Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.11.1 (protein kinase)
 81,284 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A 31 years old man with an adrenocortical carcinoma was studied. Clinically he had a bilateral and recidiving gynecomastia and showed high urinary oestrogens, 17 cetosteroids, tetra-hydro-desoxy-cortisol and pregnandiol excretion with normal cortisol production. A partial increase on ACTH, no suppression on dexamethasone and no variation on HCG administration were observed. The surgical resection of the tumor normalized this urinary excretion. The serum dehydro-epiandrosterone (DHEA) and sulfate (DHEAS), oestrone, oestradiol, androstenedione (A) levels were greatly elevated. No variations of the cortisol, A, DHEA and DHEAS was noted after ACTH injection. In vitro the lack of ACTH's action was related to an anomaly of ACTH receptor with normal protein kinase activity.
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PMID:[A feminizing adrenal carcinoma in man: in vivo and in vitro study (author's transl)]. 23 37

Plasmids that encode a bioactive amino-terminal fragment of the heat-stable inhibitor of the cAMP-dependent protein kinase, PKI(1-31), were employed to characterize the role of this protein kinase in the control of transcriptional activity mediated by three DNA regulatory elements in the JEG-3 human placental cell line. The 5'-flanking sequence of the human collagenase gene contains the heptameric sequence, 5'-TGAGTCA-3', previously identified as a "phorbol ester" response element. Reporter genes containing either the intact 1.2-kilobase 5'-flanking sequence from the human collagenase gene or just the 7-base pair (bp) response element, when coupled to an enhancerless promoter, each exhibit both cAMP and phorbol ester-stimulated expression in JEG-3 cells. Cotransfection of either construct with plasmids encoding PKI(1-31) inhibits cAMP-stimulated but not basal- or phorbol ester-stimulated expression. Pretreatment of cells with phorbol ester for 1 or 2 days abrogates completely the response to rechallenge with phorbol ester but does not alter the basal expression of either construct; cAMP-stimulated expression, while modestly inhibited, remains vigorous. The 5'-flanking sequence of the human chorionic gonadotropin-alpha subunit (HCG alpha) gene has two copies of the sequence, 5'-TGACGTCA-3', contained in directly adjacent identical 18-bp segments, previously identified as a cAMP-response element. Reporter genes containing either the intact 1.5 kilobase of 5'-flanking sequence from the HCG alpha gene, or just the 36-bp tandem repeat cAMP response element, when coupled to an enhancerless promoter, both exhibit a vigorous cAMP stimulation of expression but no response to phorbol ester in JEG-3 cells. Cotransfection with plasmids encoding PKI(1-31) inhibits both basal and cAMP-stimulated expression in a parallel fashion. The 5'-flanking sequence of the human enkephalin gene mediates cAMP-stimulated expression of reporter genes in both JEG-3 and CV-1 cells. Plasmids encoding PKI(1-31) inhibit the expression that is stimulated by the addition of cAMP analogs in both cell lines; basal expression, however, is inhibited by PKI(1-31) only in the JEG-3 cell line and not in the CV-1 cells. These observations indicate that, in JEG-3 cells, PKI(1-31) is a specific inhibitor of kinase A-mediated gene transcription, but it does not modify kinase C-directed transcription.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Plasmids encoding PKI(1-31), a specific inhibitor of cAMP-stimulated gene expression, inhibit the basal transcriptional activity of some but not all cAMP-regulated DNA response elements in JEG-3 cells. 247 35

Mechanisms of triiodothyronine (T3) negative regulation of the human thyrotropin-releasing hormone (TRH) gene were investigated with a chimeric construct of the 5' flanking region fused to a luciferase reporter gene, transfected into human neuroblastoma cells (HTB-11). Maximum negative regulation was achieved with constructs containing bases -242 to +54. Four sequences in this region exhibited homology with half sites of thyroid hormone response elements (TRE) (AGGTCA). The most important site was a sequence with an overlapping TRE/CRE, involving bases -53 to -60 (TGACCTCA). Potential combinatorial interactions of thyroid hormone receptors and CREB at this site were explored. Modest promoter stimulation was achieved with dibutyryl cyclic adenosine monophosphate (cAMP) (10(-3) M) plus IBMX (0.5 mM). Stimulation was greatly enhanced (+820%) by cotransfection of a constitutively activated protein kinase A (pPKA) construct. Cotransfection with pCREB increased stimulation further to 1350% above control. Stimulation of pPKA and pCREB interfered with stimulation by unliganded TRbeta1, and co-transfected pPKA and pCREB blocked T3 negative inhibition by TRbeta1-T3 complexes. When this site was mutated by polymerase chain reaction (PCR) mutagenesis, the mutant construct failed to respond to unliganded TRbeta1, and stimulation by pPKA and/or pCREB was inhibited markedly, from 12.5- to 2.1-fold, p < 0.001. Moreover, TRbeta1-T3 complexes failed to show any inhibition of the mutated promoter. These results suggest that negative regulation is achieved by inhibition of CREB stimulation of the TRH promoter at this overlapping TRE/CRE site. The two cosuppressors, NCoR and SMRT, were able to augment stimulation of the TRH promoter by unliganded TRbeta1 and enhance the magnitude of T3 inhibition. The potential role of the TRH gene and the pathophysiology of thyroid hormone resistance was investigated with three mutant TRbeta1 constructs. Thyroid hormone resistance was found to be expressed at the level of TRH gene regulation, due to lowered inhibition by mutant TRbeta1-T3 complexes and by their dominant negative effects on wild-type TRbeta1-T3 inhibition. TRH gene expression has been identified in the heart. Cardiac TRH mRNA was not regulated by T3, in contrast to HTB-11 cells, but cardiac TRH mRNA density could be augmented by glucocorticoids and by testosterone. TRH receptors were identified using Scatchard blots that showed a kilodalton of 1.4 nM and a bmax of 10 pmol/mg protein. TRH-R mRNA was identified also by reverse transcription polymerase chain reaction (RT-PCR). Enhanced ventricular contractility by TRH was demonstrated in both an open-chested dog preparation and in ex vivo ventricular myocytes, using video edge cinematography. Under controlled conditions, myocyte shortening was 13.3%, and TRH (10(-6) M) caused muscle shortening to increase 140%, (p < 0.005). TRH gene expression was demonstrated exclusively in Leydig cells of the testis. High affinity binding sites were identified in testicular membranes with a kilodalton of 1.6 x 10(-6) M. TRH was able to inhibit LH and HCG-activated testosterone secretion significantly. Thus, one paracrine role of TRH in the testis may be to serve as inhibitory modulator of gonadotropin-stimulated testosterone secretion.
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PMID:The thyrotropin-releasing hormone gene 1998: cloning, characterization, and transcriptional regulation in the central nervous system, heart, and testis. 982 56

Vascular endothelial growth factor (VEGF)-dependent angiogenesis is essential for normal luteal development. Although it is believed that hypoxia is the primary inducer of VEGF, in the corpus luteum it is up-regulated by human chorionic gonadotrophin (hCG). As hypoxia-inducible factor (HIF)1A has been shown to regulate VEGFA under ligand-stimulated conditions, we hypothesized that the effect of hCG on luteal VEGFA was mediated through HIF1A. We studied the effect of hCG on VEGFA and HIF1A expression in human luteinized granulosa cells in vitro and in human corpora lutea in vivo. HCG up-regulated VEGFA (P < 0.05) and HIF1A (P < 0.001) in vitro and VEGFA (P < 0.05) and HIF1A (P < 0.05) in vivo. There was a correlation between HIF1A and VEGFA in vivo (P < 0.005) and in vitro (P < 0.05). Nuclear HIF1A in granulosa-lutein cells was highest during luteal formation and absent from the fully functional corpus luteum (P < 0.05). Both VEGFA (P < 0.001) and HIF1A (P < 0.01) were up-regulated by dibutyryl-cAMP, through a PKA pathway. Hypoxia increased VEGFA (P < 0.001) and HIF1A (P < 0.05) expression and hCG further augmented VEGFA (P < 0.001) and HIF1A (P < 0.01) under hypoxic conditions. However, progesterone increased hCG-stimulated VEGFA but had no effect on HIF1A expression. The expression of HIF1A is therefore hormonally regulated in luteal cells in vitro and in vivo and may regulate VEGFA expression under normoxic and hypoxic conditions. However, the differential effects of progesterone suggest that not all regulation of VEGFA is associated with an up-regulation of HIF1A.
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PMID:HCG up-regulates hypoxia inducible factor-1 alpha in luteinized granulosa cells: implications for the hormonal regulation of vascular endothelial growth factor A in the human corpus luteum. 1859 Dec 13

Proliferin-related protein (PRP) was originally identified as an angiogenesis inhibitor in mouse placentas. Indeed, the tissue expression of PRP has mainly been documented in placentas. We report herein for the first time that PRP is expressed in male rat testes. Immunocytochemical and in situ hybridization results showed positive PRP immunostaining in Leydig cells. Immunofluorescent staining of PRP in the TM3 Leydig cell line indicates that PRP is located within the cytoplasm. The expression pattern of PRP in rat testis exhibited an age-related increase. HCG significantly up-regulated the level of expression of PRP in TM3 cells via the PKA pathway. To elucidate the function of PRP, experiments were conducted to examine the consequences of lentiviral-mediated RNA interference (RNAi) of PRP on testosterone production and expression of several genes involved in steroidogenesis. PRP silencing caused a decrease in HCG-stimulated testosterone production. In addition, PRP silencing attenuated the increase in PRLR mRNA following HCG stimulation. Moreover, the enhanced effect of PRL on HCG-induced testosterone production was also weakened following PRP silencing, indicating that PRP may be involved in PRL function through an effect on PRL receptor expression in response to stimuli. Taken together, these data suggest that PRP is regulated by HCG and plays roles in male reproduction, such as testosterone production.
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PMID:Expression of proliferin-related protein in testis and the biological significance in testosterone production. 2167 48

LH/human chorionic gonadotropin receptor (LHR) undergoes down-regulation during preovulatory LH surge or in response to exposure to a supraphysiological concentration of its ligands through a posttranscriptional mechanism involving an RNA binding protein designated as LHR mRNA binding protein (LRBP). miR-122, a short noncoding RNA, has been shown to mediate the up-regulation of LRBP. In the present study, we show that inhibition of miR-122 using a locked nucleic acid (LNA)-conjugated antagomir suppressed human chorionic gonadotropin (hCG)-induced up-regulation of LRBP as well as its association with LHR mRNA, as analyzed by RNA EMSA. Most importantly, inhibition of miR-122 resulted in the abolishment of hCG-mediated LHR mRNA down-regulation. We also show that the transcription factor, sterol regulatory element binding protein (SREBP) (SREBP-1a and SREBP-2 isoforms), is an intermediate in miR-122-mediated LHR mRNA regulation. HCG-stimulated increase in the activation of both SREBP-1a and SREBP-2 was inhibited by pretreatment with the miR-122 antagomir. The inhibition of cAMP/protein kinase A (PKA) and ERK pathways, upstream activators of miR-122, abolished SREBP activation after hCG treatment. SREBP-mediated regulation of LRBP expression is mediated by recruitment of LRBP promoter element to SREBP-1a, because chromatin immunoprecipitation assay revealed that association of LRBP promoter to SREBP was increased by hCG treatment. Pretreatment with miR-122 antagomir suppressed this response. Inhibition of SREBP activation by pretreating the rats with a chemical compound, fatostatin abrogated hCG-induced up-regulation of LRBP mRNA and protein. Fatostatin also inhibited LHR-LRBP mRNA-protein complex formation and LHR down-regulation. These results conclusively show that miR-122 plays a regulatory role in LH/hCG-induced LHR mRNA down-regulation by increasing LRBP expression through the activation of SREBP pathway.
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PMID:miR-122 Regulates LH Receptor Expression by Activating Sterol Response Element Binding Protein in Rat Ovaries. 2612 64

In humans, data on gonadotrophin-activated (LH, HCG and FSH) progesterone receptor expression and signalling pathways involved in matrix metalloproteinases (MMPs) expression presumably linked to the follicle rupture, are limited. Our hypothesis is LH, HCG and FSH increase progesterone receptor expression in granulosa cells through different signalling pathways, leading to an increased expression of ADAMTS-1 and MMP3/10, which may mediate follicular rupture through the transcription factor, HIF1A. Human granulosa cells were isolated from follicular aspirates obtained from 22 healthy women participating in our IVF programme for male-factor infertility. Progesterone receptor and HIF1A expression was assessed by immunofluorescence, and PKA-PKC-PI3K- ERK1/2, ADAMTS-1 and MMP3/10 expression by Western blot in pre-ovulatory and in cultured granulosa cells. Results show that HCG, LH and FSH regulate progesterone receptor expression and activate PKA, PKC, PI3K and ERK1/2 signalling pathways in granulosa cells but progesterone receptor expression is only mediated by PKA, PKC and ERK pathways. HCG, FSH and LH regulated MMPs expression through progesterone receptors. Moreover, HCG-progesterone-receptor-dependent HIF1A expression stimulated MMP3/10 expression but not that of ADAMTS-1. These results suggest differential downstream progesterone receptor signalling, as progesterone receptor regulates MMP3/10 expression via HIF1A, which is not involved in ADAMTS-1 expression.
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PMID:In-vitro study of gonadotrophin signaling pathways in human granulosa cells in relation to progesterone receptor expression. 2873 53