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)

Thyroid hormone (TH) effects are mediated through T(3), which regulates gene expression by binding to the nuclear TH receptors, TRalpha and TRbeta. Using microarrays and real-time PCR we found mRNAs of the following genes increased in response to T(3) in a TRbeta-specific manner: the transcription factor hypoxia-inducible factor (HIF)-1alpha, its target genes glucose transporter (GLUT)1 and platelet-type phosphofructokinase (PFKP), and the monocarboxylate transporter (MCT)4. The products of these genes have important roles in cellular glucose metabolism. HIF-1alpha expression and activity can be regulated through phosphatidylinositol-OH-3-kinase (PI3K) and MAPK signaling; thus the possibility of alternative, nonnuclear pathways of TH action was raised. We examined the involvement of these pathways in mediating TH effects by treating human skin fibroblasts with 2 nm T(3) in the absence or presence of either the PI3K inhibitor LY294002 or the MAPK inhibitor PD98059. T(3) induced HIF-1alpha mRNA by 2.7-fold (+/-0.4; P < 0.013). This increase was completely abrogated by LY294002 (1.1 +/- 0.1; nonsignificant = 0.57), but preserved in the presence of PD98059 (2.2 +/- 0.2; P < 0.009). Western blotting confirmed these results at the protein level, indicating dependency on the PI3K pathway. The same pattern of response was observed for GLUT1, PFKP, and MCT4 expression. To examine whether HIF-1alpha is directly induced, we used the translation inhibitor cycloheximide (CHX). T(3) induction of HIF-1alpha mRNA was not affected by CHX, whereas T(3) effect on GLUT1, PFKP, and MCT4 mRNA was completely abrogated by CHX. These results demonstrate that cytosolic activation of the PI3K signaling pathway has a role in TH-mediated direct (HIF-1alpha) and indirect (GLUT1, PFKP, MCT4) gene expression, and possibly provides a link between TH and cellular glucose metabolism in human fibroblasts.
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PMID:Cytosolic action of thyroid hormone leads to induction of hypoxia-inducible factor-1alpha and glycolytic genes. 1605 72

Our early reported investigations have demonstrated potent proangiogenic effects of L-thyroxine (T4) and 3,5,3'-triiodo-L-thyronine (T3) in the chick chorioallantoic membrane (CAM) model. Tetraiodothyroacetic acid (tetrac) blocks T4 binding to plasma membranes and its pro-angiogenic effect. T4/T3 stimulates expression of fibroblast growth factor 2 (FGF2) in endothelial cells. Thyroid hormone (T4/T3) is principally responsible for transcriptional activation mediated by nuclear thyroid hormone receptors TRbeta and TRalpha. In contrast, the hormone analogue GC-1 also stimulates transcriptional activation via TRbeta1. In the present study, we have defined the effect of GC-1, compared with T4 and T4-agarose, on angiogenesis in the CAM assay. GC-1 demonstrated a proangiogenic effect similar to that of T4 and T4-agarose. Tetrac inhibited GC-1- and T4-induced angiogenesis, indicating dependence on T4 and GC-1 binding to plasma membranes. The effects of GC-1, T4-agarose, and FGF2 were blocked by PD 98059, a mitogen-activated protein kinase (MAPK) pathway inhibitor. Additionally, the alphavbeta3 integrin antagonist XT199 inhibited angiogenesis induced by T4-agarose, GC-1, or FGF2. Thus, the proangiogenic effects of GC-1 and T4 are initiated at the plasma membrane, require interaction with alphavbeta3 integrin receptor, and are dependent on MAPK activation.
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PMID:The proangiogenic action of thyroid hormone analogue GC-1 is initiated at an integrin. 1611 42

Childhood hypothyroidism causes growth arrest with delayed ossification and growth-plate dysgenesis, whereas thyrotoxicosis accelerates ossification and growth. Thyroid hormone (T(3)) regulates chondrocyte proliferation and is essential for hypertrophic differentiation. Fibroblast growth factors (FGFs) are also important regulators of chondrocyte proliferation and differentiation, and activating mutations of FGF receptor-3 (FGFR3) cause achondroplasia. We investigated the hypothesis that T(3) regulates chondrogenesis via FGFR3 in ATDC5 cells, which undergo a defined program of chondrogenesis. ATDC5 cells expressed two FGFR1, four FGFR2, and one FGFR3 mRNA splice variants throughout chondrogenesis, and expression of each isoform was stimulated by T(3) during the first 6-12 d of culture, when T(3) inhibited proliferation by 50%. FGFR3 expression was also increased in cells treated with T(3) for 21 d, when T(3) induced an earlier onset of hypertrophic differentiation and collagen X expression. FGFR3 expression was reduced in growth plates from T(3) receptor alpha-null mice, which exhibit skeletal hypothyroidism, but was increased in T(3) receptor beta(PV/PV) mice, which display skeletal thyrotoxicosis. These findings indicate that FGFR3 is a T(3)-target gene in chondrocytes. In further experiments, T(3) enhanced FGF2 and FGF18 activation of the MAPK-signaling pathway but inhibited their activation of signal transducer and activator of transcription-1. FGF9 did not activate MAPK or signal transducer and activator of transcription-1 pathways in the absence or presence of T(3). Thus, T(3) exerted differing effects on FGFR activation during chondrogenesis depending on which FGF ligand stimulated the FGFR and which downstream signaling pathway was activated. These studies identify novel interactions between T(3) and FGFs that regulate chondrocyte proliferation and differentiation during chondrogenesis.
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PMID:Thyroid hormones regulate fibroblast growth factor receptor signaling during chondrogenesis. 1615 Sep 8

Thyroid hormone (TH) has a profound effect on astrocyte differentiation and maturation. Astrocytes cultured under TH-deficient conditions fail to transform from flat polygonal morphology to mature, process-bearing, stellate cells. Supplementation of physiological concentrations of TH initiate gradual transformation of the cells and the process takes approximately 48 h to complete. The signal transduction pathways associated with TH-mediated maturation of astrocytes have been investigated. TH treatment caused an initial activation of protein kinase A (PKA), with a peak activity at 2 h which fell back to basal level there after. Although there was no visible change in morphology of the cells during the observed activation of PKA, it was sufficient to drive the process of transformation to completion, suggesting the involvement of downstream regulators of PKA. PKA inhibitors as well as the MEK inhibitor PD098059 attenuated the TH-induced morphological transformation. Further studies showed that TH treatment resulted in a biphasic response on the cellular phospho-MAP kinase (p-MAPK or p-ERK) level: an initial decline in the p-ERK level followed by an induction at 18-24 h, both of which could be blocked by a PKA inhibitor. Such sustained activation of p-ERK levels by TH at this later stage coincided with initiation of morphological differentiation of the astrocytes and appeared to be critical for the transformation of astrocytes. The nitric oxide synthase (NOS) inhibitor 7-NI inhibited this induction of p-ERK activity. Moreover, the induction was accompanied by a parallel increase in phospho-CREB activity which, however, persisted at the end of the transformation of the astroglial cells.
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PMID:Thyroid hormone-induced morphological differentiation and maturation of astrocytes involves activation of protein kinase A and ERK signalling pathway. 1619 1

Protein kinase C (PKC) is a family of serine-threonine kinases that regulate many cell processes. To study the role of PKCdelta in thyroid cancer cells, we used a replication-deficient adenovirus (PKCdeltaAdV), to tightly control PKCdelta expression. In NPA cells, activation of wild-type (WT) PKCdelta with phorbol 12-myristate 13-acetate (PMA) induced an arrest in cell growth at G(1) phase, which was itself inhibited by the PKCdelta inhibitor rottlerin. Furthermore, overexpression of a dominant negative PKCdelta did not induce G(1) arrest. These findings strongly suggested that PKCdelta induced cell growth arrest in NPA cells. We investigated the mechanism of G1 arrest by examining G(1)-related proteins and mitogen-activated protein kinase (MAPK) by Western blotting. After activation of WTPKCdelta with PMA, cyclin E expression and retinoblastoma protein (Rb) phosphorylation decreased; the expression of p27(Kip1) increased and the phosphorylation of extracellular signal-regulated kinase (ERK) MAPK decreased. These results indicated that the activation of PKCdelta induced cell growth arrest in NPA cells, through an ERK MAPK-p27(Kip1)-cyclin E-pRb pathway. PKCdelta may therefore be an effective molecular target for novel therapy in thyroid cancer.
Thyroid 2006 Apr
PMID:Activation of protein kinase C delta induces growth arrest in NPA thyroid cancer cells through extracellular signal-regulated kinase mitogen-activated protein kinase. 1664 78

Anaplastic thyroid carcinoma (ATC) is one of the most malignant tumors in humans, and currently there is no effective treatment. In the present study we investigated the effect of an endogenous estrogen metabolite, 2-methoxyestradiol (2-ME), on the growth of human ATC cells. 2-ME treatment had a strong growth inhibitory effect on five human ATC cell lines (HTh7, HTh 74, HTh83, C643, and SW1736), but showed no effect on one cell line (KAT-4). Cell cycle analysis of the growth-inhibited cells showed that 2-ME induced a G2/M-arrest, followed by an increased fraction of cells in sub-G1. Analysis of internucleosomal DNA laddering as well as DNA fragmentation in a terminal deoxynucleotide transferase-mediated dUTP nick-end labeling (TUNEL) assay demonstrated a high number of cells undergoing apoptosis after 2-ME treatment. An increased activation of caspase-3 and caspase-8 by 2-ME was observed, and inhibition of caspase-3 decreased the apoptotic effect. Addition of 2-ME increased activity of p38 mitogen-activated protein kinase (MAPK) in the sensitive HTh7 as well as the refractory KAT-4 cells, however, activation of stress-activated protein kinase/c-jun aminoterminal kinase (SAPK/JNK) was seen only in the HTh7 cells. Inhibitors of p38 MAPK and SAPK/JNK significantly attenuated the 2-ME effect. Taken together, our data demonstrate an antiproliferative and apoptotic effect of 2-ME on ATC cells involving activation of MAPKs.
Thyroid 2006 Feb
PMID:2-methoxyestradiol induces apoptosis in cultured human anaplastic thyroid carcinoma cells. 1667 99

Thyroid hormone (l-thyroxine, T(4), or 3,5,3'-triiodo-l-thyronine, T(3)) treatment of human papillary and follicular thyroid cancer cell lines resulted in enhanced cell proliferation, measured by proliferating cell nuclear antigen (PCNA). Thyroid hormone also induced activation of the Ras/MAPK (ERK1/2) signal transduction pathway. ERK1/2 activation and cell proliferation caused by thyroid hormone were blocked by an iodothyronine analogue, tetraiodothyroacetic acid (tetrac), that inhibits binding of iodothyronines to the cell surface receptor for thyroid hormone on integrin alphaVbeta3. A MAPK cascade inhibitor at MEK, PD 98059, also blocked hormone-induced cell proliferation. We then assessed the possibility that thyroid hormone is anti-apoptotic. We first established that resveratrol (10 microM), a pro-apoptotic agent in other cancer cells, induced p53-dependent apoptosis and c-fos, c-jun and p21 gene expression in both papillary and follicular thyroid cancer cells. Induction of apoptosis by the stilbene required Ser-15 phosphorylation of p53. Resveratrol-induced gene expression and apoptosis were inhibited more than 50% by physiological concentrations of T(4). T(4) activated MAPK in the absence of resveratrol, caused minimal Ser-15 phosphorylation of p53 and did not affect c-fos, c-jun and p21 mRNA abundance. Thus, plasma membrane-initiated activation of the MAPK cascade by thyroid hormone promotes papillary and follicular thyroid cancer cell proliferation in vitro.
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PMID:Thyroid hormone is a MAPK-dependent growth factor for thyroid cancer cells and is anti-apoptotic. 1717 66

Thyroid hormone and p44/42 MAPK inactivation are important in intestinal differentiation. We demonstrated not only that treatment with p44/42 MAPK inhibitor U0126 in intestinal cell line Caco-2 cells reduced the phosphorylation of serine and threonine residues of TRalpha-1, but also that T(3) and U0126 synergistically induced GLUT5 gene expression. EMSA demonstrated that the binding activity of TRalpha-1-RXR heterodimer on GLUT5-TRE in nuclear proteins of Caco-2 cells was synergistically enhanced by co-incubation in vitro with T(3) and CIAP, which strongly de-phosphorylates proteins. ChIP and transfection assays revealed that co-treatment of T(3) and U0126 induces TRalpha-1-RXR binding to GLUT5-TRE on the human GLUT5 enhancer region, and recruitment of the transcriptional complex in cells. These results suggest that inactivation of p44/42 MAPK enhances T(3)-induced GLUT5 gene expression in Caco-2 cells through increasing TRalpha-1 transactivity and binding activity to the GLUT5-TRE, probably due to de-phosphorylation of TRalpha-1.
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PMID:De-phosphorylation of TRalpha-1 by p44/42 MAPK inhibition enhances T(3)-mediated GLUT5 gene expression in the intestinal cell line Caco-2 cells. 1757 79

Thyroid cancers are the most frequent endocrine neoplasms and mutations in the thyrotropin receptor (TSHR) are unusually frequent. Here we present the state-of-the-art concerning the role of TSHR in thyroid cancer and discuss it in light of the cancer stem cell theory or the classical view. We briefly review the gene and protein structure updating the cancer related TSHR mutations database. Intriguingly, hyperfunctioning TSHR mutants characterise differentiated cancers in contrast to undifferentiated thyroid cancers which very often bear silenced TSHR. It remains unclear whether TSHR alterations in thyroid cancers play a role in the onset or they appear as a consequence of genetic instability during evolution, but the presence of functional TSHR is exploited in therapy. We outline the signalling network build up in the thyrocyte between TSHR/PKA and other proliferative pathways such as Wnt, PI3K and MAPK. This networks integrity surely plays a role in the onset/evolution of thyroid cancer and needs further research. Lastly, future investigation of epigenetic events occurring at the TSHR and other loci may give better clues for molecular based therapy of undifferentiated thyroid carcinomas. Targeted demethylating agents, histone deacetylase inhibitors combined with retinoids and specific RNAis may help treatment in the future.
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PMID:TSH signalling and cancer. 1789 Dec 29

Thyroid hormone (T(3)) regulates the function of many tissues within the body. The effects of T(3) have largely been attributed to the modulation of thyroid hormone receptor-dependent gene transcription. However, nongenomic actions of T(3) via the initiation of signaling events are emerging in a number of cell types. This study investigated the ability of short-term T(3) treatment to phosphorylate and, therefore, activate signaling proteins in rat tissues in vivo. The kinases investigated included p38, AMP-activated protein kinase (AMPK), and extracellular signal-regulated kinase (ERK) 1/2. Following 2 h of T(3) treatment, p38 and AMPK phosphorylation was increased in both the slow-twitch soleus and the fast-twitch plantaris muscles. In contrast, ERK1/2 was not activated in either muscle type. Neither p38 nor AMPK was affected in heart. However, AMPK activation was decreased by T(3) in liver. ERK1/2 activation was decreased by T(3) in heart, but increased in liver. Possible downstream consequences of T(3)-induced kinase phosphorylation were investigated by measuring cAMP response element binding protein (CREB) and thyroid hormone receptor DNA binding, as well as peroxisome proliferator-activated receptor-alpha coactivator-1 mRNA levels. Protein DNA binding to the cAMP or thyroid hormone response elements was unaltered by T(3). However, peroxisome proliferator-activated receptor-alpha coactivator-1 mRNA expression was increased following 12 h of T(3) treatment in soleus. These data are the first to characterize the effects of T(3) treatment on kinase phosphorylation in vivo. We show that T(3) rapidly modifies kinase activity in a tissue-specific fashion. Moreover, the T(3)-induced phosphorylation of p38 and AMPK in both slow- and fast-twitch skeletal muscles suggests that these events may be important in mediating hormone-induced increases in mitochondrial biogenesis in skeletal muscle.
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PMID:Thyroid hormone (T3) rapidly activates p38 and AMPK in skeletal muscle in vivo. 1796 79


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