EGFR-ERK signaling for the regulation of DNA repair proteins XRCC1 and ERCC1 in prostate carcinoma cells, DU145 (TP53(mut)), displaying EGFR-TGFA-dependent autocrine growth and high MAPK (ERK1/2) activity, and LNCaP (TP53(wt)) cells expressing low constitutive levels of ERK1/2 activity. Using quantitative RT-PCR and Western analyses, we determined that ionizing radiation activated the DNA repair genes XRCC1 and ERCC1 in an ERK1/2-dependent fashion for each cell line. After irradiation, a rapid increase followed by a decrease in ERK1/2 activity preceded the increase in XRCC1/ERCC1 expression in DU145 cells, while only the rapid decrease in ERK1/2 preceded the increase in XRCC1/ERCC1 expression in LNCaP cells. Administration of EGF, however, markedly increased the up-regulation of phospho-ERK, ERCC1 and XRCC1 in both cell lines. Although the EGFR inhibitor tyrphostin (AG-1478) and the MEK inhibitor PD90859 both attenuated EGF-induced levels of the ERCC1 and XRCC1 protein, PD98059 blocked the induction of ERCC1 and XRCC1 by radiation more effectively in both cell lines. Inhibition of ERK at a level that reduced the up-regulation of DNA repair led to the persistence of apurinic/apyrimidinic (AP) sites of DNA damage and increased cell killing. Taken together, these data imply a complex control of DNA repair activation that may be more generally dependent on MAPK (ERK1/2) signaling than was previously noted. These data provide novel insights into the capacity of the EGFR-ERK signaling to modulate DNA repair in cancer cells and into the functional significance of this signaling.
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PMID:Epidermal growth factor and ionizing radiation up-regulate the DNA repair genes XRCC1 and ERCC1 in DU145 and LNCaP prostate carcinoma through MAPK signaling. 1264 88

Flavopiridol, a synthetic flavone, has been previously shown to induce apoptosis in B-cell chronic lymphocytic leukaemia (B-CLL) cells in vitro. The apoptosis was associated with a concomitant activation of caspase-3 without evidence of dependence on functional p53 or Bcl-2 family modulation. In this study, we examined flavopiridol-induced apoptosis in terms of upstream caspase activity, cell cycle distribution and signal transduction, in order to elucidate the mechanism of action of this potent cytotoxic agent. Flavopiridol-induced apoptosis was significantly abrogated by the caspase-9 inhibitor Z-LEHD-FMK (p = 0.002; paired t-test) but was not altered by the caspase-8 inhibitor Z-IETD-FMK (p = 0.37; paired t-test). There was a concentration-dependent increase in a sub G0/G1 peak indicative of apoptotic cells but if these cells were excluded by gating no other cell cycle perturbations were observed suggesting that flavopiridol is capable of inducing apoptosis in cells in all phases of the cell cycle. Significantly, apoptosis was associated with activation of p38 MAP kinase and suppression of ERK activity (p = 0.0036 and p = 0.0048, respectively; paired t-test). These results show for the first time that flavopiridol modulates specific cellular signal transduction pathways in B-CLL cells thereby altering the balance between survival and cell death signals and providing a rationale for the p53-independent nature of flavopiridol-induced apoptosis. Further work is required to identify whether combinations of conventional chemotherapeutic drugs and novel agents like flavopiridol can be used to improve patient outcomes in the treatment of B-CLL.
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PMID:Flavopiridol induces apoptosis in B-cell chronic lymphocytic leukaemia cells through a p38 and ERK MAP kinase-dependent mechanism. 1268 54

The human egr-1 gene encodes a zinc finger transcription factor induced by endogenous and exogenous stimuli such as growth factors, cytokines, and mitogens. Egr-1 regulates other genes involved in growth and differentiation. The present study investigated the influence of genotoxic agents, such as chemotherapy drugs and other DNA damaging agents, on egr-1 expression in normal and neoplastic cells. A transcriptional fusion between the human egr-1 promoter and the enhanced green fluorescent protein (EGFP) gene was used for direct visualization of intracellular Egr-1 regulation. The transcriptional activity of the egr-1 promoter in this reporter system faithfully reflects intrinsic egr-1 expression and induction, as demonstrated by FACS analysis of fluorescence and by RT-PCR for egr-1. EGFP was expressed under the control of the egr-1 promoter in stably transfected immortalized cell lines, such as HEK293, T98G, LNZ308, and 9L, which were then treated with genotoxic agents.A multitude of DNA damaging agents and therapeutic drugs caused significant upregulation of egr-1 transcription. Furthermore, cytotoxic compounds without a direct DNA damaging effect, such as resveratrol and vincristine, which interfere with DNA replication and cell division, were also able to activate egr-1 transcription. This suggests that cell cycle arrest rather than DNA damage seems to be the condition triggering egr-1 transcription. Moreover, treatment with the MAP kinase (MAPK) inhibitor SB203580, which specifically blocks the stress inducible p38/SAPK2 pathway, did not alter egr-1 induction. On the other hand, treatment with the inhibitor PD98059, which specifically blocks the MAPK/ERK pathway, partially suppressed the induction effect. In addition, the egr-1 induction effect caused by genotoxic stress was found to be at least in part independent from the cellular p53 status, as it was observed in p53-deficient as well as in wild type p53 cell lines. These results suggest that induction of egr-1, a gene to which until now no relation to DNA repair has been assigned, may belong to the fundamental cellular responses elicited by genotoxic and mitotic stress in normal as well as in neoplastic cells, and that enhanced levels of Egr-1 protein may be needed to regulate genes involved in DNA repair, cell survival, and apoptosis.
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PMID:The egr-1 gene is induced by DNA-damaging agents and non-genotoxic drugs in both normal and neoplastic human cells. 1270 85

We have isolated a novel gene, LDOC1, which encodes for a leucine zipper protein that was downregulated in a series of human pancreatic cancer cell lines but was expressed in corresponding normal tissues. We report the initial characterization of LDOC1 as a novel regulator of the transcriptional response mediated by the nuclear factor kappa B (NF-kappaB). Transient expression of LDOC1 significantly inhibited the luciferase activity in LDOC1-negative BxPC-3 pancreatic cancer cell line transfected with the NF-kappaB reporter plasmid, activated with mitogen-activated protein kinase/ERK kinase kinase-1 (MEEK). LDOC1, however, does not affect p53, AP1 and CRE-dependent reporter gene expression. The activation of NF-kappaB through ligand-induced stimulation by tumor necrosis factor-alpha (TNF-alpha) or phorbol 12-myristate 13-acetate (PMA) was also inhibited by transient expression of LDOC1 in a dose dependent manner. To determine the growth effect of LDOC1 expression on cancer cells, BxPC-3 cells were stably transfected with LDOC1 cDNA. Viability studies demonstrated that TNF-alpha or PMA-induced antiproliferative effects were significantly enhanced by stable transfection of cells with LDOC1. These observations suggest that LDOC1 is a novel regulator of NF-kappaB that can affect the PMA or TNF-alpha-mediated pathway to apoptosis through inhibition of NF-kappaB activation in BxPC3 pancreatic cancer cells.
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PMID:Leucine-zipper protein, LDOC1, inhibits NF-kappaB activation and sensitizes pancreatic cancer cells to apoptosis. 1271 34

TGF-beta induces growth suppression and apoptosis of various types of cells, but supports fibroblast growth. We previously isolated TIAF1 (TGF-beta1-induced antiapoptotic factor 1), which protects murine L929 fibroblasts from TNF cytotoxicity. Here, we show that TIAF1 induced growth inhibition and apoptosis of monocytic U937 and other types of cells. In contrast, like TGF-beta1, TIAF1 supported transforming growth of L929 fibroblasts. TIAF1 increased the expression of p53, Cip1/p21, and Smad proteins; suppressed ERK phosphorylation; and altered TGF-beta1-mediated Smad2/3 phosphorylation in U937 cells. Antisense TIAF1 mRNA significantly enhanced the proliferation of mink lung Mv1Lu epithelial cells. Together, these observations indicate that TIAF1 participates in the TGF-beta-mediated growth regulation.
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PMID:TIAF1 participates in the transforming growth factor beta1--mediated growth regulation. 1281 35

Although RhoA plays an important role in cell proliferation and in Ras transformation in fibroblasts and mammary epithelial cells, its role in intestinal epithelial cells (IEC) is unknown. In a previous study (Ray RM, Zimmerman BJ, McCormack SA, Patel TB, and Johnson LR. Am J Physiol Cell Physiol 276: C684-C691, 1999), we showed that polyamine depletion [dl-alpha-difluoromethylornithine (DFMO) treatment] strongly inhibits the proliferation of IEC. In this report, we examined the effect of RhoA on IEC-6 cell proliferation and whether polyamine depletion inhibits cell proliferation in the presence of constitutively active RhoA. Constitutively active RhoA and vector-transfected IEC-6 cell lines were grown in the presence or absence of DFMO, which causes polyamine depletion by inhibiting ornithine decarboxylase, the first rate-limiting step in polyamine synthesis. Constitutively active RhoA significantly increased the rate of cell proliferation. These cells also lost contact inhibition and formed conspicuous foci when they were fully confluent. Decreased p21Waf1/Cip1 expression and increased cyclin-dependent kinase (Cdk2) mRNA levels and activity accompanied the increased proliferation. The inhibition of p21Waf1/Cip1 was independent of p53. There was no activation of the Ras-Raf-MEK-ERK pathway in the RhoA-transfected cell line. Polyamine depletion totally prevented the effect of activated RhoA on IEC-6 cell proliferation, focus formation, and Cdk2 expression. The stability of mRNA and protein for Cdk2 and p21Waf1/Cip1 in V14-RhoA cells was not significantly different from that of vector-transfected cells. In conclusion, RhoA activation decreased p21Waf1/Cip1 expression and increased basal and serum-induced ornithine decarboxylase activity, Cdk2 expression, Cdk2 protein, and Cdk2 activity, leading to the stimulation of IEC proliferation and transformation. Polyamine depletion totally prevented RhoA's effect on proliferation by decreasing Cdk2 expression and activity.
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PMID:RhoA stimulates IEC-6 cell proliferation by increasing polyamine-dependent Cdk2 activity. 1281 57

Assessment of specific apoptosis and survival pathways implicated in anticancer drug action is important for understanding drug mechanisms and modes of resistance in order to improve the benefits of chemotherapy. In order to better examine the role of mitogen-activated protein kinases, including JNK and ERK, as well as the tumor suppressor p53, in the response of tumor cells to chemotherapy, we compared the effects on these pathways of three structurally and functionally distinct antitumor agents. Drug concentrations equal to 50 times the concentration required to reduce cell proliferation by 50% were used. Vinblastine, doxorubicin, or etoposide (VP-16) induced apoptotic cell death in KB-3 carcinoma cells, with similar kinetic profiles of PARP cleavage, caspase 3 activation, and mitochondrial cytochrome c release. All three drugs strongly activated JNK, but only vinblastine induced c-Jun phosphorylation and AP-1 activation. Inhibition of JNK by SP600125 protected cells from drug-induced cytotoxicity. Vinblastine caused inactivation of ERK whereas ERK was unaffected in cells exposed to doxorubicin or VP-16. Inhibition of ERK signaling by the MEK inhibitor, U0126, potentiated the cytotoxic effects of vinblastine and doxorubicin, but not that of VP-16. Vinblastine induced p53 downregulation, and chemical inhibition of p53 potentiated vinblastine-induced cell death, suggesting a protective effect of p53. In contrast, doxorubicin and VP-16 induced p53, and inhibition of p53 decreased drug-induced cell death, suggesting a pro-apoptotic role for p53. These results highlight the differential roles played by several key signal transduction pathways in the mechanisms of action of key antitumor agents, and suggest ways to specifically potentiate their effects in a context-dependent manner. In addition, the novel finding that JNK activation can occur without c-Jun phosphorylation or AP-1 activation has important implications for our understanding of JNK function.
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PMID:The JNK, ERK and p53 pathways play distinct roles in apoptosis mediated by the antitumor agents vinblastine, doxorubicin, and etoposide. 1290 45


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