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 cancer is the most common malignant tumor of the endocrine system. The most frequent type of thyroid malignancy is papillary carcinoma. These tumors frequently have genetic alterations leading to the activation of the mitogen-activated protein kinase (MAPK) signaling pathway. Most common mutations in papillary carcinomas are point mutations of the BRAF and RAS genes and RET/PTC rearrangement. These genetic alterations are found in >70% of papillary carcinomas and they rarely overlap in the same tumor. Most frequent alterations in follicular carcinomas, the second most common type of thyroid malignancy, include RAS mutations and PAX8-PPARgamma rearrangement. RET point mutations are crucial for the development of medullary thyroid carcinomas. Many of these mutations, particularly those leading to the activation of the MAPK pathway, are being actively explored as therapeutic targets for thyroid cancer. A number of compounds have been studied and showed antitumor effects in preclinical studies and are being tested in ongoing clinical trials.
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PMID:Thyroid carcinoma: molecular pathways and therapeutic targets. 1843 72

RET/PTC rearrangements are one of the genetic hallmarks of papillary thyroid carcinomas. RET/PTC oncoproteins lack extracellular or transmembrane domains, and activation takes place through constitutive dimerization mediated through coiled-coil motifs in the NH(2) terminus of the chimeric protein. Based on the observation that the epidermal growth factor receptor (EGFR) kinase inhibitor PKI166 decreased RET/PTC kinase autophosphorylation and activation of downstream effectors in thyroid cells, despite lacking activity on the purified RET kinase, we proceeded to examine possible functional interactions between RET/PTC and EGFR. Conditional activation of RET/PTC oncoproteins in thyroid PCCL3 cells markedly induced expression and phosphorylation of EGFR, which was mediated in part through mitogen-activated protein kinase signaling. RET and EGFR were found to coimmunoprecipitate. The ability of RET to form a complex with EGFR was not dependent on recruitment of Shc or on their respective kinase activities. Ligand-induced activation of EGFR resulted in phosphorylation of a kinase-dead RET, an effect that was entirely blocked by PKI166. These effects were biologically relevant, as the EGFR kinase inhibitors PKI166, gefitinib, and AEE788 inhibited cell growth induced by various constitutively active mutants of RET in thyroid cancer cells as well as NIH3T3 cells. These data indicate that EGFR contributes to RET kinase activation, signaling, and growth stimulation and may therefore be an attractive therapeutic target in RET-induced neoplasms.
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PMID:RET/PTC-induced cell growth is mediated in part by epidermal growth factor receptor (EGFR) activation: evidence for molecular and functional interactions between RET and EGFR. 1851 77

Phorbol 12-myristate 13-acetate (PMA) is known to affect a variety of cellular processes, including cell proliferation, differentiation, and migration. PMA has been shown to promote antiproliferative and antimigratory effects in many types of cancer cells. Our findings show that PMA induced a strong antiproliferative effect in two anaplastic (FRO and ARO) and one follicular (ML-1) thyroid cancer cell lines, and increased the fraction of FRO cells in G1 phase of the cell cycle. The fractions in the S and G2 phases were decreased. Moreover, PMA evoked a significant increase in the levels of the cell cycle regulators p21Waf1/Cip1 and p27Kip1. The levels of cyclin D3 and the cyclin-dependent kinases cdk4 and cdk6 decreased, as did the phosphorylation of the Rb-protein. PMA did not induce apoptosis. PMA stimulated the translocation of protein kinase C (PKC) alpha, betaI and delta isoforms to the cell membrane. PKCdelta small interfering RNA attenuated the PMA-induced antiproliferative effect and prevented the upregulation of p21Waf1/Cip1 and p27Kip1. Prolonged stimulation with PMA decreased the phosphorylation of mitogen-activated protein (MAP) kinase. PMA also decreased the phosphorylation of Akt and evoked a biphasic change in the phosphorylation of the forkhead box class-O protein (FOXO): an increase in phosphorylation, followed by a dephosphorylation. In addition, PMA inhibited FRO, ARO and ML-1 cell migration toward serum. The inactive phorbol ester analog 4alpha-phorbol and the diacylglycerol analog 1,2-dioctanoyl-sn-glycerol were without an effect on proliferation and migration. The results indicate that PMA is an effective inhibitor of thyroid cancer cell proliferation and migration by a mechanism involving PKC-MAP kinase/Akt and FOXO signaling.
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PMID:Phorbol 12-myristate 13-acetate inhibits FRO anaplastic human thyroid cancer cell proliferation by inducing cell cycle arrest in G1/S phase: evidence for an effect mediated by PKCdelta. 1854 61

The forkhead box transcription factor FOXO3a has recently been identified as central mediator of the cellular response to oxidative stress inducing cell cycle arrest or apoptosis. The aim of our study was to investigate the regulation of FOXO3a in the thyroid and to determine whether alterations in FOXO3a activity occur in thyroid carcinogenesis. In vitro, we demonstrate that FOXO3a activity is negatively regulated by the PI3K/Akt cascade promoting increased phosphorylation and cytoplasmatic accumulation of FOXO3a with decreased transcription of the target genes p27kip (CDKN1B) and Bim (BCL2L11), but increased expression of GADD45A. By contrast, we show that H(2)O(2) exposure activates FOXO3a in thyrocytes with JNK (MAPK8)-mediated nuclear accumulation of FOXO3a and increased expression of the cell cycle arrest genes p27kip and GADD45A. In vivo, we observed a marked cytoplasmatic accumulation of FOXO3a in differentiated thyroid cancers versus an exclusive nuclear accumulation in follicular adenoma and normal thyroid tissue. Moreover, this cytosolic accumulation of FOXO3a correlated with an increased phospho-Akt expression in thyroid malignancies and was accompanied by decreased expression of the FOXO targets p27kip and Bim and an increase in GADD45A mRNA expression in the thyroid cancers. Our data suggest FOXO3a as a novel player of cellular stress response in the thyroid, mediating the thyrocyte's fate either to survive or to undergo apoptosis. Furthermore, PI3K-dependent FOXO3a inactivation may be a novel pathomechanism for the escape from apoptosis in thyroid cancer cells, in particular in follicular thyroid carcinoma.
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PMID:FOXO3a: a novel player in thyroid carcinogenesis? 1884 47

Thyroid cancer is the most common endocrine malignancy. With a rapidly rising incidence in recent years, novel efficient management strategies are increasingly needed for this cancer. Remarkable advances have occurred in understanding several major biologic areas of thyroid cancer, including the molecular alterations for the loss of radioiodine avidity of thyroid cancer, the pathogenic role of the MAP kinase and PI3K/Akt pathways and their related genetic alterations, and the aberrant methylation of functionally important genes in thyroid tumorigenesis and pathogenesis. These exciting advances provide unprecedented opportunities for the development of molecular-based novel diagnostic, prognostic, and therapeutic strategies for thyroid cancer.
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PMID:Recent advances in molecular biology of thyroid cancer and their clinical implications. 1904 Sep 74

Constitutive activation of MAPK in cancer occurs through activating mutations or overexpression of upstream effectors in the pathway, primarily of genes encoding receptor tyrosine kinases, RAS and BRAF. Arguably, the evidence for MAPK activation is most compelling in thyroid cancers and in melanomas. In this review we discuss the mechanisms of tumor development by oncogenic BRAF in these two cancer cell lineages, since this kinase signals preferentially through this pathway. We describe recent information on the mediators of BRAF-induced tumor initiation and escape from senescence. In addition, we review the biochemical events implicated in cellular growth triggered by oncogenic BRAF and the determinants of oncogene addiction. The biology of thyroid cancers induced by oncogenic BRAF is quite distinct, both in humans and in mice. There is great interest in using these insights to design rational new therapies, for which it will become crucial to understand the determinants of sensitivity and resistance to compounds designed to block the pathway. In thyroid cancer, this interest is further heightened by new information on the role of activated BRAF and MAPK pathway activation in disrupting iodine transport and thyroid hormonogenesis.
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PMID:Role of MAPK pathway oncoproteins in thyroid cancer pathogenesis and as drug targets. 1923 Nov 49

Thyroid tumors arising from the follicular cells often harbor mutations leading to the constitutive activation of the PI3K and Ras signaling cascades. However, it is still unclear what their respective contribution to the neoplastic process is, as well as to what extent they interact. We have used mice harboring a Kras oncogenic mutation and a Pten deletion targeted to the thyroid epithelium to address in vivo these questions. Here, we show that although each of these two pathways, alone, is unable to transform thyroid follicular cells, their simultaneous activation is highly oncogenic, leading to invasive and metastatic follicular carcinomas. In particular, phosphatidylinositol-3-kinase (PI3K) activation suppressed Kras-initiated feedback signals that uncouple mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK) kinase (MEK) and ERK activation, thus stunting MAPK activity; in addition, PI3K and Kras cooperated to drastically up-regulate cyclin D1 mRNA levels. Finally, combined pharmacologic inhibition of PI3K and MAPK completely inhibited the growth of double-mutant cancer cell lines, providing a compelling rationale for the dual targeting of these pathways in thyroid cancer.
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PMID:Oncogenic Kras requires simultaneous PI3K signaling to induce ERK activation and transform thyroid epithelial cells in vivo. 1935 16

Mitogen-activated protein kinase (MAPK) signaling pathway plays an important role in the pathogenesis of melanoma, colon cancer and thyroid cancer, which commonly harbor RAS and BRAF mutations. However, mutations in exon 2 of MEK1 and exon 7 of ERK2 have not been investigated in these cancers although they are occasionally found in some other cancers or cell lines. In this study, we performed mutational analysis to search for these mutations in 185 samples, including 167 tumor samples and 18 cell lines of melanoma, colon cancer and thyroid cancer. We found one MEK1 mutation in 1 of 37 (3%) melanoma tumor samples and another MEK1 mutation in 1 of 45 (2.2%) colon cancer samples. We did not find any MEK1 mutation in 99 thyroid tumor samples and 12 thyroid cancer cell lines. We also did not find any ERK2 mutation in melanoma, colon cancer and thyroid cancer. We thus report for the first time a low prevalence of MEK1 mutations in melanoma and colon cancer. Both of the two mutants have been demonstrated to be activating in the MAPK signaling pathway and may therefore provide potential target for effective therapy in cases of melanomas and colon cancer harboring these mutations.
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PMID:MEK1 mutations, but not ERK2 mutations, occur in melanomas and colon carcinomas, but none in thyroid carcinomas. 1941 38

The activating mutation BRAF(V600E) is a frequent genetic event in papillary thyroid carcinomas (PTC) that predicts a poor prognosis, leading to loss of sodium/iodide symporter (NIS) expression and subsequent radioiodide-refractory metastatic disease. The molecular basis of such an aggressive behavior induced by BRAF remains unclear. Here, we show a mechanism through which BRAF induces NIS repression and promotes epithelial to mesenchimal transition and invasion based on the operation of an autocrine transforming growth factor (TGF)beta loop. BRAF induces secretion of functional TGFbeta and blocking TGFbeta/Smad signaling at multiple levels rescues BRAF-induced NIS repression. Although this mechanism is MAP/extracellular signal-regulated kinase (ERK) kinase (MEK)-ERK independent, secreted TGFbeta cooperates with MEK-ERK signaling in BRAF-induced cell migration, Matrigel invasion, and EMT. Consistent with this process, TGFbeta and other key components of TGFbeta signaling, such as TbetaRII and pSmad2, are overexpressed in human PTC, suggesting a widespread activation of this pathway by locally released TGFbeta. Moreover, this high TGFbeta/Smad activity is associated with PTC invasion, nodal metastasis, and BRAF status. Interestingly, TGFbeta is overexpressed in the invasive front, whereas NIS is preferentially expressed in the central regions of the tumors, suggesting that this negative correlation between TGFbeta and NIS occurs locally inside the tumor. Our study describes a novel mechanism of NIS repression in thyroid cancer and provides evidence that TGFbeta may play a key role in promoting radioiodide resistance and tumor invasion during PTC progression.
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PMID:The BRAFV600E oncogene induces transforming growth factor beta secretion leading to sodium iodide symporter repression and increased malignancy in thyroid cancer. 1986 38

Differentiated thyroid carcinoma is the most frequent neoplasm of the endocrine system. Although thyroid cancer usually has an excellent prognosis, no therapeutic options are available for patients that develop metastases and are or became resistant to radioiodine therapy. The deeper knowledge of molecular aberrations that characterize tumor growth has provided novel targets in cancer therapy. Several proteins have been implicated as having a crucial role in the carcinogenesis of differentiated thyroid cancer, such as those involved in RET/PTC-RAS-RAF-MAPK pathway. Moreover, vascular aberrations and angiogenesis equilibrium have also been related to tumor growth. The development of new, targeted therapies and their encouraging initial results have opened a hopeful opportunity of treatment for these orphan therapy tumor patients.
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PMID:Targeted therapies in thyroid cancer. 1990


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