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)

17beta-Estradiol (E(2)) is a steroid hormone well known for its roles in the regulation of various cell functions. However, the precise role that E(2) plays in the proliferation of human mesenchymal stem cells (hMSCs) has not been completely elucidated. In the present study, we examined the effects of E(2) on cell proliferation and the related signaling pathways using hMSCs. We showed that E(2), at > or =10(-9) M, significantly increased [3H]thymidine incorporation after 24 h of incubation, and E(2) also increased [3H]thymidine incorporation at >6 h. Also, E(2) significantly increased the percentage of the cell population in the S phase based on FACS analysis. Moreover, E(2) increased estrogen receptor (ER), PKC, phosphatidylinositol 3-kinase (PI3K)/Akt, and MAPK phosphorylation. Subsequently, these signaling molecules were involved in an E(2)-induced increase of [3H]thymidine incorporation. E(2) also increased hypoxia-inducible factor (HIF)-1alpha and VEGF protein levels. These levels of protein expression were inhibited by ICI-182,780 (10(-6) M, an ER antagonist), staurosporine and bisindolylmaleimide I (10(-6) M, a PKC inhibitor), LY-294002 (10(-6) M, a PI3K inhibitor), Akt inhibitor (10(-5) M), SP-600125 (10(-6) M, a SAPK/JNK inhibitor), and PD-98059 (10(-5) M, a p44/42 MAPKs inhibitor). In addition, HIF-1alpha small interfering (si)RNA and ICI-182,780 inhibited E(2)-induced VEGF expression and cell proliferation. VEGF siRNA also significantly inhibited E(2)-induced cell proliferation. In conclusion, E(2) partially stimulated hMSC proliferation via HIF-1alpha activation and VEGF expression through PKC, PI3K/Akt, and MAPK pathways.
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PMID:Role of HIF-1alpha and VEGF in human mesenchymal stem cell proliferation by 17beta-estradiol: involvement of PKC, PI3K/Akt, and MAPKs. 1898 49

Hypoxia (reduced oxygen tension) is a critical stimulus which switches on a cell rapid response, determining damage and death in some cells, and adaptation and survival in others. Here we report that K562 erythroleukemia cells exposed to hypoxia, proliferated more slowly and the percentage of dead cells increased after 22 h. In parallel HIF (Hypoxia Inducible Factor)-1alpha and Bax level increased, as well as the PKC (Protein Kinase C) delta/Erk (Extracellular Signal Regulated Kinase) pathways being activated. The low level of ROS after 5h of hypoxia did not modify cell cycle progression or affect cell death, whereas HIF-1alpha/CBP (CREB Binding Protein) co-immunoprecipitation and MAPK (Mitogen Activated Protein Kinase)/CREB (c-AMP Response Element Binding) protein signalling pathway activation determined the adaptive survival response. We suggest a dual role for HIF-1alpha in providing a survival or death signal, based on hypoxia duration, and consider the nuclear transcription factor, CREB, to be a possible target for hypoxic therapy against leukemia disease.
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PMID:Dual role of HIF-1alpha in delivering a survival or death signal in hypoxia exposed human K562 erythroleukemia cells. 1899 91

von Hippel-Lindau (VHL) tumor suppressor loss results in hypoxia-inducible factor alpha (HIF-alpha) stabilization and occurs in 70% of sporadic clear cell renal carcinomas (ccRCCs). To determine whether opposing influences of HIF-1alpha and HIF-2alpha on c-Myc activity regulate human ccRCC progression, we analyzed VHL genotype and HIF-alpha expression in 160 primary tumors, which segregated into three groups with distinct molecular characteristics. Interestingly, ccRCCs with intact VHL, as well as pVHL-deficient HIF-1alpha/HIF-2alpha-expressing ccRCCs, exhibited enhanced Akt/mTOR and ERK/MAPK signaling. In contrast, pVHL-deficient ccRCCs expressing only HIF-2alpha displayed elevated c-Myc activity, resulting in enhanced proliferation and resistance to replication stress. These reproducible distinctions in ccRCC behavior delineate HIF-alpha effects on c-Myc in vivo and suggest molecular criteria for selecting targeted therapies.
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PMID:HIF-alpha effects on c-Myc distinguish two subtypes of sporadic VHL-deficient clear cell renal carcinoma. 1906 30

3,5,3'-Triiodo-l-thyronine (T(3)), but not l-thyroxine (T(4)), activated Src kinase and, downstream, phosphatidylinositol 3-kinase (PI3-kinase) by means of an alpha(v)beta(3) integrin receptor on human glioblastoma U-87 MG cells. Although both T(3) and T(4) stimulated extracellular signal-regulated kinase (ERK) 1/2, activated ERK1/2 did not contribute to T(3)-induced Src kinase or PI3-kinase activation, and an inhibitor of PI3-kinase, LY-294002, did not block activation of ERK1/2 by physiological concentrations of T(3) and T(4). Thus the PI3-kinase, Src kinase, and ERK1/2 signaling cascades are parallel pathways in T(3)-treated U-87 MG cells. T(3) and T(4) both caused proliferation of U-87 MG cells; these effects were blocked by the ERK1/2 inhibitor PD-98059 but not by LY-294002. Small-interfering RNA knockdown of PI3-kinase confirmed that PI3-kinase was not involved in the proliferative action of T(3) on U-87 MG cells. PI3-kinase-dependent actions of T(3) in these cells included shuttling of nuclear thyroid hormone receptor-alpha (TRalpha) from cytoplasm to nucleus and accumulation of hypoxia-inducible factor (HIF)-1alpha mRNA; LY-294002 inhibited these actions. Results of studies involving alpha(v)beta(3) receptor antagonists tetraiodothyroacetic acid (tetrac) and Arg-Gly-Asp (RGD) peptide, together with mathematical modeling of the kinetics of displacement of radiolabeled T(3) from the integrin by unlabeled T(3) and by unlabeled T(4), are consistent with the presence of two iodothyronine receptor domains on the integrin. A model proposes that one site binds T(3) exclusively, activates PI3-kinase via Src kinase, and stimulates TRalpha trafficking and HIF-1alpha gene expression. Tetrac and RGD peptide both inhibit T(3) action at this site. The second site binds T(4) and T(3), and, via this receptor, the iodothyronines stimulate ERK1/2-dependent tumor cell proliferation. T(3) action here is inhibited by tetrac alone, but the effect of T(4) is blocked by both tetrac and the RGD peptide.
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PMID:L-Thyroxine vs. 3,5,3'-triiodo-L-thyronine and cell proliferation: activation of mitogen-activated protein kinase and phosphatidylinositol 3-kinase. 1915 3

The lymphatic vasculature is essential for tissue fluid homeostasis and cancer metastasis, although the molecular mechanisms involved remain poorly characterized. Endothelin-1 (ET-1) axis plays a crucial role in angiogenesis and tumorigenesis. Here, we first report that ET-1 acts as a lymphangiogenic mediator. We performed in vitro and in vivo studies and show that lymphatic endothelial cells produce ET-1, ET-3, and express the endothelin B receptor (ET(B)R). In these cells, ET-1 promotes proliferation, invasiveness, vascular-like structures formation, and phosphorylation of AKT and p42/44 mitogen-activated protein kinase through ET(B)R. In normoxic conditions, ET-1 is also able to up-regulate the expression of vascular endothelial growth factor (VEGF)-C, VEGF receptor-3, and VEGF-A, and to stimulate hypoxia-inducible factor (HIF)-1alpha expression similarly to hypoxia. Moreover, HIF-1alpha silencing by siRNA desensitizes VEGF-C and VEGF-A production in response to ET-1 or hypoxia, implicating HIF-1alpha/VEGF as downstream signaling molecules of ET-1 axis. Double immunofluorescence analysis of human lymph nodes reveals that lymphatic vessels express ET(B)R together with the lymphatic marker podoplanin. Furthermore, a Matrigel plug assay shows that ET-1 promotes the outgrowth of lymphatic vessels in vivo. ET(B)R blockade with the specific antagonist, BQ788, inhibits in vitro and in vivo ET-1-induced effects, demonstrating that ET-1 through ET(B)R directly regulates lymphatic vessel formation and by interacting with the HIF-1alpha-dependent machinery can amplify the VEGF-mediated lymphatic vascularization. Our results suggest that ET-1 axis is indeed a new player in lymphangiogenesis and that targeting pharmacologically ET(B)R and related signaling cascade may be therapeutically exploited in a variety of diseases including cancer.
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PMID:Endothelin-1 stimulates lymphatic endothelial cells and lymphatic vessels to grow and invade. 1927 84

Our previous study revealed that estrogen regulates nm23-H1 expression thus promoting cell migration-invasion via activating PIK3/Akt pathway. In this study, we explored the effect of hormone on hypoxia-inducible factor-1 (HIF-1alpha), a key factor in cancer invasion and metastasis, via activation of Akt signaling transduction pathway. We treated two ovarian cancer cell lines ES-2 and SKOV3 with 17beta-estradiol, methoxyprogesterone acetate (MPA) only, or hormone combined with and Akt, MAPK pathway inhibitor, or transefected with siRNA targeting Akt sequenced with hormone. Expression of HIF-1alpha was measured by Western blotting. We observed the effect of hormone on nm23-H1 expression after the cells were transfected by siRNA targeting HIF-1alpha or treated with CoCl2 to induce HIF-1alpha overexpression. The 17beta-estradiol increased HIF-1alpha expression in ovarian cancer cells, and this upregulatory effect was abrogated by Akt inhibitor LY294002 (P<0.05) and Akt siRNA interference (P<0.05), but not affected by MAPK inhibitor PD980059 (P>0.05). MPA had the opposite effect. Nm23-H1 protein expression in ES-2 and SKOV3 cells were decreased after treatment with 17beta-estradiol (P<0.05), whereas MPA had the opposite effect. The effect was attenuated by HIF-1alpha siRNA (P<0.05) and enhanced by HIF-1alpha overexpression after CoCl2 treatment (P<0.05). Our data suggest that estrogen and progestin regulate HIF-1alpha expression via Akt signaling pathway, affecting nm23-H1 expression in influencing cell metastasis.
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PMID:Estrogen and progestin regulate HIF-1alpha expression in ovarian cancer cell lines via the activation of Akt signaling transduction pathway. 1928 85

Hypoxia, a common phenomenon in human solid tumors, is associated with invasion and metastasis in various tumors. Hypoxia inducible factors (HIFs) are key molecules in the hypoxic response, and regulate the activation of specific genes, which mediate many of the adaptations to hypoxia. CC chemokine receptor 7 (CCR7) has been shown to play a critical role in cell chemotaxis and homing, which are key steps in cancer metastasis. A study has demonstrated that hypoxia could upregulate CCR7 in breast cancer cells. The CCR7 gene presents hypoxia response element (HRE; (A)/(G)CGTG). We presumed that hypoxia induced upregulation of HIFs promoted the expression of CCR7 facilitating tumor cells invasion and metastasis. In this study, we firstly examined the relationship of CCR7 and HIF-1alpha, HIF-2alpha in 94 cases non-small cell lung cancer (NSCLC) tissues by immunohistochemistry. The results showed that CCR7 expression correlated positively with HIF-1alpha and HIF-2alpha, all of them correlated with clinical stage and lymph node metastasis. Then, we investigated whether hypoxia induce the expression of CCR7 through HIF-1alpha and/or HIF-2alpha and observed the effects of upregulated CCR7 on the migration and invasion of lung cancer cells. We found that hypoxia induced HIF-1alpha and HIF-2alpha expression, which upregulated CCR7 expression; inhibiting HIF-1alpha or HIF-2alpha expression in BE1 and A549 cells by RNAi led to the decrease of CCR7 expression, inhibition of migratory and invasive abilities, and the effects of HIF-1alpha were more significant. Moreover, the migration and invasion of BE1 cells were increased as well as the expression of p-ERK1/2 after CCR7 transfection, but the cells invasive ability was inhibited after blocking p-ERK1/2 with PD98059 and CCR7 with specific antibody. In summary, our study demonstrated that hypoxia-HIF-1alpha, 2alpha-CCR7-ERK1/2 pathway could regulate the migration and invasion of lung cancer cells under hypoxic conditions and promote metastasis of lung cancer.
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PMID:Hypoxia induced CCR7 expression via HIF-1alpha and HIF-2alpha correlates with migration and invasion in lung cancer cells. 1930 50

Recent advances in molecular biology and the use of DNA microarrays for gene expression profiling are providing new insights into the animal stress response, particularly the effects of stress on gene regulation. However, interpretation of the complex transcriptional changes that occur during stress still poses many challenges because the relationship between changes at the transcriptional level and other levels of biological organisation is not well understood. To confront these challenges, a conceptual model linking physiological and transcriptional responses to stress would be helpful. Here, we provide the basis for one such model by synthesising data from organismal, endocrine, cellular, molecular, and genomic studies. We show using available examples from ectothermic vertebrates that reduced oxygen levels and oxidative stress are common to many stress conditions and that the responses to different types of stress, such as environmental, handling and confinement stress, often converge at the challenge of dealing with oxygen imbalance and oxidative stress. As a result, a common set of stress responses exists that is largely independent of the type of stressor applied. These common responses include the repair of DNA and protein damage, cell cycle arrest or apoptosis, changes in cellular metabolism that reflect the transition from a state of cellular growth to one of cellular repair, the release of stress hormones, changes in mitochondrial densities and properties, changes in oxygen transport capacities and changes in cardio-respiratory function. Changes at the transcriptional level recapitulate these common responses, with many stress-responsive genes functioning in cell cycle control, regulation of transcription, protein turnover, metabolism, and cellular repair. These common transcriptional responses to stress appear coordinated by only a limited number of stress-inducible and redox-sensitive transcription factors and signal transduction pathways, such as the immediate early genes c-fos and c-jun, the transcription factors NFkappaB and HIF-1alpha, and the JNK and p38 kinase signalling pathways. As an example of environmental stress responses, we present temperature response curves at organismal, cellular and molecular levels. Acclimation and physiological adjustments that can shift the threshold temperatures for the onset of these responses are discussed and include, for example, adjustments of the oxygen delivery system, the heat shock response, cellular repair system, and transcriptome. Ultimately, however, an organism's ability to cope with environmental change is largely determined by its ability to maintain aerobic scope and to prevent loss in performance. These systemic constraints can determine an organism's long-term survival well before cellular and molecular functions are disturbed. The conceptual model we propose here discusses some of the crosslinks between responses at different levels of biological organisation and the central role of oxygen balance and oxidative stress in eliciting these responses with the aim to help the interpretation of environmental genomic data in the context of organismal function and performance.
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PMID:Animal performance and stress: responses and tolerance limits at different levels of biological organisation. 1934 29

Calcium ion is one of the most important second messengers of cellular signal transduction including hypoxia-elicited signals. In this study, we investigated the effects of the L-type calcium channel blockers such as nifedipine, efonidipine cilnidipine, diltiazem, and verapamil, on the activity of hypoxia-inducible factor-1 (HIF-1), a key transcription factor in control of hypoxia-induced gene expression. Using the lung carcinoma cell line A549 cells, human aortic smooth muscle cells, and human umbilical vein endothelial cells, we demonstrated that cilnidipine exclusively suppressed HIF-1 activity and the expressions of downstream genes in a cell-type specific manner. We also demonstrated that cilnidipine blocked the synthesis of the HIF-1alpha protein not by affecting activity of the intracellular hypoxia-sensing element prolyl hydroxylases but inhibiting activity of Akt and mitogen-activated protein kinase and that the inhibition is not dependent on the effect on calcium homeostasis.
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PMID:The calcium channel blocker cilnidipine selectively suppresses hypoxia-inducible factor 1 activity in vascular cells. 1937 68

Hypoxia-inducible factor-1 (HIF-1) plays a central role in tumor progression by regulating genes involved in proliferation, glycolysis, angiogenesis, and metastasis. To improve our understanding of HIF-1 regulation by kinome, we screened a kinase-specific small interference RNA library using a hypoxia-response element (HRE) luciferase reporter assay under hypoxic conditions. This screen determined that depletion of cellular SMG-1 kinase most significantly modified cellular HIF-1 activity in hypoxia. SMG-1 is the newest and least studied member of the phosphoinositide 3-kinase-related kinase family, which consists of ATM, ATR, DNA-PKcs, mTOR, and SMG-1. We individually depleted members of the phosphoinositide 3-kinase-related kinase family, and only SMG-1 deficiency significantly augmented HIF-1 activity in hypoxia. We subsequently discovered that SMG-1 kinase activity was activated by hypoxia, and depletion of SMG-1 up-regulated MAPK activity under low oxygen. Suppressing cellular MAPK by silencing ERK1/2 or by treatment with U0126, a MAPK inhibitor, partially blocked the escalation of HIF-1 activity resulting from SMG-1 deficiency in hypoxic cells. Increased expression of SMG-1 but not kinase-dead SMG-1 effectively inhibited the activity of HIF-1alpha. In addition, cellular SMG-1 deficiency increased secretion of the HIF-1alpha-regulated angiogenic factor, vascular epidermal growth factor, and survival factor, carbonic anhydrase IX (CA9), as well as promoted the hypoxic cell motility. Taken together, we discovered that SMG-1 negatively regulated HIF-1alpha activity in hypoxia, in part through blocking MAPK activation.
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PMID:Kinome siRNA screen identifies SMG-1 as a negative regulator of hypoxia-inducible factor-1alpha in hypoxia. 1940 46


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