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)

Tamoxifen (TAM), an antiestrogen, also acts as an antilactogen in mammary cells. In the present study we analyze the effect of TAM on the signal transduction pathway for prolactin (Prl). TAM bound specifically to NOG-8, an estrogen receptor-negative mammary cell line. Within 5 min of Prl treatment, raf-1, MEK and MAP kinase were induced 2-3-fold over the control level. TAM completely inhibited this Prl-induced activation of kinases as well as Prl binding and cell growth. These results indicate the potential role of TAM as an antilactogen in Prl responsive systems.
Cancer Lett 1997 Jun 03
PMID:Tamoxifen inhibits prolactin signal transduction in ER - NOG-8 mammary epithelial cells. 917 56

Exposure of mammalian cells to solar ultraviolet (UV) radiation leads to the expression of several genes, and UV has been recognized as a major initiator and promoter of skin cancer. The component of the solar radiation that contributes most to human skin malignancy is UVB (280-320 nm) and, to a lesser extent, UVA (320-400 nm), whereas the high-energy UVC (100-280 nm) is absorbed by the earth's upper atmosphere. Sublethal doses of UVB produce strong induction of c-jun and c-fos transcripts in several cells including human primary keratinocytes. The present report confirms that this is also the case in the HaCaT cell line and shows that similar UVB doses are potent inducers of the JNK/SAPK family of mitogen-activated protein kinases but only weak activators of ERKs. Epidermal growth factor (EGF) caused rapid induction of both JNK- and ERK-signaling pathways, and the downmodulation of the EGF-signaling pathway by EGF pre-treatment inhibited the UVB-induced JNK1 activation. Prior UVB irradiation of the cells decreased the level of the ERK2 activation by a subsequent EGF treatment, but this sensitized the cells and allowed for the super-activation of JNK1 after a rechallenge with either UVB or EGF. The antioxidant N-acetylcysteine impaired the UVB- and EGF-induced activation of JNK1. Our data suggest the presence of shared signaling component(s) in the UVB- and EGF-induced cellular response pathways and imply that oxidative stress plays a significant role in the activation of JNK1 by UVB and EGF.
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PMID:Differential stimulation of ERK and JNK activities by ultraviolet B irradiation and epidermal growth factor in human keratinocytes. 918 16

Cytoplasmic phospholipase A2 (PLA2) is known to be phosphorylated and activated by MAP kinase (Lin et al 1993, Cell 72: 269-278), an important downstream component of signal transduction, whereas paclitaxel has been shown to inhibit isoprenylation of ras proteins (Danesi et al 1995, Mol Pharmacol 47: 1106-1111). Given that quinacrine (Q), a PLA2 inhibitor, and paclitaxel (P) might act at different sites in the cell signalling pathway, our aim was to test whether they were synergistic in combination against prostate cancer cells. Cell viability of PC-3, PC-3M and DU145 cells in 96 - well plates was assessed 96 h after drugs were added concurrently. Using Chou analysis, we demonstrated synergy for the combination against all three cell lines. Further, synergy was present under both conservative (mutually non-exclusive) and non-conservative (mutually exclusive) models. Studies in the nude mouse xenograft model support the finding of synergy in vitro. In DU145-bearing mice, Q (50 mg kg(-1)) and P (0.5 mg kg(-1)) given daily for 12 consecutive days, either concurrently or sequentially, was more effective than either drug alone, at twice the dose intensity. In an enzyme-linked immunosorbent (ELISA) apoptosis assay, arachidonic acid was able to partially reverse Q- and P-induced apoptosis, suggesting PLA2 pathway involvement. Finally, the combination of lovastatin, another inhibitor of ras isoprenylation, and quinacrine had synergistic inhibitory effects on the growth of PC-3 cells in vitro, suggesting that the combination of these two classes of compounds might serve as an attractive therapeutic approach for prostate cancer.
Br J Cancer 1997
PMID:Enhancement of paclitaxel activity against hormone-refractory prostate cancer cells in vitro and in vivo by quinacrine. 918 73

SSeCKS (pronounced essex) encodes a major protein kinase C substrate, the expression of which is down-regulated in src- and ras-transformed rodent fibroblasts but not in raf-transformed rodent fibroblasts (X. Lin et al., Mol. Cell. Biol., 15: 2754-2762, 1995). Using a panel of ras-transformed or revertant Rat-6 cells that exhibit selective parameters of transformation, we show that down-regulation of SSeCKS correlates with anchorage-independent growth. Cotransfection of NIH3T3 fibroblasts with an SSeCKS expression plasmid decreased 6-30-fold the ability of a v-src expressor plasmid to induce colonies in soft agar. To differentiate between possible tumor suppressive or growth-inhibitory effects of SSeCKS, we developed conditionally transformed cell lines (expressing ts72v-src) with tetracycline-regulated SSeCKS expression. SSeCKS suppressed the ability of v-src to induce increased cellular refractility, focus formation, soft agar colony formation, in vitro invasiveness in Matrigel, and growth in low serum (0.5%) but did not inhibit cell proliferation in high serum (10%) at the permissive (35 degrees C) temperature for src kinase activity. However, at the nonpermissive (39.5 degrees C) temperature, SSeCKS induced growth arrest. SSeCKS expression did not affect: (a) the protein level, in vivo or in vitro kinase activity of ts72src; (b) the activity of jun NH2-terminal kinase; and (c) the level of mitogen-activated protein kinase (extracellular signal-regulated kinase 2) protein. However, extracellular signal-regulated kinase 2 activity was induced 5-10-fold by SSeCKS in the presence of active src. SSeCKS reversed the ability of v-src to decrease the formation of vinculin-associated adhesion plaques, actin-based stress fibers, and filopodia structures. These data suggest a tumor suppressive role for SSeCKS via the control of cytoskeletal architecture and cell signaling.
Cancer Res 1997 Jun 01
PMID:Reexpression of the major protein kinase C substrate, SSeCKS, suppresses v-src-induced morphological transformation and tumorigenesis. 918 36

PD 089828, a novel protein tyrosine kinase inhibitor of a new structural class, the 6-aryl-pyrido-[2,3-d]pyrimidines, was identified by screening a compound library with assays that measured protein tyrosine kinase activity. PD 089828 was found to inhibit human full-length fibroblast growth factor (FGF) receptor-1 (FGFR-1), platelet-derived growth factor (PDGF) receptor beta subunit (PDGFR-beta), Src nonreceptor tyrosine kinase (c-Src) and epidermal growth factor (EGF) receptor (EGFR) tyrosine kinases with half-maximal inhibitory potencies (IC50 values) of 0.15 +/- 0.02 (n = 4), 0.18 +/- 0.04 (n = 3), 1.76 +/- 0.28 (n = 4) and 5.47 +/- 0.78 (n = 6) microM, respectively. PD 089828 was further characterized as an ATP competitive inhibitor of the growth factor receptor tyrosine kinases (FGFR-1, PDGFR-beta and EGFR) but a noncompetitive inhibitor of c-Src tyrosine kinase with respect to ATP. In addition, PD 089828 inhibited PDGF- and EGF-stimulated receptor autophosphorylation in vascular SMC (VSMC) and basic FGF-mediated tyrosine phosphorylation in A121 cells with IC50 values similar to the potencies observed for inhibition of receptor tyrosine kinase activity. The inhibition of PDGF receptor autophosphorylation in VSMC by PD 089828 occurred rapidly, with maximal effects reached within 5 min of drug exposure. Inhibition after single exposure was long lasting but also rapidly reversible, occurring within 5 min after drug removal. The PDGF-induced association of downstream signaling proteins, including phosphoinositide-3-kinase (PI-3K), growth factor receptor binding protein-2 (GRB2), SH-2 domain and collagen like (Shc) and phospholipase Cgamma (PLCgamma), with VSMC PDGF receptors was also blocked as a result of the inhibition of PDGF-stimulated receptor autophosphorylation by PD 089828. PD 089828 also inhibited the PDGF-induced tyrosine phosphorylation of the 44- and 42-kDa mitogen-activated protein kinase isoforms. Moreover, the effects of PD 089828 were demonstrated in functional assays in which PDGF-stimulated DNA synthesis, PDGF-directed migration and serum-stimulated growth of VSMC were all inhibited to the same extent as PDGF receptor autophosphorylation (IC50 = 0.8, 4.5 and 1.8 microM, respectively). These results highlight the biological characteristics of PD 089828 as a novel, broadly active protein tyrosine kinase inhibitor with long-lasting but reversible cellular effects. The potential therapeutic use of these broadly acting, nonselective inhibitors as antiproliferative and antimigratory agents could extend to such diseases as cancer, atherosclerosis and restenosis in which redundancies in growth-signaling pathways are known to exist.
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PMID:Inhibition of growth factor-mediated tyrosine phosphorylation in vascular smooth muscle by PD 089828, a new synthetic protein tyrosine kinase inhibitor. 919 Aug 82

Cyclooxygenase-2 (Cox-2), the inducible form of cyclooxygenase, is up-regulated in tumors and transformed cells. Because this enzyme catalyzes the formation of prostaglandins from arachidonic acid, chemopreventive strategies that suppress its expression could be useful for preventing cancer. We investigated whether retinoids suppressed basal expression of Cox-2 or EGF-mediated induction of Cox-2 in human oral squamous carcinoma cells. Treatment with retinoids [all-trans-retinoic acid (all-trans-RA), 9-cis-RA, 13-cis-RA, and retinyl acetate] suppressed both basal levels of Cox-2 and EGF-mediated induction of Cox-2 protein and synthesis of prostaglandin E2. Retinoids also suppressed the induction of Cox-2 mRNA by EGF. Transient transfection experiments showed that EGF caused about a 100% increase in Cox-2 promoter activity, an effect that was suppressed by retinoids. Levels of epidermal growth factor receptor were unaffected by retinoids. Epidermal growth factor caused a nearly 10-fold increase in mitogen-activated protein kinase activity; this effect was not blocked by retinoids.
Cancer Res 1997 Jul 15
PMID:Retinoids suppress epidermal growth factor-induced transcription of cyclooxygenase-2 in human oral squamous carcinoma cells. 923 Jan 97

We demonstrate herein the ability of transforming growth factor-beta-2 (TGFbeta2) to potently activate extracellular signal-regulated kinase 2 (ERK2) in the highly TGFbeta-sensitive breast cancer cell (BCC) line Hs578T. The ERK2 isoform was activated by 3-fold within 5 min of TGFbeta2 addition to Hs578T cells. However, TGFbeta2 only slightly activated ERK2 (1.5-fold) in the partially TGFbeta-responsive BCC line MDA-MB-23 1. The magnitude of the difference in activation of ERK2 by TGFbeta2 in the two cell lines paralleled the difference in the IC50 values for TGFbeta inhibition of DNA synthesis; the IC50 value in the MDA-MB-231 cells was 32-fold greater than that in the Hs578T cells. Further, our data demonstrate that TGFbeta2 activated the stress-activated protein kinase/Jun N-terminal kinase (SAPK/JNK) type of mitogen-activated protein kinases (MAPKs); maximal induction levels were 2.5-fold above basal values and were attained at 30 min after TGFbeta2 treatment. Transient co-transfection of a luciferase reporter construct (3TP-Lux) containing three AP-1 sites and the plasminogen activator inhibitor-1 (PAI-1) promoter, in conjunction with a construct that directs expression of a dominant-negative mutant ERK2 (TAYF) protein, did not block the ability of TGFbeta to induce AP-1 or PAI-1 activity. In contrast, TAYF ERK2 was able to block EGF and insulin-induced 3TP-Lux-reporter activity. These results indicate that in these BCCs, the activation of ERK2 by TGFbeta is more tightly linked to the ability of TGFbeta to inhibit DNA synthesis than to the ability to stimulate promoter regions important for TGFbeta production and control of the extracellular matrix. In addition, this is the first demonstration that TGFbeta can activate the SAPK/JNK type of MAPK in TGFbeta-sensitive human BCCs.
Cancer Lett 1997 Jul 15
PMID:TGFbeta regulation of mitogen-activated protein kinases in human breast cancer cells. 923 30

In a previous study, we demonstrated that bufalin, which is an active principle of Chinese medicine, chan'su, caused apoptosis in human leukemia U937 cells by anomalous activation of mitogen-activated protein kinase (MAPK) via the signaling pathway of Ras, Raf-1, and MAPK kinase-1. Here, we report the effect of overexpression of bcl-2 in U937 cells on the signaling pathway of apoptosis that is induced by bufalin. The results indicated that the apoptosis induced by bufalin in U937 cells was significantly inhibited by overexpression of the Bcl-2 protein. No significant difference was detected in the activation of MAPK kinase-1 that is induced by bufalin in wild-type or Bcl-2-overexpressed U937 cells; however, the activation of MAPK by bufalin was significantly attenuated in the cells overexpressing Bcl-2. Bufalin treatment activated activator protein-1 transcriptional activity; however, this activation was decreased to 40% in bcl-2-overexpressed U937 cells. These results indicate that Bcl-2 acts downstream of MAPK kinase-1 but upstream of MAPK and suggest that, in the signaling pathway of the apoptotic process induced by bufalin, the transcriptional activity of activator protein-1 may be down-regulated through the inhibition of MAPK activity by Bcl-2.
Cancer Res 1997 Aug 01
PMID:Bcl-2 protein inhibits bufalin-induced apoptosis through inhibition of mitogen-activated protein kinase activation in human leukemia U937 cells. 924 31

Thapsigargin is a non-phorbol ester-type tumor promoter that elevates the intracellular Ca2+ (Ca(i)2+) levels by blocking the microsomal Ca2+ ATPase. At present, the consequence of this Ca(i)2+ increase and the nature of the tumorigenicity of thapsigargin still remain to be elucidated. Previously, we demonstrated that thapsigargin activates the mitogen-activated protein (MAP) kinase via Ca(i)2+ but independently of protein kinase C or Ca2+ influx. Here, we show that thapsigargin also rapidly stimulates the Src tyrosine kinase. Transfection of a v-Src gene into a hippocampal cell line (H19-7) renders a constitutive activation of MAP kinase, whereas transfection of a kinase-deficient Src mutant blocks the activation by thapsigargin, suggesting that Src is required for the thapsigargin-induced MAP kinase activation. Cotransfection of a dominant-inhibitory Raf-1 and the v-Src genes into H19-7 cells results in an inhibition of the otherwise constitutively elevated MAP kinase activity, suggesting that Raf-1 is required for the Src-dependent activation of MAP kinase. Similarly, in the LA-90 cells, expression of a temperature-sensitive allele of v-Src constitutively activates Raf-1 and MAP kinase, whereas expression of a dominant-inhibitory Raf-1 mutant abolishes the MAP kinase activation induced by either v-Src or thapsigargin treatment. Together, these results suggest that thapsigargin stimulates MAP kinase signaling via Src and Raf-1. The activation of this Src-MAP kinase pathway suggests a biochemical mechanism for the tumorigenic nature of thapsigargin.
Cancer Res 1997 Aug 01
PMID:Src tyrosine kinase mediates stimulation of Raf-1 and mitogen-activated protein kinase by the tumor promoter thapsigargin. 924 45

The c-Abl nonreceptor tyrosine kinase and the c-Jun NH2-terminal kinase (JNK/stress-activated protein kinase) are activated during the injury response to the DNA-damaging agent cisplatin. Loss of DNA mismatch repair activity results in resistance to cisplatin in human cancer cells, suggesting that the mismatch repair proteins function as a detector for cisplatin DNA adducts. To identify signaling pathways activated by this detector, we investigated the effect of the loss of DNA mismatch repair function on the ability of cisplatin to activate the JNK and c-Abl kinases. The results demonstrate that cisplatin activates JNK kinase 3.8 +/- 0.2-fold more efficiently in DNA mismatch repair-proficient than repair-deficient cells, and that activation of c-Abl is completely absent in the DNA mismatch repair-deficient cells. Furthermore, the results show that cisplatin-induced activation of JNK occurs through a stress-activated protein kinase/extracellular signal-regulated kinase kinase 1-independent mechanism. We conclude that activation of JNK and c-Abl by cisplatin is in part dependent upon the integrity of DNA mismatch repair function, suggesting that these kinases are part of the signal transduction pathway activated when mismatch repair proteins recognize cisplatin adducts in DNA.
Cancer Res 1997 Aug 01
PMID:Differential induction of c-Jun NH2-terminal kinase and c-Abl kinase in DNA mismatch repair-proficient and -deficient cells exposed to cisplatin. 924 57


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