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)

In this study, we describe a novel activating transcription factor 3 (ATF3)-dependent death pathway triggered by ultraviolet (UV) irradiation. We demonstrate that ATF3 contributes to UV-induced apoptosis through the regulation of hypoxia inducible factor (Hif)-2alpha expression, which in turn induces the expression of proapoptotic genes, such as Caspase7 or TRAIL (tumor necrosis factor (ligand) superfamily, member 10). Gain of function of Hif-2alpha as well as ATF3 is sufficient to trigger cell death, whereas loss of function of both proteins drastically inhibits UV-induced apoptosis. Repression of Hif-2alpha strongly impairs ATF3-mediated death, providing evidences that Hif-2alpha is the major death effector of ATF3. In addition, Hif-1alpha, already known as a proapoptotic gene, upon UV irradiation, is not able to compensate for the lack of Hif-2alpha expression, thereby confirming the major contribution of Hif-2alpha in UV-mediated cell death. We further demonstrate that this cascade of gene activation depends on p38 and c-Jun N-terminal kinase (JNK) activity. Impairment of such a pathway is likely to contribute to oncogenesis by promoting survival of cells that could accumulate severe chromosomal alterations.
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PMID:Hif-2alpha mediates UV-induced apoptosis through a novel ATF3-dependent death pathway. 1851 33

Natural killer (NK) cells are crucial components of the innate immune system, providing the first line of defense against infectious pathogens and tumors. Interleukin (IL)-12 is an interleukin produced primarily by antigen-presenting cells that play an essential role in the interaction between the innate and adaptive arms of immunity acting upon T and NK cells to generate cytotoxic lymphocytes. In the present study, we explored the effect of IL-12 upregulation on the NK receptor NKG2D and on the promotion of NK cell function. IL-12 enhanced the cytotoxicity of NK cells to different solid and hematological tumor cell lines and promoted interferon-gamma secretion by NK cells. The IL-12-induced cytolytic effect was dependent on the interaction of NKG2D with its ligand, MICA, because blockade of either protein attenuated the effect of IL-12 on NK cytolysis. Reverse transcriptase-polymerase chain reaction and fluorescence-activated cell sorting analyses indicated that IL-12 treatment increased NKG2D transcripts and surface expression in NK cells. Also, IL-12 augmented the expression of cytotoxic effector molecules, TRAIL and perforin, and the phosphorylation of STAT1, STAT4, and ERK1/2, which may also contribute to lysis by NK cells. These results are encouraging for the potential use of IL-12 as part of immunotherapy.
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PMID:Interleukin-12 improves cytotoxicity of natural killer cells via upregulated expression of NKG2D. 1861 7

Activation of PKCdelta in androgen-dependent LNCaP prostate cancer cells leads to apoptosis via the activation of p38 MAPK and JNK cascades. We have recently shown that treatment of LNCaP cells with phorbol 12-myristate 13-acetate (PMA) leads to a PKCdelta-mediated autocrine release of death factors, including the cytokines TNFalpha and TRAIL, and that conditioned medium (CM) collected from PMA-treated LNCaP cells promotes the activation of the extrinsic apoptotic cascade. Interfering with this autocrine loop either at the level of factor release or death receptor activation/signaling markedly impaired the PMA apoptotic response. In the present study we show that this PKCdelta-dependent autocrine mechanism is greatly influenced by androgens. Indeed, upon androgen depletion, which down-regulates PKCdelta expression, TNFalpha and TRAIL mRNA induction and release by PMA are significantly diminished, resulting in a reduced apoptogenic activity of the CM and an impaired ability of the CM to activate p38 MAPK and JNK. These effects can be rescued by addition of the synthetic androgen R1881. Furthermore, RNAi depletion of the androgen-receptor (AR) from LNCaP cells equally impaired PMA responses, suggesting that PKC-mediated induction of death factor secretion and apoptosis in LNCaP prostate cancer cells are highly sensitive to hormonal control.
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PMID:PKC-mediated secretion of death factors in LNCaP prostate cancer cells is regulated by androgens. 1875 41

Adult multipotent stromal cells (MSCs), also known as mesenchymal stem cells, represent an important source of cells for the repair of a number of damaged tissues. Both bone marrow (BM)-derived and amniotic MSCs expressed detectable surface levels of two (tumor necrosis factor-related apoptosis-inducing ligand receptor 2 [TRAIL-R2] and TRAIL-R4) of four transmembrane TRAIL receptors. Although the best-characterized activity of TRAIL-R2 is the transduction of apoptotic signals, neither recombinant TRAIL (rTRAIL) nor infection with an adenovirus-expressing TRAIL induced cytotoxic effects on MSCs. Moreover, whereas rTRAIL did not affect proliferation or differentiation of MSCs along the osteogenic and adipogenic lineages, it significantly promoted the migration of human MSCs in range of concentrations comparable to that of soluble TRAIL in human plasma (100 pg/ml). Since rTRAIL induced the rapid phosphorylation of extracellular signal-regulated kinase 1/2 (ERK1/2) in MSC cultures and pretreatment with pharmacological inhibitors of the ERK1/2 pathway efficiently counteracted the rTRAIL-induced human MSC migration, these data indicate that ERK1/2 is involved in mediating the ability of rTRAIL to stimulate MSC migration. Taking into consideration that the soluble factors able to induce MSC migration have not been extensively characterized, our current data indicate that the TRAIL/TRAIL-R system might play an important role in the biology of MSCs. Disclosure of potential conflicts of interest is found at the end of this article.
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PMID:Tumor necrosis factor-related apoptosis-inducing ligand promotes migration of human bone marrow multipotent stromal cells. 1877 12

The flexible heteroarotinoid, SHetA2, is a novel compound with apoptosis-inducing and anticancer activities in vitro and in vivo. Our previous research showed that up-regulation of death receptor 5 plays a critical role in the mechanism of SHetA2-induced apoptosis in human lung cancer cells. The hypothesis of this study was that the mechanism of SHetA2-induced apoptosis requires modulation of additional proteins critical for regulation of apoptosis, including cellular FLICE-inhibitory protein (c-FLIP), survivin, X-linked inhibitor of apoptosis, Bcl-2, Bcl-X(L), Bax, and Bim. Western blot analysis showed that c-FLIP and survivin were substantially reduced in all of the tested cell lines exposed to SHetA2 compared with other proteins that were reduced only in a subset of the cell lines tested. Strikingly, overexpression of c-FLIP, but not survivin, protected cells from SHetA2-induced apoptosis and enhancement of TRAIL-initiated apoptosis, although knockdown of endogenous survivin did slightly sensitize cells to SHetA2-induced apoptosis. Consistent with these results, small interfering RNA-mediated reduction of c-FLIP was more effective than survivin down-regulation in triggering apoptosis in these cell lines. SHetA2 increased ubiquitination of c-FLIP and the consequent degradation was abrogated by the proteasome inhibitor MG132. Although SHetA2 treatment led to increased c-Jun phosphorylation, the JNK inhibitor SP600125 did not prevent c-FLIP down-regulation by SHetA2. Thus, it appears that SHetA2 down-regulates c-FLIP levels by facilitating its ubiquitin/proteasome-mediated degradation independent of JNK activation. Collectively, the present study indicates that, in addition to death receptor 5 up-regulation, c-FLIP down-regulation is another important component of flexible heteroarotinoid (SHetA2)-induced apoptosis as well as enhancement of TRAIL-induced apoptosis.
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PMID:Involvement of c-FLIP and survivin down-regulation in flexible heteroarotinoid-induced apoptosis and enhancement of TRAIL-initiated apoptosis in lung cancer cells. 1900 38

Resistance to apoptosis is one reason for the poor response of malignant brain tumors to therapy. The PPARgamma-modulating drug Troglitazone downregulates the anti-apoptotic FLIP protein and sensitizes glioblastoma cells to apoptosis induced by the death ligand TRAIL. To investigate the molecular basis of an experimental combination therapy for malignant gliomas with TRAIL and Troglitazone, we investigated the Troglitazone-induced signaling cascades and the expression of TRAIL receptors and FLIP in malignant gliomas. Troglitazone downregulated the FLIP protein through accelerated ubiquitin/proteasome-dependent degradation, which might be mediated by a Troglitazone-induced increase in reactive oxygen species. Moreover, Troglitazone induced the phosphorylation of the MAP kinase ERK1/2 as well as of the BAD protein. Inhibition of either PPARgamma or MEK1/2 blocked the Troglitazone-mediated phosphorylation of BAD and further increased the synergistic induction of glioma cell death by TRAIL and Troglitazone. Immunohistochemical analysis demonstrated that FLIP and TRAIL-R2 were significantly higher expressed in anaplastic (WHO grade III) than in diffuse (WHO grade II) gliomas. High FLIP and low TRAIL-R2 expression levels were associated with a poor prognosis of patients. Our findings warrant a further pre-clinical evaluation of an experimental anti-glioma therapy with TRAIL and Troglitazone, potentially in conjunction with a MAP kinase inhibitor.
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PMID:Troglitazone-mediated sensitization to TRAIL-induced apoptosis is regulated by proteasome-dependent degradation of FLIP and ERK1/2-dependent phosphorylation of BAD. 1915 81

Apoptosis or programmed cell-death is an important process involved in tissue homeostasis, development and a variety of immune responses.(1) The apoptotic program can be activated via transmembrane receptors stimulated by their cognate ligands. The presence of a well-conserved region of 80 amino acids in their intracellular tail, the Death-Domain (DD), has conferred those receptors the general name of "death receptors". Death receptors are a subfamily of the TNF receptor superfamily, which includes the TNF receptor-I (TNFR1), TRAMP, DR3/APO-3, TRAIL-receptor 1 (TRAIL-R1/DR4), TRAIL-receptor 2 (TRAIL-R1/DR5), DR6 and CD95 (Fas/Apo-1). The pro-apoptotic properties of the CD95 system have been extensively studied during the past decades. Nevertheless, CD95 has now emerged as an important activator of other major signaling pathways leading to a variety of phenotypes. In the last years, stimulation of CD95 has been described to activate the MAPK pathways p38, JNK and ERK. (2-6) CD95 has also been shown to activate the transcription factor NFkB. (67-9) However, the molecular mechanisms leading to activation of such pathways are not fully understood and their contribution to the final phenotype is still unclear. CD95 has been shown to be particularly involved in tumor cell invasion, (6) neurite sprouting and outgrowth,(5,10) as well as cell proliferation(11,12)--functions that lay to rest the general assumption of CD95 as a death receptor. In our group we have recently described a novel molecular link between CD95 and the phosphatydilinositol-3-kinase (PI3K) pathway in Glioblastoma multiforme. In the present review we will discuss the past and present knowledge of the CD95/CD95L system and its role in PI3K signaling.
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PMID:Tyrosine phosphorylation and CD95: a FAScinating switch. 1922 5

We recently reported that LY294002 (LY29) and LY303511 (LY30) sensitized tumor cells to drug-induced apoptosis independent of the phosphoinositide 3-kinase/Akt pathway. Here, we investigated the mechanism of LY30-induced sensitization of human neuroblastoma cells to TRAIL-mediated apoptosis. We provide evidence that LY30-induced increase in intracellular H(2)O(2) up-regulates the expression of TRAIL receptors (DR4 and DR5) in SHEP-1 cells by activating mitogen-activated protein kinases, resulting in a significant amplification of TRAIL-mediated caspase-8 processing and activity, cytosolic translocation of cytochrome c, and cell death. Involvement of the death receptors was further confirmed by the ability of blocking antibodies against DR4 and/or DR5 to inhibit LY30-induced TRAIL sensitization. Pharmacologic inhibition of c-Jun NH(2) terminal kinase (JNK) and extracellular signal-regulated kinase (ERK) activation by SP600125 and PD98059, respectively, blocked LY30-induced increase in sensitization to TRAIL-mediated death. Finally, small interfering RNA-mediated gene silencing of JNK and ERK inhibited LY30-induced increase in surface expression of DR4 and DR5, respectively. These data show that JNK and ERK are two crucial players involved in H(2)O(2)-mediated increase in TRAIL sensitization of tumor cells upon exposure to LY30 and underscore a novel mode of action of this inactive analogue of LY29. Our findings could have implications for the use of LY30 and similar compounds for enhancing the apoptotic sensitivity of neuroblastoma cells that often become refractory to chemotherapy.
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PMID:LY303511 enhances TRAIL sensitivity of SHEP-1 neuroblastoma cells via hydrogen peroxide-mediated mitogen-activated protein kinase activation and up-regulation of death receptors. 1922 50

Cancers in the gastrointestinal system account for a large proportion of malignancies and cancer-related deaths with gastric cancer and colorectal cancer being the most common ones. For those patients in whom surgical resection is not possible, other therapeutic approaches are necessary. Disordered apoptosis has been linked to cancer development and treatment resistance. Apoptosis occurs via extrinsic or intrinsic signaling each triggered and regulated by many different molecular pathways. In recent years, the selective induction of apoptosis in tumor cells has been increasingly recognized as a promising approach for cancer therapy. A detailed understanding of the molecular pathways involved in the regulation of apoptosis is essential for developing novel effective therapeutic approaches. Apoptosis can be induced by many different approaches including activating cell surface death receptors (for example, Fas, TRAIL and TNF receptors), inhibiting cell survival signaling (such as EGFR, MAPK and PI3K), altering apoptosis threshold by modulating pro-apoptotic and anti-apoptotic members of the Bcl-2 family, down-regulating anti-apoptosis proteins (such as XIAP, survivin and c-IAP2), and using other pro-apoptotic agents. In this review, the authors reviewed the currently reported apoptosis-targeting approaches in gastrointestinal cancers.
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PMID:Targeting apoptosis as an approach for gastrointestinal cancer therapy. 1927 96

We have previously reported that TRAIL is upregulated on T cells from patients with lupus and that T cell associated TRAIL enhances autoimmune parameters in a murine model of lupus. Whether TRAIL/TRAIL-R interaction plays a role in organ involvement such as lupus nephritis has not yet been assessed. We demonstrate here that TRAIL, DR4 and DR5 are upregulated in proximal and distal tubules of patients with proliferative lupus nephritis. In vitro, expression of TRAIL, DR4 and DR5 on primary proximal tubular epithelial cells (PTEC) was induced by TNFalpha and IFNgamma. Functionally, TRAIL did not induce apoptosis but rather enhanced the proliferation of PTEC through activation of PI3 kinase/AKT and ERK1/2, increased IL-8 production and upregulated ICAM-1 expression. These data demonstrate that cytokine induced upregulation of TRAIL, DR4 and DR5 in tubules from patients with proliferative lupus nephritis may play a protective role by enhancing PTEC survival while also exerting a proinflammatory effect that may contribute to local inflammation and injury.
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PMID:TRAIL, DR4 and DR5 are upregulated in kidneys from patients with lupus nephritis and exert proliferative and proinflammatory effects. 1934 11


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