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)

Bim (Bcl-2-interacting mediator of cell death) is a BH3-only protein (BOP), a pro-apoptotic member of the Bcl-2 protein family. The Bim mRNA undergoes alternate splicing to give rise to the short, long and extra long protein variants (Bim(S), Bim(L) and Bim(EL)). These proteins have distinct potency in promoting death and distinct modes of regulation conferred by their interaction with other proteins. Quite how Bim and other BOPs promote apoptosis has been the subject of some debate. Bim was isolated by it's interaction with pro-survival proteins such as Bcl-2 and it has been suggested that this is key to the ability of Bim to induce apoptosis. However, an alternative model argues that some forms of Bim can bind directly to the pro-apoptotic Bax and Bak proteins to initiate apoptosis. A new study may finally put this debate to rest as it provides strong evidence to suggest that Bim and other BOPs act primarily by binding to pro-survival Bcl-2 proteins, thereby releasing Bax or Bak proteins to promote apoptosis. The importance of the interaction between Bim and the pro-survival Bcl-2 proteins is underlined by our demonstration that it is regulated by ERK1/2-dependent phosphorylation of Bim(EL). ERK1/2-dependent dissociation of Bim(EL) from pro-survival proteins is the first step in a process by which the pro-survival ERK1/2 pathway promotes the destruction of this most abundant Bim splice variant. In this review we outline the significance of these new studies to our understanding of how BOPs such as Bim initiate apoptosis and how this process is regulated by growth factor-dependent signalling pathways.
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PMID:Bim and the pro-survival Bcl-2 proteins: opposites attract, ERK repels. 1788 96

Mitochondrial alterations have been associated with the cytotoxic effect of 6-hydroxydopamine (6-OHDA), a widely used toxin to study Parkinson's disease. In previous work, we have demonstrated that 6-OHDA increases mitochondrial membrane permeability leading to cytochrome c release, but the precise mechanisms involved in this process remain unknown. Herein we studied the mechanism of increased mitochondrial permeability of SH-SY5Y neuroblastoma cells in response to 6-OHDA. Cytochrome c release induced by 6-OHDA occurred, in both SH-SY5Y cells and primary cultures, in the absence of mitochondrial swelling or a decrease in mitochondrial calcein fluorescence, suggesting little involvement of the mitochondrial permeability transition pore in this process. In contrast, 6-OHDA-induced cell death was associated with a significant translocation of the pro-apoptotic Bax protein from the cytosol to mitochondria and with a significant induction of the BH3-only protein PUMA. Experiments in mouse embryonic fibroblasts deficient in Bax or PUMA demonstrated a role for both proteins in 6-OHDA-induced apoptosis. Although 6-OHDA elevated both total and nuclear p53 protein levels, activation of p53 was not essential for subsequent cell death. In contrast, we found that p38 mitogen-activated protein kinase (MAPK) was activated early during 6-OHDA-induced apoptosis, and that treatment with the p38 MAPK inhibitor SKF86002 potently inhibited PUMA induction, green fluorescent protein-Bax redistribution and apoptosis in response to 6-OHDA. These data demonstrate a critical involvement of p38 MAPK, PUMA, and Bax in 6-OHDA-induced apoptosis.
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PMID:6-Hydroxydopamine activates the mitochondrial apoptosis pathway through p38 MAPK-mediated, p53-independent activation of Bax and PUMA. 1799 28

T-cell acute lymphoblastic leukemias (T-ALLs) are highly malignant tumors with 20% of patients continues to fail therapy, in part due to chemoresistance of T-ALL cells via largely unknown mechanisms. Here, we showed that lack of Bcl-2-interacting mediator of cell death (Bim)(EL) protein expression, a BH3-only member of the Bcl-2 family proteins, conferred resistance of a T-ALL cell line, Sup-T1, to etoposide-induced apoptosis. Overexpression of Bim(EL) significantly restored its sensitivity to etoposide-induced caspase activation and poly(ADP-ribose) polymerase cleavage. Surprisingly, we found that constitutive activation of the c-Jun N-terminal kinase (JNK) pathway in Sup-T1 cells promoted phosphorylation and degradation of Bim(EL) via the proteosome. Blocking with a proteosome inhibitor yielded an elevated level of Bim(EL) and accumulation of Bim(EL) species phosphorylated at Ser(69). Pretreatment of Sup-T1 cells with a specific JNK inhibitor, SP600125, also increased the Bim(EL) level and resensitized the cells to etoposide-induced apoptosis. Together, our findings suggest that the JNK activation status may correlate with the Bim(EL) level and in turn can control the sensitivity of T-ALL cells to chemotherapeutic agents.
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PMID:Activation of the JNK pathway promotes phosphorylation and degradation of BimEL--a novel mechanism of chemoresistance in T-cell acute lymphoblastic leukemia. 1817 37

The molecular causes for resistance of melanoma to apoptosis are currently only partly understood. In the present study, we examined gene transfer and expression of the proapoptotic BH3-only protein Noxa as an alternative approach to chemotherapy and investigated the molecular mechanisms regulating Noxa-induced apoptosis. Noxa gene transfer caused dysregulation of both mitochondria and, as shown for the first time, also the endoplasmic reticulum, resulting in the accumulation of reactive oxygen species. Interestingly, expression of Noxa not only triggered the classical mitochondrial caspase cascade, but also resulted in the activation of apoptosis signal-regulating kinase1 and its downstream effectors c-Jun N-terminal kinase and p38. The activation of these kinases was abolished by antioxidants. Moreover, inhibition of the kinases by RNA interference or pharmacological inhibitors significantly attenuated Noxa-induced apoptosis. Thus, our data provide evidence for the involvement of multiple pathways in Noxa-induced apoptosis that are triggered at mitochondria and the endoplasmic reticulum, and suggest Noxa gene transfer as a complementary approach to chemotherapy.
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PMID:The BH3-only member Noxa causes apoptosis in melanoma cells by multiple pathways. 1840 51

The mitogen-activated protein kinase JNK1 suppresses interleukin-3 withdrawal-induced cell death through phosphorylation of the BH3-only pro-apoptotic Bcl-2 family protein Bad at Thr-201. It is unknown whether JNK1 regulates glycolysis, an important metabolic process that is involved in cell survival, and if so, whether the regulation depends on Thr-201 phosphorylation of Bad. Here we report that phosphorylation of Bad by JNK1 is required for glycolysis through activation of phosphofructokinase-1 (PFK-1), one of the key enzymes that catalyze glycolysis. Genetic disruption of Jnk1 alleles or silencing of Jnk1 by small interfering RNA abrogates glycolysis induced by growth/survival factors such as serum or interleukin-3. Proteomic analysis identifies PFK-1 as a novel Bad-associated protein. Although the interaction between PFK-1 and Bad is independent of JNK1, Thr-201 phosphorylation of Bad by JNK1 is required for PFK-1 activation. Thus, our results provide a novel molecular mechanism by which JNK1 promotes glycolysis for cell survival.
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PMID:Phosphorylation of Bad at Thr-201 by JNK1 promotes glycolysis through activation of phosphofructokinase-1. 1846 2

The proapoptotic BH3-only protein Bim is established to be an important mediator of signaling pathways that induce cell death. Multisite phosphorylation of Bim by several members of the MAP kinase group is implicated as a regulatory mechanism that controls the apoptotic activity of Bim. To test the role of Bim phosphorylation in vivo, we constructed mice with a series of mutant alleles that express phosphorylation-defective Bim proteins. We show that mutation of the phosphorylation site Thr-112 causes decreased binding of Bim to the antiapoptotic protein Bcl2 and can increase cell survival. In contrast, mutation of the phosphorylation sites Ser-55, Ser-65, and Ser-73 can cause increased apoptosis because of reduced proteasomal degradation of Bim. Together, these data indicate that phosphorylation can regulate Bim by multiple mechanisms and that the phosphorylation of Bim on different sites can contribute to the sensitivity of cellular apoptotic responses.
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PMID:Multisite phosphorylation regulates Bim stability and apoptotic activity. 1849 46

Bcl-2 family proteins are implicated as essential regulators in tumor necrosis factor-alpha (TNFalpha)-induced apoptosis. Bim(L), a BH3-only member of Bcl-2 family, can directly or indirectly activate the proapoptotic Bax and the subsequent mitochondrial apoptotic pathway. However, the molecular mechanism of Bim(L) activating Bax activation during TNFalpha-induced apoptosis is not fully understood. In this study, the role of Bim(L) in Bax activation during TNFalpha-induced apoptosis was investigated in differentiated PC12 and MCF7 cells, with real-time single-cell analysis. The experimental results show that Bax translocated to mitochondria and cytochrome c (Cyt c) released from mitochondria after TNFalpha treatment. Furthermore, SP600125 (specific inhibitor of JNK) could inhibit the Cyt c release from mitochondria. Co-immunoprecipitation results show that, the interaction between Bcl-x(L) and Bax decreased after TNFalpha treatment, while that between Bcl-x(L) and Bim(L) increased. Bax did not co-immunoprecipitate with Bim(L) before or after the TNFalpha treatment. In addition, the increased interaction between Bim(L) and Bcl-x(L) was dynamically monitored by using fluorescence resonance energy transfer (FRET) technique. Most importantly, there was no evidence of Bim(L) redistribution to mitochondria until cell apoptosis. By comprehensively analyzing these data, it is concluded that Bim(L) displaces Bcl-x(L) in the mitochondria and promotes Bax translocation during TNFalpha-induced apoptosis.
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PMID:Bim(L) displacing Bcl-x(L) promotes Bax translocation during TNFalpha-induced apoptosis. 1850 May 55

Recent studies have revealed that B-Raf mutations are very common in malignant melanoma and are required for tumor growth and maintenance. The majority of melanoma-associated B-Raf mutations involve a single point mutation, V600E, which results in greatly elevated B-Raf kinase activity and constitutive activation of MAPK/ERK downstream. Here we show that B-Raf(V600E) increases resistance to apoptosis induced by chemotherapeutic drugs and promotes ERK-dependent phosphorylation of the BH3-only proteins Bim and Bad that are involved in setting thresholds for apoptosis. ERK-dependent phosphorylation of Bim resulted in degradation of this BH3-only protein, whereas phosphorylation of Bad has previously been shown to result in its sequestration by 14-3-3 proteins. Consistent with this, inhibition of ERK activity in a panel of melanoma cell lines resulted in stabilization of Bim and dephosphorylation of Bad. Furthermore, apoptosis induced through overexpression of Bad or Bim was efficiently blocked by coexpression of mutant B-Raf(V600E). However, small interfering RNA-mediated silencing of Bim and Bad expression conferred only modest protection against cytotoxic drugs, whereas oncogenic B-Raf strongly protected against the same stimuli. These observations suggest that B-Raf-initiated inactivation of Bad and Bim only partly contributes to the anti-apoptotic activities of this oncogene and that other points within the cell death machinery are also targeted by deregulated ERK signaling.
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PMID:Oncogenic B-RafV600E inhibits apoptosis and promotes ERK-dependent inactivation of Bad and Bim. 1850 62

Chronic lymphocytic leukemia (CLL) is a B-cell lymphoid neoplasm with deregulated apoptosis and overexpression of several antiapoptotic BCL-2 proteins. GX15-070/Obatoclax is a small-molecule BH3 mimetic compound that has shown activity against several hematologic malignancies and solid tumors. In the present work, we report that GX15-070 led to the disruption of BCL-2/BIM and MCL-1/BAK complexes in CLL cells, followed by the activation of the mitochondrial apoptotic pathway. CLL cells showed lower sensitivity to GX15-070 than primary mantle cell lymphoma (MCL) ones, in correlation with higher levels of phosphorylated BCL-2 at serine 70 residue (pBCL-2(Ser70)) in CLL cells. Decrease in BCL-2 phosphorylation by extracellular signal-regulated kinase (ERK)1/2 inhibition increased CLL sensitivity to GX15-070, while blocking BCL-2 dephosphorylation using a PP2A antagonist reduced the activity of this BH3 mimetic. GX15-070 activity was increased by cotreatment with the proteasome inhibitor bortezomib. However, as proteasome inhibition led to the accumulation of phosphorylated BCL-2, the degree of interaction between GX15-070 and bortezomib was regulated by basal pBCL-2(Ser70) levels. These results support the role of BCL-2 phosphorylation as a mechanism of resistance to BH3 mimetic compounds, and demonstrate that combination approaches including ERK inhibitors could enhance BH3 mimetics activity both alone or in combination with proteasome inhibitors.
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PMID:BCL-2 phosphorylation modulates sensitivity to the BH3 mimetic GX15-070 (Obatoclax) and reduces its synergistic interaction with bortezomib in chronic lymphocytic leukemia cells. 1859 39

In the present study, the toxicity of arsenic trioxide and lead acetate was assessed in adult hepatic stem cells induced in the 2-acetyl-aminofluorene/partial hepatectomy rat model. Isolated oval cells were incubated separately for 6 h with 40 muM each of arsenic trioxide and lead acetate. 3-(4,5-Dimethylthiazole-2-yl)-2,5-diphenyltetrazolium bromide assay denoted significant time-dependent cell death in arsenic and lead treated oval cells. The degree of stress imposed by these metals was evidenced by induction of heat shock protein (HSP) 70 and HSP 90. Arsenic and lead were found to trigger apoptosis as revealed by DNA ladder formation, Western blots of apoptotic factors, and reverse transcriptase polymerase chain reaction analyses of bax and bcl-2. Results clearly indicate that both arsenic and lead induced apoptosis is caspase-mediated and accompanied by extracellular signal-regulated kinase (ERK) dephosphorylation. Full-length BH3-interacting-domain death agonist expression in presence of caspase 3 inhibitor unravels a direct involvement of caspase in As and Pb induced apoptosis. Expression patterns of apoptosis inducing factor, B cell lymphoma-2 (Bcl-2) antagonist of cell death, Bcl-2-associated X protein, and Bcl2 also signify mitochondrial regulation of apoptosis effected by lead and arsenic. It is concluded that stimulation of caspase cascade and simultaneous ERK dephosphorylation are the most significant operative pathways directly associated with apoptotic signals triggered by arsenic and lead in the oval cells.
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PMID:Arsenic trioxide and lead acetate induce apoptosis in adult rat hepatic stem cells. 1861 74


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