Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:2.7.11.1 (protein kinase)
81,284 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Thyroid-stimulating hormone (TSH)-secreting tumors (TSH-omas) are pituitary tumors that constitutively secrete TSH. The molecular genetics underlying this abnormality are not known. We discovered that a knock-in mouse harboring a mutated thyroid hormone receptor (TR) beta (PV; TRbeta(PV/PV) mouse) spontaneously developed TSH-omas. TRbeta(PV/PV) mice lost the negative feedback regulation with highly elevated TSH levels associated with increased thyroid hormone levels (3,3',5-triiodo-l-thyronine [T3]). Remarkably, we found that mice deficient in all TRs (TRalpha1(-/-) TRbeta(-/-)) had similarly increased T3 and TSH levels, but no discernible TSH-omas, indicating that the dysregulation of the pituitary-thyroid axis alone is not sufficient to induce TSH-omas. Comparison of gene expression profiles by cDNA microarrays identified overexpression of cyclin D1 mRNA in TRbeta(PV/PV) but not in TRalpha1(-/-) TRbeta(-/-) mice. Overexpression of cyclin D1 protein led to activation of the cyclin D1/cyclin-dependent kinase/retinoblastoma protein/E2F pathway only in TRbeta(PV/PV) mice. The liganded TRbeta repressed cyclin D1 expression via tethering to the cyclin D1 promoter through binding to the cyclic AMP response element-binding protein. That repression effect was lost in mutant PV, thereby resulting in constitutive activation of cyclin D1 in TRbeta(PV/PV) mice. The present study revealed a novel molecular mechanism by which an unliganded TRbeta mutant acts to contribute to pituitary tumorigenesis in vivo and provided mechanistic insights into the understanding of pathogenesis of TSH-omas in patients.
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PMID:An unliganded thyroid hormone beta receptor activates the cyclin D1/cyclin-dependent kinase/retinoblastoma/E2F pathway and induces pituitary tumorigenesis. 1560 36

Thyroid hormone inhibits neonatal Sertoli cell proliferation and recent results have shown that thyroid hormone upregulates cyclin-dependent kinase inhibitors (CDKIs) p27Kip1 and p21Cip1 (also known as CDKN1B and CDKN1A, respectively) in neonatal Sertoli cells. This suggests that these CDKIs, which negatively regulate the cell cycle, could be critical in Sertoli cell proliferation. Consistent with this hypothesis, mice lacking p27Kip1 develop testicular organomegaly, but Sertoli cell numbers have not been determined. Likewise, effects of loss of p21Cip1 or both p27 and p21 on Sertoli cell number and testicular development were unknown. To determine if p27 and/or p21 regulate Sertoli cell proliferation, we measured Sertoli cell proliferation at Postnatal Day 16 and testis weight, Sertoli cell number, and daily sperm production (DSP) in 4-mo-old wild-type (WT), p21 knockout (p21KO), p27 knockout (p27KO), and p27/p21 double-knockout (DBKO) mice. Testis weights were increased 27%, 42%, and 86% in adult p21KO, p27KO, and DBKO mice, respectively, compared with WT. Sertoli cell number also was increased 48%, 126%, and 126% in p21KO, p27KO, and DBKO mice, respectively, versus WT. DSP in p21KO, p27KO, and DBKO testes also showed significant increases compared with WT mice. Although DSP was increased, there were increased spermatogenic defects observed in both p27KO and DBKO mice compared with WT. These data indicate that both p27 and p21 play an inhibitory role in regulating adult Sertoli cell number such that loss of either CDKI produces primary increases in Sertoli cell number and secondary increases in DSP and testis weight. Furthermore, loss of both CDKIs causes additive effects on DSP and testis weight, suggesting a central role for these CDKIs in testis development.
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PMID:Cell-cycle inhibitors p27Kip1 and p21Cip1 regulate murine Sertoli cell proliferation. 1572 90

Thyroid hormone is known to cause hypertrophy, tachycardia, vasorelaxation, and enhanced contractile function. The exact mechanisms responsible for these effects are unknown but classical regulation of gene expression through binding to nuclear receptors has been widely implicated. Data have also accumulated suggesting that TH can exert effects through non-classical mechanisms involving activation of signal transduction pathways. Whether thyroid hormone can activate signal transduction pathways in the heart is unknown. In this study, we treated neonatal rat cardiomyocytes with T3 and determined the expression and phosphorylation of signaling molecules. T3 caused specific activation of Akt/PKB signaling after 24 h of treatment. Since Akt is known to protect against cell death, cells were serum-starved in the presence or absence of T3 to determine whether T3 could protect against serum starvation-induced cell death. Indeed, myocytes treated with T3 displayed enhanced sarcomeric structure after 4 days of serum starvation. T3 increased cell viability as measured by MTT assays, prevented DNA laddering, and reduced TUNEL positive cells, which was associated with increased phosphorylated Akt and glycogen synthase kinase 3beta (GSK-3beta). The protective effect of T3 on cell viability, DNA laddering and TUNEL positive cells were blocked by LY294002, a phosphoinositide-3 kinase (PI3K) inhibitor that blocks Akt signaling. Overall these data suggest that T3 can activate Akt in cardiomyocytes which protects myocytes against cell death.
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PMID:Thyroid hormone activates Akt and prevents serum starvation-induced cell death in neonatal rat cardiomyocytes. 1617 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

Thyroid hormone receptor alpha2 (TRalpha2) is an alternative splice product of the TRalpha primary transcript whose unique carboxyl terminus does not bind T3 or activate transcription. The physiological function of TRalpha2 is unknown. We have found that TRalpha2 is a single stranded RNA binding protein and that the RNA binding domain localizes to a 41 amino acid region immediately distal to the second zinc finger. TRalpha2 contains a single protein kinase CK2 phosphorylation site in its amino terminus and potentially nine CK2 sites in its unique carboxyl terminus. In vitro CK2 treatment of TRalpha2 eliminated its RNA binding. Mutational analysis indicated that phosphorylations at the N- and C-terminal sites both contribute to this inhibitory effect. Cellular localization studies demonstrated that phosphorylated TRalpha2 is primarily cytoplasmic, whereas unphosphorylated TRalpha2 is primarily nuclear. Since RNA binding is a property of unphosphorylated TRalpha2, the TRalpha2-RNA interaction likely represents a nuclear function of TRalpha2.
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PMID:Regulation of thyroid hormone receptor alpha2 RNA binding and subcellular localization by phosphorylation. 1635 27

: Thyroid hormones play important roles in brain function. However, few information is available about the effect of 3,5,3'-triiodo-L-thyronine (T(3)) or thyroxine (T(4)) on the in vitro phosphorylation of intermediate filament (IF) proteins from cerebral cortex of rats. In this study we investigated the involvement of GABAergic mechanisms mediating the effects of T(3) and T(4) on the in vitro incorporation of (32)P into IF proteins from cerebral cortex of 10-day-old male rats. Tissue slices were incubated with or without T(3), T(4), gamma-aminobutiric acid (GABA), kinase inhibitors or specific GABA antagonists and (32)P-orthophosphate for 30 min. The IF-enriched cytoskeletal fraction was extracted in a high salt Triton-containing buffer and the in vitro (32)P incorporation into IF proteins was measured. We first observed that 1 microM T(3) and 0.1 microM T(4) significantly increased the in vitro incorporation of (32)P into the IF proteins studied through the PKA and PKCaMII activities. A similar effect on IF phosphorylation was achieved by incubating cortical slices with GABA. Furthermore, by using specific GABA antagonists, we verified that T(3) induced a stimulatory effect on IF phosphorylation through noncompetitive mechanisms involving GABA(A), beyond GABA(B) receptors. In contrast, T(4) effects were mediated mainly by GABA(B) mechanisms. In conclusion, our results demonstrate a rapid nongenomic action of T(3) and T(4) on the phosphorylating system associated to the IF proteins in slices of cerebral cortex of 10 day-old male rats and point to GABAergic mechanisms mediating such effects.
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PMID:Short-term effects of thyroid hormones on cytoskeletal proteins are mediated by GABAergic mechanisms in slices of cerebral cortex from young rats. 1676 83

Thyroid hormones (TH) play important roles in brain development. Although most of the nongenomic actions of TH are known to be calcium-dependent, the effects of 3,5,3'-triiodo-L-thyronine (T(3)) or thyroxine (T(4)) on calcium influx in cerebral cortex of rats are not clear. In this study we investigate some mechanisms involved in the effect of T(3) and T(4) on Ca(2+) uptake in slices of cerebral cortex from 10-day-old male rats. Results indicated 10(-6)M T(3) or 10(-7)M T(4) was able to increase (45)Ca(2+) uptake after 30s of hormone exposure. The involvement of L- and T-type voltage-dependent Ca(2+) channels (VDCC) on the effect of TH on (45)Ca(2+) uptake was evidenced by using nifedipine and flunarizine, L- and T-type channel blockers, respectively. Otherwise, chloride currents were not involved in the hormone actions, as demonstrated by using 9-anthracene carboxylic acid, a Cl(-)-channel blocker. In addition, results demonstrated a PKC-dependent mechanism for both T(3) and T(4), as evidenced by stearoylcarnitine chloride, a specific PKC inhibitor. Furthermore, we verified that the T(3) action was also mediated by PKA activity, as demonstrated coincubating T(3) and KT 5720 (PKA inhibitor), and reinforced by using theophylline, a phosphodiesterase inhibitor. In contrast, concerning the effect of T(4), results suggest a partial involvement of PKA activity, and demonstrated that high cAMP levels were not able to support the effect of T(4), suggesting the participation of G inhibitory protein-coupled receptor in the action of this hormone on (45)Ca(2+) uptake. In conclusion, our results evidence a nongenomic action of TH promoting Ca(2+) influx by ionic channels involving mechanisms dependent on kinase activities. It is possible that the modulation of Ca(2+) channels by kinase activities represent an important membrane action of TH signaling mechanism in the central nervous system during development.
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PMID:Ionic involvement and kinase activity on the mechanism of nongenomic action of thyroid hormones on 45Ca2+ uptake in cerebral cortex from young rats. 1706 9

Thyroid stimulating hormone (TSH) is known to increase intracytoplasmic cyclic adenosine monophosphate (cAMP) and to regulate the growth of normal follicular cells. The aim of this study was to explore the role of the cAMP-mediated signaling pathway stimulated by TSH as a cell growth modulator in human thyroid cancer cells. One papillary thyroid cancer cell line, K1 cells and two anaplastic thyroid cancer cell lines, TTA1 and TTA2 cells were treated with forskolin, which directly activates adenyl cyclase to raise the level of intracellular cAMP. Forskolin suppressed thyroid cancer cell proliferations, especially in K1 cells, in a dose-dependent manner and induced growth arrest at the G0/G1 phase of the cell cycle. We also examined the expression of mitogen activated protein kinase (MAPK) after the forskolin treatment. Forskolin reduced the activation of growth factor induced MAPK activity. In conclusion, we demonstrated that forskolin was involved in G1 arrest and MAPK activation in K1 thyroid cancer cells. Our study suggests that the TSH signal mediated by cAMP acts as a negative regulator in thyroid cancer cells, unlike that in normal follicular cells.
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PMID:Growth suppression of thyroid cancer cells by adenylcyclase activator. 1761 68

Thyroid-stimulating hormone (TSH) has long been recognized as the major proliferative and functional stimulus for thyroid follicular cells. TSH receptor (TSHR) engagement stimulates the production of cyclic AMP and the subsequent activation of downstream effector molecules, including protein kinase A, S6K1, and Rap1, whereas the role of the RAS and phosphatidylinositol-3-kinase signaling cascades downstream of TSHR is still controversial. Despite the abundance of candidates, it is still unclear which of these pathways represent(s) the key mitogenic output of TSH-initiated signaling. We have used an in vivo model of goitrogenesis to dissect the contribution of these pathways to TSH-induced thyrocyte proliferation and thyroid hyperplasia. We show that the in vivo proliferative response to chronic TSHR stimulation relies heavily on the activation of the mTOR/S6K1 axis, and that mTOR inhibition during goitrogenic stimulation abrogates the hyperplastic but not the hypertrophic thyrocyte responses to TSH, thus functionally uncoupling these two processes. Strikingly, goitrogenesis was not associated with an increase in AKT phosphorylation levels, underlining the existence of an AKT-independent pathway leading to mTOR activation upon TSH stimulation.
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PMID:Thyroid-stimulating hormone initiated proliferative signals converge in vivo on the mTOR kinase without activating AKT. 1780 10

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


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