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)

We have reported previously that reactivation of progesterone receptor (PR) expression in estrogen receptor (ER)- and PR-negative MDA-MB-231 breast cancer cells enabled progesterone to inhibit cell growth and invasiveness, and to induce remarkable focal adhesions. The present study addressed molecular mechanisms that mediate these anticancer effects of progesterone in the PR-transfected breast cancer cells ABC28. In response to progesterone treatment are the marked up-regulation of cyclin-dependent kinase inhibitor protein p21WAF1/CIP1 and decreased expression of cyclin A, cyclin B1, and cyclin D1 that are required for G1 progression and during cell mitosis. Progesterone also induced down-regulation of phosphorylated MAPK (p42/44 MAPK). Furthermore, this study also demonstrated that MEK inhibitor PD98059 that inhibits the phosphorylation of p42/44 MAPK also caused reduction of cyclin D1 level and inhibition of cell proliferation. These results suggest that inhibition of p42/44 MAPK pathway is part of the mechanisms mediating progesterone's growth-inhibitory effect. On the other hand, progesterone-induced focal adhesion is mediated by separate pathway. Whereas PD98059 exhibited no effects on cell adhesion, inhibitory antibody to beta1-integrin was able to reverse progesterone-induced focal adhesion and progesterone-induced increase in the phosphorylation of focal adhesion kinase. On the other hand, beta1-integrin antibody had no effect on progesterone-mediated growth inhibition and on progesterone-mediated expression of cyclins p21CIP1/WAF1 and phosphorylation of P42/P44 MAPK. In the context of complex functions of progesterone in breast cancer and reproductive organs, identification of distinct pathways offers new strategies for designing therapeutic agents to target the specific pathway so as to minimize the side effects.
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PMID:Distinct molecular pathways mediate progesterone-induced growth inhibition and focal adhesion. 1297 Jan 68

We investigated the mechanism of ligand-independent activation of the estrogen receptor (ER) by 3,3'-diindolylmethane (DIM), a promising anticancer agent derived from vegetables of the Brassica genus, in Ishikawa and HEC-1B human endometrial cancer cells. DIM stimulated the activity of an ER-responsive reporter by over 40-fold, equivalent to the maximum induction produced by estradiol (E2), whereas cotreatment of cells with the ER antagonist, ICI-182,780 (ICI), abolished the stimulatory effect of DIM. DIM also induced the expressions of the endogenous genes, TGF-alpha, alkaline phosphatase, and progesterone receptor similar to levels induced by E2. Induction of gene expression by DIM was inhibited by the protein synthesis inhibitor, cycloheximide. In addition, cotreatment of cells with the protein kinase A (PKA) inhibitor, H89, or the MAPK inhibitor, PD98059, reduced DIM activation of the ER by 75% and 50%, respectively. Simultaneous treatment of cells with both inhibitors completely abolished the effect of DIM. DIM stimulated MAPK activity and induced phosphorylation of the endogenous PKA target, cAMP response element binding protein (CREB), in a PKA-dependent manner. Expression of MCREB, a nonphosphorylatable CREB mutant, partially abolished activation of the ER by DIM. These results demonstrate that DIM is a mechanistically novel activator of the ER that requires PKA-dependent phosphorylation of CREB.
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PMID:Potent ligand-independent estrogen receptor activation by 3,3'-diindolylmethane is mediated by cross talk between the protein kinase A and mitogen-activated protein kinase signaling pathways. 1464 98

Tibolone, a hormone replacement drug, protects postmenopausal women against osteoporosis and climacteric symptoms without inducing adverse effects on the endometrium and breast. Compared with other estrogens, little is known about the cardiovascular effects of tibolone. Because abnormal growth of smooth muscle cells (SMCs) is a prerequisite for coronary artery disease, here we investigated the effects of tibolone on SMC growth. We examined the effects of tibolone and its metabolites on human arterial SMC growth (DNA synthesis, cellular proliferation, cell migration, collagen synthesis) and MAPK expression. Fetal calf serum-induced SMC growth, phosphorylated MAPK expression, and platelet-derived growth factor-induced SMC-migration were concentration-dependently inhibited by tibolone and its endogenous estrogenic and progestogenic/androgenic metabolites in the following order of potency: Delta 4-tibolone>3 beta-OH-tibolone congruent with 3 alpha-OH-tibolone. The antimitogenic effects of tibolone were partially blocked by ER antagonist (ICI182780), progesterone receptor antagonist (RU486) but not by the androgen receptor antagonist (flutamide); moreover, RU486 was more potent than ICI182780. The antimitogenic effects of tibolone were completely blocked by RU486 plus ICI182780. In addition, the inhibitory effects of equimolar concentrations of the three tibolone metabolites summed up to the inhibitory effects of tibolone. In conclusion, tibolone inhibits SMC growth and MAPK phosphorylation via both its estrogenic and progestogenic metabolites, and these inhibitory effects involve both progesterone and ERs. Hence, tibolone may induce antivasoocclusive actions and protect women against coronary artery disease.
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PMID:Tibolone and its metabolites induce antimitogenesis in human coronary artery smooth muscle cells: role of estrogen, progesterone, and androgen receptors. 1476 5

A biologically aggressive subset of human breast cancers has been demonstrated to overexpress fatty acid synthase (FAS), the key enzyme of endogenous FA biosynthesis. This breast cancer-specific activation of FAS-dependent lipogenesis, an anabolic-energy-storage pathway of minor importance in normal cells, would render breast cancer cells more vulnerable to anti-metabolite interventions with FAS as therapeutic target. Not surprisingly, pharmacological inhibitors of FAS have been reported to produce both cytostatic and cytotoxic effects in human breast cancer cells, as well as to suppress DNA replication. However, the signal transduction pathway(s) that link FAS hyperactivity and breast cancer cell growth has been unresolved. Here, we have attempted to provide a systematic approach to assess the role of FAS signaling on the survival and proliferation of human breast cancer cells. First, we assessed the level of FAS protein in a panel of human breast cancer cell lines (MCF-7, MDA-MB-231, MDA-MB-453, MDA-MB-435, ZR-75B, T47-D, BT-474, and SK-Br3). FAS expression was graded from ++++ (overexpression) in SK-Br3 cells to + (very low expression) in MDA-MB-231 cells. No correlation was noted between FAS overexpression and estrogen receptor (ER) or progesterone receptor (PR) status, whereas a positive correlation was found between high levels of FAS expression and the amplification and/or overexpression of HER-2/neu oncogene. Because metabolic adaptation of breast cancer cells to the ambient fatty acid concentration may be relevant to the goal of utilizing FAS inhibition as a chemotherapeutic target, we evaluated the effect of exogenous dietary fatty acids on the cytotoxicity resulting from the inhibition of FAS activity. Pharmacological inhibition of FAS activity by the natural antibiotic cerulenin [(2S,3R)-2,3-epoxy-4-oxo-7E,10E-dodecadienamide] resulted in a dose-dependent cytotoxicity which positively paralleled the endogenous level of FAS. Supraphysiological levels of exogenous oleic acid (OA), a omega-9 monounsaturated fatty acid synthesized from a primary-end product of FAS palmitate, significantly diminished cell toxicity caused by cerulenin. Indeed, OA exposure significantly reduced FAS activity and expression by 55% in FAS-overexpressing SK-Br3 cells. omega-3 (alpha-linolenic acid, eicosapentaenoic acid and docosahexaenoic acid) and omega-6 (linoleic acid and arachidonic acid) polyunsaturated fatty acids (PUFAs), however, were unable to rescue breast cancer cells from cerulenin-induced cytotoxicity. Pharmacological blockade of FAS activity in FAS-overexpressing SK-Br3 cells resulted in apoptosis as determined by an enzyme-linked immunosorbent assay for histone-associated DNA fragments, and confirmed by TUNEL DNA-end labeling experiments. We further characterized signaling molecules that participate in the cellular events that follow inhibition of FAS activity and precede apoptosis in breast cancer cells. In SK-Br3 cells, cerulenin-induced inhibition of FAS activity resulted in down-regulation of p53, and up-regulation of cyclin-dependent kinase inhibitor (CDKi) p21WAF1/CIP1. Treatment with cerulenin or a novel small-molecule inhibitor of FAS C75 resulted in a dramatic accumulation of CDKi p27KIP1, which was accompanied by a noteworthy translocation of p27KIP1 from cytosol to cell nuclei. Strikingly, FAS inhibition also caused a significant activation of the Raf-mitogen-activated protein kinase (MEK) extracellular signal-regulated kinase (ERK1/2) cell survival pathway. Interestingly, we demonstrated that inhibition of FAS activity increased the nuclear-to-cytoplasmic ratio of BRCA1, a breast cancer tumor suppressor protein, as well as it induced a nuclear translocalization of the anti-apoptotic nuclear transcription factor-kappaB (NF-kappaB). In conclusion, here we demonstrate that: a) breast cancer cells retain dependence on endogenous fatty acid synthesis and sensitivity to FAS inhibition in the presence of supraphysiological levels of dietary fatty acids, supporting the notion that FAS inhibition may be useful in treFAS inhibition may be useful in treating breast cancer in vivo; b) endogenous fatty acid synthesis is functional in breast cancer cells and is vital since its pharmacological inhibition is cytotoxic by promoting apoptosis, and c) specific blockade of FAS activity induces the accumulation, activation, and/or cellular relocalization of multiple and diverse pro- and anti-apoptotic signaling pathways, suggesting that p53-p21WAF1/CIP1, ERK1/2 MAPK, p27KIP1, BRCA1, and NF-kappaB play a novel role in the breast cancer cell response to a metabolic stress after perturbation of FAS-dependent de novo fatty acid biosynthesis.
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PMID:Novel signaling molecules implicated in tumor-associated fatty acid synthase-dependent breast cancer cell proliferation and survival: Role of exogenous dietary fatty acids, p53-p21WAF1/CIP1, ERK1/2 MAPK, p27KIP1, BRCA1, and NF-kappaB. 1476 44

In addition to their role as direct regulators of gene transcription mediated by classical nuclear hormone receptors, steroid hormones have also been described to exert rapid effects on intracellular signalling pathways independent of gene transcription. This chapter focuses on recent advances in our understanding of the receptors and mechanisms that mediate these rapid signalling actions of oestrogens and progesterone. Increasing evidence suggests that at least some of these rapid actions are mediated by a subpopulation of the classical nuclear oestrogen receptor (ER) and progesterone receptor (PR) that localize to the cytoplasm or associate with the plasma membrane. Human PR has been shown to mediate rapid progestin activation of the Src/Ras/Raf/mitogen-activated protein kinase signalling pathway in mammalian cells by a direct interaction with the Src homology 3 domain of Src tyrosine kinases through a Pro-Xaa-Xaa-Pro-Xaa-Arg motif located in the N-terminal domain of the receptor. Moreover, this is an extranuclear action of PR that is separable from its direct transcriptional activity. Additionally, a novel membrane protein unrelated to nuclear PR was recently identified that has properties of a G-protein-coupled receptor for progesterone and has been shown to be involved in mediating the extranuclear signalling actions of progesterone that promotes oocyte maturation in fish. The role of this membrane PR (mPR) in mammalian cells is less clear and the relationship of the membrane and classical nuclear PR in mediating rapid non-transcriptional signalling of progestins has not been explored. To date, a novel membrane ER unrelated to classical nuclear receptors has not been cloned and characterized, and many of the known rapid extranuclear signalling actions of oestrogen appear also to be mediated by a subpopulation of nuclear ER, or a closely related receptor. A novel protein termed modulator of non-genomic activity of ER (MNAR) has been identified that acts as an adaptor between ER and Src, and thus provides a mechanisms for coupling of oestrogen and ER with rapid oestrogen-induced activation of Src and the downstream mitogen-activated protein kinase signalling cascade. The physiological relevance of rapid extranuclear signalling by the classical ER has been provided by experiments showing that these actions contribute to the anti-apoptotic effect of oestrogen in bone in vivo and to the rapid effects of oestrogen on vasodilation and protection of endothelial cells against injury.
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PMID:Receptor mechanisms of rapid extranuclear signalling initiated by steroid hormones. 1524 42

The cooked meat carcinogen 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) induces tumours of the breast, colon and prostate in rats. Here we show that in addition to its well-established genotoxicity, which can be detected at concentrations >10(-6) M, PhIP is also oestrogenic. In COS-1 cells transiently transfected with an oestrogen-responsive reporter gene, PhIP (10(-10)-10(-6) M) mediated transcription through oestrogen receptor (ER) alpha, but not ER-beta, and inhibition by the pure ER antagonist ICI 182 780 demonstrated a requirement for a functional ER. In contrast, the structurally related food-derived carcinogen 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx) failed to induce reporter gene transcription. Additionally, we show that in a hormonally responsive breast cancer cell line (MCF-7 cells), PhIP induced transcriptional activation using endogenously expressed ER. Examination of the genotoxic potential of PhIP using a model mammalian cell mutation assay (hprt(-) locus) demonstrated that the genetic toxicology of PhIP was readily detectable, but separate, in terms of effective concentration, from its oestrogenic activity. To determine whether the oestrogenicity of PhIP could mediate oestrogen-dependent responses such as cell growth, we examined the growth of hormonally responsive cells (MCF-7 cells). We show that PhIP can stimulate cell proliferation and, again, this was dependent upon a functional ER. Using ligand blotting, we further show that PhIP can stimulate the expression of progesterone receptor (PR-A and PR-B) and c-MYC and activate the MAPK signal transduction pathway. These responses were similar to that produced by oestradiol, in terms of temporal aspects, potency and a requirement for a functional ER. Each of these dose-dependent mitogenic responses occurred at concentrations of PhIP ( approximately 10(-9)-10(-11)M) that are likely to be equivalent to systemic human exposure via consumption of cooked meat. Thus PhIP can induce cellular responses that encompass altered gene expression and mitogenesis. We suggest that the combination of genetic toxicology and oestrogen-like promotion of genomic and cellular events provide a mechanism for the tissue-specific tumorigenicity of this compound.
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PMID:The cooked food derived carcinogen 2-amino-1-methyl-6-phenylimidazo[4,5-b] pyridine is a potent oestrogen: a mechanistic basis for its tissue-specific carcinogenicity. 1531 1

We evaluated the signaling pathways involved in regulating vascular endothelial growth factor (VEGF), a potent angiogenic growth factor, in response to natural and synthetic progestins in breast cancer cells. Inhibition of the phosphoinositide-3'-kinase (PI3-kinase) signaling pathway or the specificity protein-1 (SP-1) transcription factor abolished both progesterone- and medroxyprogesterone acetate (MPA)-induced VEGF secretion from BT-474 and T47-DCO)cells. Inhibitors of the MAPK kinase 1/2/MAPK and N-terminal jun kinase/MAPK signaling pathways blocked both progesterone- and MPA-induced VEGF secretion in BT-474 cells. However, these inhibitors blocked only progesterone-, but not MPA-induced VEGF secretion in T47-DCO cells. Inhibitors of PI3-kinase or SP-1 blocked both progesterone- and MPA-induced increases in VEGF mRNA levels in T47-DCO cells. The proximal SP-1 sites within the VEGF promoter were critical for progestin-dependent induction of VEGF. In contrast, MAPK inhibitors did not block the progesterone- or MPA-induced increases in VEGF mRNA in T47-DCO cells, suggesting that MAPK inhibitors decreased progesterone-induced VEGF secretion in T47-DCO cells by blocking posttranscriptional mechanisms. The MAPK kinase/ERK/MAPK-independent induction of VEGF mediated by MPA was associated with the PRB [progesterone receptor (PR) B] isoform of the PR in T47-DCO cells. None of the inhibitors tested reduced basal PR levels or abrogated PR-dependent gene expression from a reporter plasmid, indicating that loss of PR function cannot explain any of the observed effects. Because the PI3-kinase signaling pathway and SP-1 transcription factor play critical roles in progestin-dependent VEGF induction, these may be useful targets for developing antiangiogenic therapies to prevent progression of progestin-dependent human breast cancers.
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PMID:Ligand- and cell-specific effects of signal transduction pathway inhibitors on progestin-induced vascular endothelial growth factor levels in human breast cancer cells. 1552 72

Breast cancers often have increased mitogen-activated protein kinase (MAPK) activity; this pathway influences breast cancer cell growth in part by targeting steroid hormone receptors. Activation of p42 and p44 MAPKs increases progesterone receptor (PR) transcriptional activity in the presence of progestins, and triggers their rapid down-regulation by the ubiquitin-proteasome pathway. In turn, progestins increase the expression of type I growth factor receptor tyrosine kinases that feed into MAPK activation. Most recently, progestins have been shown to activate the p42/p44 MAPK module in a progesterone receptor (PR) dependent manner, but independently of their function as transcription factors. Indeed, mechanisms of bi-directional cross-talk between these two pathways are becoming well-documented. In this reveiw we provide an overview of the primary ways in which steroid hormone receptor and growth factor cross-talk occurs, using examples from our work and others with human PR as a model receptor. We highlight the regulation of PR by phosphorylation and the role of intracellular protein kinases as key mediators of PR action. Cross-talk between growth factor and PR-mediated signaling events is an important means by which growth regulatory genes may be coordinately regulated, and may contribute to the growth and development of hormonally responsive normal breast tissue and to breast cancer progression.
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PMID:Cross-talk between growth factor and progesterone receptor signaling pathways: implications for breast cancer cell growth. 1568 86

ICI 182,780 (Faslodex), considered a pure anti-estrogen, is approved for treatment of post-menopausal breast cancer patients who fail to respond to tamoxifen therapy. We recently reported that, like mifepristone, ICI 182,780 exhibits anti-progestin activity, blocking the progestin-dependent increase in endogenous vascular endothelial growth factor (VEGF) mRNA and protein release. Some anti-progestins have partial agonist-like activity in breast cancer cells expressing high levels of progesterone receptor B (PRB). Our results show that ICI 182,780 can also induce reporter activity from a plasmid containing a simple progestin responsive element (PRE) in these cells. Using small interfering RNA, we determined that induction is dependent on the presence of PR, estrogen receptor and SRC-1. Regulation of more complex progestin-responsive promoters was context-dependent; induction was observed from the MMTV promoter but not from the VEGF promoter. In contrast, ICI 182,780 increased the release of angiogenically active VEGF from cells expressing elevated levels of PRB. This effect was dependent on the phosphatidylinositol-3 kinase and ERK/MAPK signaling pathways. We hypothesize that these agonist-like properties of ICI 182,780 (one genomic and one non-genomic) may contribute to the acquisition of drug resistance, suggesting that both anti-hormonal and anti-angiogenic treatment may be appropriate in these patients.
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PMID:Complex agonist-like properties of ICI 182,780 (Faslodex) in human breast cancer cells that predominantly express progesterone receptor-B: implications for treatment resistance. 1627 21

Emerging data suggest that p21-activated kinase 1 (Pak1), a downstream signaling molecule of the small GTPases, growth factors, and lipid signaling, is upregulated or hyperactivated in human breast cancer. Until now, however, no direct causative role had been found for Pak1 in mammary tumor formation. We therefore sought to identify the role that Pak1 plays in mammary gland tumorigenesis. Our results showed that in a transgenic mouse model, overexpression of catalytically active Pak1 leads to the development of malignant mammary tumors and to a variety of other breast lesions, including focal solid nodules, ductal hyperplasia, and mini-intraductal neoplasm and adenoma. We also found that Pak1 hyperactivation increases the stimulation of downstream proliferative signaling effectors MEK1/2 and p38-MAPK in mammary tumor epithelial cells. Moreover, in our study, we detected expression of estrogen receptor-alpha expression and progesterone receptor expression during early stages of the lesions, but their expression was lost during the cells' transition to malignant invasive tumors. Finally, we found that consistent with a role in breast tumor progression, Pak1 expression and its nuclear accumulation was increased progressively during the transition from ductal hyperplasia to ductal carcinoma in situ to adenocarcinoma in widely used multistep polyoma-middle T-antigen transgenic mice. Together, these findings provide the first direct evidence that Pak1 deregulation may be sufficient for the formation of mammary gland tumors.
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PMID:PAK1 hyperactivation is sufficient for mammary gland tumor formation. 1633 Dec 48


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