Gene/Protein Disease Symptom Drug Enzyme Compound
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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 chondrogenesis, members of the transforming growth factor-beta (TGF-beta) superfamily play critical roles by inducing gene expression of cartilage-specific molecules. By using a chondrogenic cell line, ATDC5, we investigated the TGF-beta-mediated signaling pathways involved in expression of the aggrecan gene (Agc). At confluency, TGF-beta induced Agc expression within 3 h, and cycloheximide blocked this induction, indicating that de novo protein synthesis is essential for this response. At this stage, TGF-beta induced rapid, transient phosphorylation of Smad2, extracellular signal-activated kinase 1/2 (ERK1/2), and p38 mitogen-activated protein kinase (MAPK). Inhibition of the Smad pathways by transfection with a dominant negative Smad4 construct significantly reduced TGF-beta-induced Agc expression, indicating that Smad signaling is essential for this response. Furthermore, an inhibitor of the ERK1/2 pathway, U0126, or inhibitors of the p38 MAPK pathway, SB203580 and SKF86002, repressed TGF-beta-induced Agc expression in a dose-dependent manner, indicating that ERK1/2 or p38 MAPK activation is also required for TGF-beta-induced Agc expression in confluent ATDC5 cells. In differentiated ATDC5 cells, persistently high basal levels of ERK1/2 and p38 MAPK phosphorylation correlated with elevated basal Agc expression, which was inhibited by incubation with inhibitors of these pathways. Whereas Smad2 was rapidly phosphorylated by TGF-beta and involved in the initial activation of Agc expression in confluent cells, Smad2 activation was not required for maintaining the high level of Agc expression. Taken together, these results suggest an important role for transcriptional cross-talk between Smad and MAPK pathways in expression of early chondrocytic phenotypes and identify important changes in the regulation of Agc expression following chondrocyte differentiation.
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PMID:Transcriptional cross-talk between Smad, ERK1/2, and p38 mitogen-activated protein kinase pathways regulates transforming growth factor-beta-induced aggrecan gene expression in chondrogenic ATDC5 cells. 1127 90

Lefty polypeptides, novel members of the transforming growth factor-beta (TGF-beta) superfamily, are involved in the formation of embryonic lateral patterning. Members of the TGF-beta superfamily require processing for their activation, suggesting cleavage to be an essential step for lefty activation. Transfection of different cell lines with lefty resulted in expression of a 42-kDa protein, which was proteolytically processed to release two polypeptides of 34 and 28 kDa. Since members of the proprotein convertase (PC) family cleave different TGF-beta factors and are involved in the establishment of embryonic laterality, we studied their role in lefty processing. Cotransfection analysis showed that PC5A processed the lefty precursor to the 34-kDa form in vivo, whereas furin, PACE4, PC5B, and PC7 had a limited activity. None of these PCs showed activity in the processing of the lefty polypeptide to the 28-kDa lefty form. The mutation of the consensus sequences for PC cleavage in the lefty protein allowed the lefty cleavage sites to be identified. Mutations of the sequence RGKR to GGKG (amino acids 74-77) and of RHGR to GHGR (amino acids 132-135) prevented the proteolytic processing of the lefty precursor to the 34- and 28-kDa forms, respectively. To identify the biologically active form of lefty, we studied the effect of lefty treatment on pluripotent P19 cells. Lefty did not induce Smad2 or Smad5 phosphorylation, Smad2/Smad4 heterodimerization, or nuclear translocation of Smad2 or Smad4, but activated the MAPK pathway in a time- and dose-dependent fashion. Further analysis showed the 28-kDa (but not the 34-kDa) polypeptide to induce MAPK activity. Surprisingly, the 42-kDa lefty protein was also capable of inducing MAPK activity, indicating that the lefty precursor is biologically active. The data support a molecular model of processing as a mechanism for regulation of lefty signaling.
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PMID:Lefty proteins exhibit unique processing and activate the MAPK pathway. 1127 22

We previously demonstrated that exposure of CCL39 lung fibroblast cells to alpha-thrombin inhibits interleukin-6 (IL-6)-induced tyrosine phosphorylation of Stat3 (signal transducers and activators of transcription-3) protein via a mitogen-activated protein (MAP)-kinase dependent mechanism. In the present study, we investigated the mechanism of regulation of IL-6-induced signaling by transforming growth factor-beta (TGF-beta) and compared this to alpha-thrombin-mediated inhibition. We demonstrate that exposure of CCL39 cells to TGF-beta completely inhibits IL-6-induced Stat3 tyrosine phosphorylation and gp130 gene expression. However, in contrast to alpha-thrombin, TGF-beta-mediated inhibition did not require activation of the MAP kinase pathway. Also, unlike alpha-thrombin, TGF-beta-mediated inhibition requires synthesis of new proteins. Interestingly, TGF-beta and alpha-thrombin both inhibit IL-6-induced expression of gp130 mRNA levels. These results demonstrate that although the end effects are the same, alpha-thrombin and TGF-beta utilize distinct mechanisms to inhibit IL-6-induced Stat3 signaling.
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PMID:Distinct mechanisms of inhibition of interleukin-6-induced Stat3 signaling by TGF-beta and alpha-thrombin in CCL39 cells. 1128 29

We have previously shown that p38 mitogen-activated protein kinase (MAPK) inhibitors, which block the production and action of inflammatory cytokines such as tumor necrosis factor (TNF) and interleukin-1 (IL-1), are effective in models of bone and cartilage degradation. To further investigate the role of p38 MAPK, we have studied its activation in osteoblasts and chondrocytes, following treatment with a panel of proinflammatory and osteotropic agents. In osteoblasts, significant activation of p38 MAPK was observed following treatment with IL-1 and TNF, but not parathyroid hormone, transforming growth factor-beta (TGF-beta), 1,25(OH)(2)D(3), insulin-like growth factor-1 (IGF-1), or IGF-II. Similar results were obtained using primary bovine chondrocytes and an SV40-immortalized human chondrocyte cell line, T/C28A4. SB 203580, a selective inhibitor of p38 MAPK, inhibited IL-1 and TNF-induced p38 MAPK activity and IL-6 production (IC(50)s 0.3--0.5 microM) in osteoblasts and chondrocytes. In addition, IL-1 and TNF also activated p38 MAPK in fetal rat long bones and p38 MAPK inhibitors inhibited IL-1- and TNF-stimulated bone resorption in vitro in a dose-dependent manner (IC(50)s 0.3--1 microM). These data support the contention that p38 MAPK plays a central role in regulating the production of, and responsiveness to, proinflammatory cytokines in bone and cartilage. Furthermore, the strong correlation between inhibition of kinase activity and IL-1 and TNF-stimulated biological responses indicates that selective inhibition of the p38 MAPK pathway may have therapeutic utility in joint diseases such as rheumatoid arthritis (RA).
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PMID:IL-1- and TNF-induced bone resorption is mediated by p38 mitogen activated protein kinase. 1131 53

Bone morphogenetic protein (BMP)-2, a member of the transforming growth factor-beta (TGF-beta) superfamily, is able to induce osteoblastic differentiation of C2C12 cells. Both Smad and mitogen-activated protein kinase (MAPK) pathways are essential components of the TGF-beta superfamily signaling machinery. Although Smads have been demonstrated to participate in the BMP-2-induced osteoblastic differentiation of C2C12 cells, the role of MAPK has not been addressed. This report shows that BMP-2 activates ERK and p38, but not JNK, in C2C12 cells. Pretreatment of cells with the p38 inhibitor, SB203580, dramatically reduced BMP-2-induced expression of the osteoblast markers alkaline phosphatase (ALP) and osteocalcin (OC). Nevertheless, overexpression of MKK3, a protein kinase that phosphorylates and activates p38, failed to induce ALP or OC expression in the absence of BMP-2, indicating that p38 activation is necessary but not sufficient for the acquisition of the osteoblast phenotype by these cells. Although ALP induction was increased slightly in the presence of PD-98059, a selective inhibitor of the ERK cascade, this compound significantly inhibited both steady-state and BMP-2-induced OC RNA levels. Our results indicate that p38 and ERK cascades play a crucial role in the osteoblast differentiation of C2C12 cells mediated by BMP-2.
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PMID:Activation of mitogen-activated protein kinase cascades is involved in regulation of bone morphogenetic protein-2-induced osteoblast differentiation in pluripotent C2C12 cells. 1134 48

X-linked inhibitor of apoptosis protein (XIAP) is a potent suppressor of apoptotic cell death, which functions by directly inhibiting caspases, the principal effectors of apoptosis. Here we report that XIAP can also function as a cofactor in the regulation of gene expression by transforming growth factor-beta (TGF-beta). XIAP, but not the related proteins c-IAP1 or c-IAP2, associated with several members of the type I class of the TGF-beta receptor superfamily and potentiated TGF-beta-induced signaling. Although XIAP-mediated activation of c-Jun N-terminal kinase and nuclear factor kappa B was found to require the TGF-beta signaling intermediate Smad4, the ability of XIAP to suppress apoptosis was found to be Smad4-independent. These data implicate a role for XIAP in TGF-beta-mediated signaling that is distinct from its anti-apoptotic functions.
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PMID:X-linked inhibitor of apoptosis protein functions as a cofactor in transforming growth factor-beta signaling. 1135 28

The loss of growth-inhibitory responses to transforming growth factor-beta (TGF-beta) is a frequent consequence of malignant transformation. Smad2, Smad3, and Smad4 proteins are important mediators of the antiproliferative responses to TGF-beta and may become inactivated in some human cancers. Epithelial cells harboring oncogenic Ras mutations often exhibit a loss of TGF-beta antiproliferative responses. To further investigate the effect of oncogenic Ras in TGF-beta signaling, we used an isopropyl-1-thio-beta-d-galactopyranoside-inducible expression system to express Ha-Ras(Val-12) in intestinal epithelial cells. Induction of Ha-Ras(Val-12) caused a decrease in the level of Smad4 expression, inhibited TGF-beta-induced complex formation between Smad2/Smad3 and Smad4, blocked Smad4 nuclear translocation, inhibited the TGF-beta-mediated decrease in [(3)H]thymidine incorporation, and repressed TGF-beta-activated transcriptional responses. The withdrawal of isopropyl-1-thio-beta-d-galactopyranoside or the addition of an inhibitor of the ubiquitin-proteasome pathway restored the Smad4 level and TGF-beta-induced Smad complex formation. Forced expression of Smad4 resulted in partial recovery of the TGF-beta-mediated growth inhibition and transcriptional responses in the presence of oncogenic Ras. Further, PD98059, a specific inhibitor of the MEK/ERK/mitogen-activated protein kinase pathway prevented the Ras-induced decrease in Smad4 expression and complex formation. Our results suggest a novel mechanism by which oncogenic Ras represses TGF-beta signaling by mitogen-activated protein kinase-dependent down-regulation of Smad4, thereby subverting the tumor suppressor function of TGF-beta.
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PMID:Oncogenic ras represses transforming growth factor-beta /Smad signaling by degrading tumor suppressor Smad4. 1137 52

Bone morphogenetic protein-2 (BMP-2), a member of the transforming growth factor-beta (TGF-beta) family, regulates osteoblast differentiation and bone formation. Here we show a novel function of BMP-2 in human osteoblasts and identify a signaling pathway involved in this function. BMP-2 promotes apoptosis in primary human calvaria osteoblasts and in immortalized human neonatal calvaria osteoblasts, as shown by terminal deoxynucleotidyl transferase-mediated nick end labeling analysis. In contrast, TGF-beta 2 inhibits apoptosis in human osteoblasts. Studies of the mechanisms of action showed that BMP-2 increases the Bax/Bcl-2 ratio, whereas TG beta-2 has a negative effect. Moreover, BMP-2 increases the release of mitochondrial cytochrome c to the cytosol. Consistent with these results, BMP-2 increases caspase-9 and caspase-3, -6, and -7 activity, and an anti-caspase-9 agent suppresses BMP-2-induced apoptosis. Overexpression of dominant-negative Smad1 effectively blocks BMP-2-induced expression of the osteoblast transcription factor Runx2 but not the activation of caspases or apoptosis induced by BMP-2, indicating that the Smad1 signaling pathway is not involved in the BMP-2-induced apoptosis. The proapoptotic effect of BMP-2 is PKC-dependent, because BMP-2 increases PKC activity, and the selective PKC inhibitor calphostin C blocks the BMP-2-induced increased Bax/Bcl-2, caspase activity, and apoptosis. In contrast, the cAMP-dependent protein kinase A inhibitor H89, the p38 MAPK inhibitor SB203580, and the MEK inhibitor PD-98059 have no effect. The results show that BMP-2 uses a Smad-independent, PKC-dependent pathway to promote apoptosis via a Bax/Bcl-2 and cytochrome c-caspase-9-caspase-3, -6, -7 cascade in human osteoblasts.
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PMID:Bone morphogenetic protein-2 promotes osteoblast apoptosis through a Smad-independent, protein kinase C-dependent signaling pathway. 1139 80

Activation of c-Jun NH2-terminal kinase (JNK), a member of the mitogen-activated protein kinase (MAPK) family, is involved in apoptosis or cell proliferation. We have previously demonstrated that ionizing radiation or thyroid-stimulating hormone activated JNK without linking to thyroid cell apoptosis. To clarify the involvement of JNK activation in thyroid cell survival, we investigated the effects of various growth factors on induction of JNK activation in cultured human thyroid cells. JNK activation was observed at 30 minutes after fetal bovine serum (FBS) stimulation and returned to basal level at 240 minutes. Epidermal growth factor (EGF), transforming growth factor-beta (TGF-beta) and hepatocyte growth factor (HGF) also induced JNK activation, but did not trigger apoptotic cell death. Furthermore, we observed high basal activation of JNK in four of five human thyroid cancer cell lines. Overexpression of c-Met, an HGF receptor, was observed in two of the four cell lines with high basal JNK activity. Our results suggest that JNK activation does not induce apoptosis but is associated with survival or transformation of human thyroid cells.
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PMID:Transient activation of c-Jun NH2-terminal kinase by growth factors influences survival but not apoptosis of human thyrocytes. 1148 91

RRR-alpha-tocopherol succinate (vitamin E succinate, VES) is a potent, selective apoptotic agent for cancer cells but not normal cells. VES has been shown to inhibit the growth of a wide variety of tumor cells in cell culture and animal models. Studies addressing mechanisms of action of VES-induced apoptosis have identified transforming growth factor-beta, Fas/CD95-APO-1, and mitogen-activated protein kinase (MAPK) signaling pathway involvement. Here we show that MAPKs, the extracellular signal-regulated kinases (ERK), and the stress-activated protein kinases, c-Jun NH2-terminal kinases (JNK), but not p38, are critical mediators in VES-induced apoptosis of human breast cancer MDA-MB-435 cells. VES activates ERK1/2 and JNK both in level and duration of kinase activity. Expression of dominant negative mutants of ERK1, MAPK/ERK activator-1, or JNK1 but not p38 blocked phosphorylation of the substrate glutathione S-transferase-c-Jun and inhibited VES-induced apoptosis. Increased phosphorylation and transactivation activity of nuclear transcription factors c-Jun, ATF-2, and Elk-1 are observed after VES treatments; however, only c-Jun and ATF-2 appear to be involved in VES-induced apoptosis based on antisense blockage experiments. Collectively, these results imply a critical role for ERK1 and JNK1 but not p38 in VES-induced apoptosis of human MDA-MB-435 breast cancer cells.
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PMID:Activation of extracellular signal-regulated kinase and c-Jun-NH(2)-terminal kinase but not p38 mitogen-activated protein kinases is required for RRR-alpha-tocopheryl succinate-induced apoptosis of human breast cancer cells. 1152 56


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