Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.11.24 (mitogen-activated protein kinase)
 95,810 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

DNA topoisomerase (topo) II inhibitors either stabilize DNA-topo II complexes by blocking DNA religation (e.g. etoposide) or block the enzyme's catalytic activity (e.g. dexrazoxane). The former class of drugs causes direct DNA damage through topo II, while the latter class does not, but both classes cause apoptosis. We cloned the Fas ligand (FasL) promoter and coupled it to the luciferase gene. Treatment of cells transfected with this construct revealed that complex-stabilizing (DNA-damaging) agents induce FasL expression, but the catalytic inhibitors do not, suggesting that the FasL pathway may not be involved in all cases of topoisomerase-mediated apoptosis. Some topo II inhibitors activate a pathway involving stress-activated protein kinases, which include c-Jun N-terminal kinase-1 (JNK-1). We will discuss the effects of these agents on components of this pathway. Our earlier work revealed that topo IIalpha interacts with the cell cycle regulatory protein, retinoblastoma protein (Rb). This interaction and the subcellular distribution of these proteins are altered by topo II inhibitory drugs and lead to apoptosis. In addition, agents that affect Rb, such as E1A and E2F1/DP-1, when transfected into cells, also alter topo IIalpha-Rb localization, activate jun kinase pathways and cause apoptosis. This paper discusses current studies that are designed to determine the contributions of these signalling events to the alterations in subcellular protein distribution and apoptosis. We suggest that protein-protein interactions are important for mediation of cytotoxic signalling by anticancer drugs.
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PMID:Cytotoxic signalling by inhibitors of DNA topoisomerase II. 1170 58

Long-term estrogen deprivation causes human breast cancer cells to develop hypersensitivity to the mitogenic effect of estradiol (E(2)). Our prior studies demonstrated an association between enhanced MAPK activation and hypersensitivity in long-term estrogen-deprived (LTED) MCF-7 cells. Herein, we report that MAPK is constitutively activated in LTED cells and not dependent on serum factors. Additionally, activated MAPK levels fall upon reversion of the hypersensitivity. Importantly, we now provide direct evidence that enhanced MAPK causes hypersensitivity to E(2). We activated MAPK in wild-type MCF-7 cells using TGFalpha, and demonstrated a 2-3 log enhancement of sensitivity to E(2). PD98059 abrogated the TGFalpha-induced effect, indicating that MAPK activation is responsible for E(2) hypersensitivity. To determine the level at which MAPK activation enhanced E(2) sensitivity, we examined the dose-response effects of E(2) on several transcriptional readouts, including ERE-reporter activity and the levels of progesterone receptor and pS2. Wild-type and LTED cells exhibited nearly identical responses to E(2), suggesting that mechanisms downstream of estrogen receptor-mediated transcription are involved in inducing hypersensitivity. In support of this possibility, LTED and TGFalpha-treated wild-type cells were hypersensitive to the effects of E(2) on the key cell cycle regulator, E2F1.
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PMID:Activation of the MAPK pathway enhances sensitivity of MCF-7 breast cancer cells to the mitogenic effect of estradiol. 1219 33

Aberrant activation of the Rb/E2F1 pathway in cycling cells, in response to mitogenic or nonmitogenic stress signals, leads to apoptosis through hyperphosphorylation of Rb. To test whether in postmitotic neurons the Rb/E2F1 pathway can be activated by the nonmitogenic stress signaling, we examined the role of the p38 stress-activated protein kinase (SAPK) in regulating Rb phosphorylation in response to Fas (CD95/APO1)-mediated apoptosis of cultured cerebellar granule neurons (CGNs). Anti-Fas antibody induced a dramatic and early activation of p38. Activated p38 was correlated with the induction of hyperphosphorylation of both endogenous and exogenous Rb. The p38-selective inhibitor, SB203580, attenuated such an increase in pRb phosphorylation and significantly protected CGNs from Fas-induced apoptosis. The cyclin-dependent kinase-mediated Rb phosphorylation played a lesser role in this neuronal death paradigm, since cyclin-dependent kinase inhibitors, such as olomoucine, roscovitine, and flavopiridol, did not significantly prevent anti-Fas antibody-evoked neuronal apoptosis. Hyperphosphorylation of Rb by p38 SAPK resulted in the release of Rb-bound E2F1. Increased E2F1 modulated neuronal apoptosis, since E2F1-/- CGNs were significantly less susceptible to Fas-mediated apoptosis in comparison with the wild-type CGNs. Taken together, these studies demonstrate that neuronal Rb/E2F1 is modulated by the nonproliferative p38 SAPK in Fas-mediated neuronal apoptosis.
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PMID:Activation of the Rb/E2F1 pathway by the nonproliferative p38 MAPK during Fas (APO1/CD95)-mediated neuronal apoptosis. 1235 30

Neurogenesis, or the production of new neurons, is regulated by physiological and pathological processes including aging, stress, and brain injury. Many mitogenic and trophic factors that regulate proliferation of nonneuronal cells are also involved in neurogenesis. These include vascular endothelial cell growth factor (VEGF), which stimulates the incorporation of bromodeoxyuridine (BrdU) into neuronal precursor cells in vitro and in the adult rat brain in vivo. Using BrdU labeling as an index of cell proliferation, we found that the in vitro neuroproliferative effect of VEGF was associated with up-regulation of E2F family transcription factors, cyclin D1, cyclin E, and cdc25. VEGF also increased nuclear expression of E2F1, E2F2, and E2F3, consistent with regulation of the G1/S phase transition of the cell cycle. The proliferative effect of VEGF was inhibited by the extracellular signal-regulated kinase kinase (MEK) inhibitor PD98059, the phospholipase C (PLC) inhibitor U73122, the protein kinase C (PKC) inhibitor GF102390X, and the phosphatidylinositol 3-kinase (PI3K) inhibitor wortmannin, indicating involvement of multiple signaling pathways. These findings help to provide a molecular basis for some of the recently identified neuronal effects of VEGF.
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PMID:Vascular endothelial growth factor promotes proliferation of cortical neuron precursors by regulating E2F expression. 1255 97

Constitutive cell surface receptor kinase signaling and persistent phosphorylation/inactivation of the retinoblastoma (pRb) family of proteins (pRb, p107 and p130, known as pocket proteins) have been implicated in conferring uncontrolled growth to melanoma cells. However, the signals linking receptor kinase activity to neutralization of pocket proteins have not yet been fully elucidated. We therefore used specific chemical inhibitors to examine pRb regulation in melanoma cells. The most efficient agent, AG1024, known as an inhibitor of insulin-like growth factor 1 receptor and insulin receptor, arrested melanoma cell growth in vitro at nanomolar concentrations within 24 h of application. AG1024 inhibited the mitogen-activated protein kinase/extracellular signal-regulated kinase pathway and restored pRb tumor suppressive function. The latter was observed by the reduction in the phosphorylated forms of pRb, p107 and p130, and the formation of growth suppressive DNA binding complexes consisting of pRb and E2F1 or E2F3. The loss of phosphorylated forms of pRb at early time points after AG1024 application was not associated with suppression of cyclin-dependent kinases 2 and 4 activity but rather with proteasomal and nonproteasomal degradation. Thus, inhibition of melanoma cell proliferation by AG1024 is mediated by inhibition of mitogen-activated protein kinase/extracellular signal-regulated kinase 2 signaling and activation of pRb by a mechanism involving protein degradation.
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PMID:The tyrphostin AG1024 accelerates the degradation of phosphorylated forms of retinoblastoma protein (pRb) and restores pRb tumor suppressive function in melanoma cells. 1264 8

The full mechanisms underlying neuronal death following excitotoxic insult remain unclear, despite many in vivo and in vitro studies. Recent work has focused on various signaling molecules and pathways, normally strictly regulated, that can trigger death if perturbed. The transcription factor, E2F1 is pivotal in controlling cell death under stress situations. The current study aimed to investigate the role of this transcription factor in modulating neuronal death following kainic acid (KA) treatment of cultured mouse cerebellar granule cells (CGCs). KA-induced death of CGCs was attenuated by the selective KA/AMPA receptor antagonist CNQX, but not MK-801. Such neuronal death was caspase-3-independent and did not activate many known death genes, such as Fas receptor, caspase-8 and p38. However, hyperphosphorylation of Rb showed a transient increase which may lead to activation of E2F1. Indeed E2F1 +/+ and -/- CGCs showed a differential response to KA-mediated toxicity, in that E2F1 -/- neurons were significantly less susceptible to KA compared to E2F1 +/+ neurons, albeit both E2F1 +/+ and -/- neurons expressed similar levels of KA receptors and responded similarly to kainate antagonist, CNQX. Using selective inhibitors to CDKs, such as olomoucine, roscovitine and flavopiridol, and the inhibitor SB203580 to p38 MAPK, we ruled out the possibility that Rb inactivation through hyperphosphorylation was due to either upstream kinases. Therefore activation of Rb/E2F1 pathway appears to involve novel interactions yet to be elucidated.
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PMID:Involvement of the transcription factor E2F1/Rb in kainic acid-induced death of murine cerebellar granule cells. 1294 62

After balloon angioplasty, locally expressed tumor necrosis factor (TNF)-alpha disrupts endothelial cell (EC) proliferation and reendothelialization of the injured vessel. We have previously reported that TNF inhibits the EC cycle and downregulates the transcription factor E2F1. Ectopic expression of E2F1 at the site of injury improves reendothelialization of the injured vessel. In this study, we report that c-Jun N-terminal kinase (JNK) 1 and p38 mitogen-activated protein kinases (MAPKs) are differentially required for E2F1 expression and activity in ECs. Overexpression of constitutively active JNK1 mimicked TNF-mediated inhibitory events, whereas dominant-negative JNK1 prevented these effects. E2F cis elements in the promoter of E2F1 gene mediate suppressive actions of TNF, because removal of these sites rendered E2F1 promoter activity insensitive to TNF. JNK1 physically interacted with E2F1 and inactivated it via direct phosphorylation. Additionally, TNF inhibited Rb phosphorylation and dissociation from E2F1. Overexpression of constitutively active p38 MAPK facilitated Rb-E2F1 dissociation, whereas that of dominant-negative p38 MAPK did not. Taken together, these data suggest a differential requirement of JNK1 and p38 MAPK in TNF regulation of E2F1. Targeted inactivation of JNK1 at arterial injury sites may represent a potential therapeutic intervention for ameliorating TNF-mediated EC dysfunction.
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PMID:Tumor necrosis factor-mediated E2F1 suppression in endothelial cells: differential requirement of c-Jun N-terminal kinase and p38 mitogen-activated protein kinase signal transduction pathways. 1457 93

Elevation of cellular cyclic AMP (cAMP) levels inhibits cell cycle reentry in a variety of cell types. While cAMP can prevent the activation of Raf-1 and extracellular signal-regulated kinases 1 and 2 (ERK1/2) by growth factors, we now show that activation of ERK1/2 by DeltaRaf-1:ER is insensitive to cAMP. Despite this, DeltaRaf-1:ER-stimulated DNA synthesis is still inhibited by cAMP, indicating a cAMP-sensitive step downstream of ERK1/2. Although cyclin D1 expression has been proposed as an alternative target for cAMP, we found that cAMP could inhibit DeltaRaf-1:ER-induced cyclin D1 expression only in Rat-1 cells, not in CCl39 or NIH 3T3 cells. DeltaRaf-1:ER-stimulated activation of CDK2 was strongly inhibited by cAMP in all three cell lines, but cAMP had no effect on the induction of p21(CIP1). cAMP blocked the fetal bovine serum (FBS)-induced degradation of p27(KIP1); however, loss of p27(KIP1) in response to DeltaRaf-1:ER was less sensitive in CCl39 and Rat-1 cells and was completely independent of cAMP in NIH 3T3 cells. The most consistent effect of cAMP was to block both FBS- and DeltaRaf-1:ER-induced expression of Cdc25A and cyclin A, two important activators of CDK2. When CDK2 activity was bypassed by activation of the ER-E2F1 fusion protein, cAMP no longer inhibited expression of Cdc25A or cyclin A but still inhibited DNA synthesis. These studies reveal multiple points of cAMP sensitivity during cell cycle reentry. Inhibition of Raf-1 and ERK1/2 activation may operate early in G(1), but when this early block is bypassed by DeltaRaf-1:ER, cells still fail to enter S phase due to inhibition of CDK2 or targets downstream of E2F1.
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PMID:DeltaRaf-1:ER* bypasses the cyclic AMP block of extracellular signal-regulated kinase 1 and 2 activation but not CDK2 activation or cell cycle reentry. 1464 40

Embryonic carcinoma (EC) cells and embryonic stem (ES) cells have short cell cycles and, accordingly, proliferate very fast. Serum starvation does not suppress proliferation of EC and ES cells that allows to assume independence of their proliferation from the activity of cascades induced by serum. In the present work, we used flow cytometry to investigate how specific MAP-kinase and PI3-kinase inhibitors may influence proliferation and cell cycle of EC F9 cells. It is established that inhibitors of ERK-, JNK- and p38-kinases do not suppress EC F9 cell proliferation. It is possible to assume that proliferation of EC cells is supported by constitutive activity of down-stream cell cycle regulators, for example, E2F1 transcription factor. Since PI3-kinase inhibitor LY294002 causes reduction of S-phase and accumulation of G1-phase F9 cells, PI3-kinase mediated cascades seem to be constantly activated and involved in phosphorylation of important cell cycle regulators. The analysis of transcription of immediate-early genes in undifferentiated cells has shown that c-fos and c-jun genes are strongly activated by serum, and that ERK-kinase plays the main role in activation of c-fos transcription, while activation of c-jun transcription depends predominantly on p38-kinase. It is necessary to note that PI3-kinase inhibitor increases effect of serum stimulation of c-fos promoter. It means that the PI3-kinase dependent cascade negatively influences the cascade, which activates c-fos transcription. Thus, the transcription of c-fos and c-jun is not connected with of EC F9 cell proliferation. The proliferation of these cells depends on PI3-kinase activity.
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PMID:[PI 3-kinase activity is necessary for F9 mouse embryonic carcinoma cell proliferation]. 1511 28

Cancer genes exert their greatest influence on the cell cycle by targeting regulators of a critical checkpoint in late G(1). Once cells pass this checkpoint, they are fated to replicate DNA and divide. Cancer cells subvert controls at work at this restriction point and remain in cycle. Previously, we showed that RACK1 inhibits the oncogenic Src tyrosine kinase and NIH 3T3 cell growth. RACK1 inhibits cell growth, in part, by prolonging G(0)/G(1). Here we show that RACK1 overexpression induces a partial G(1) arrest by suppressing Src activity at the G(1) checkpoint. RACK1 works through Src to inhibit Vav2, Rho GTPases, Stat3, and Myc. Consequently, cyclin D1 and cyclin-dependent kinases 4 and 2 (CDK4 and CDK2, respectively) are suppressed, CDK inhibitor p27 and retinoblastoma protein are activated, E2F1 is sequestered, and G(1)/S progression is delayed. Conversely, downregulation of RACK1 by short interference RNA activates Src-mediated signaling, induces Myc and cyclin D1, and accelerates G(1)/S progression. RACK1 suppresses Src- but not mitogen-activated protein kinase-dependent platelet-derived growth factor signaling. We also show that Stat3 is required for Rac1 induction of Myc. Our results reveal a novel mechanism of cell cycle control in late G(1) that works via an endogenous inhibitor of the Src kinase.
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PMID:RACK1 regulates G1/S progression by suppressing Src kinase activity. 1525 45


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