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)

Prolactin induces milk protein gene expression in rabbit primary mammary cells without any concomitant cell multiplication. Prolactin or other lactogenic hormones is the major inducer of cell division in the rat lymphoid Nb2 cells. In Nb2 cells, prolactin also rapidly induces the expression of the c-myc gene, and beta-actin and stathmin gene expression is induced more slowly. The possible involvement of casein kinase II (CKII), mitogen-activated protein kinase (MAPK) and protein kinase C (PKC) in these process is not well known. The present work was undertaken to evaluate the effect of prolactin on these protein kinases and to determine the possible involvement of these enzymes in the activity of several genes under the control of the hormone. In rabbit mammary cells, prolactin did not alter CKII activity but did transiently stimulate MAP kinase activity. Prolactin also stimulated Ca(2+)-independent PKC. This effect was visible after 10 min and was maintained for at least 24 hr. Staurosporine, an inhibitor of PKC and of several tyrosine kinases altered Ca(2+)-independent PKC only moderately. In contrast, GF 109203X, a potent and specific inhibitor of PKC, abrogated almost all PKC activity. Staurosporine, but not GF 109203X, prevented the induction of the casein gene by prolactin. In Nb2 cells, prolactin induced a slow stimulation of CKII activity. The hormone did not induce MAP kinase activity. Prolactin stimulated Ca(2+)-independent PKC over periods of 24 hr. GF 109203X, but not staurosporine, inhibited PKC activity, whereas staurosporine but not GF 109203X, inhibited the induction of Nb2 cell multiplication and the accumulation of c-myc, beta-actin and stathmin mRNAs. From these data, it can be concluded that (1) the stimulation of CKII by prolactin in Nb2 cells is concomitant with cell multiplication: (2) MAPK stimulation is not necessary for prolactin to induce Nb2 cell multiplication; and (3) PKC is stimulated in mammary and Nb2 cells, but this stimulation is not required for prolactin to stimulate casein, c-myc, beta-actin and stathmin gene expression and Nb2 cell division.
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PMID:The effect of prolactin on casein kinase II, MAP kinase and PKC in rabbit mammary cells and Nb2 rat lymphoid cells. 898 34

The present study deals with the effects of withdrawal of dopamine (DA) on the translocation of protein kinase C (PKC) isozymes and release of prolactin (Prl) in resting- and substance P (SP)-stimulated cultures of enriched rat pituitary lactotrophs. Following a brief tonic input (10 min), DA withdrawal induced a redistribution of PKC alpha- and beta-immunoreactivity (IR) to the particulate fraction with maximal levels, attained after 5 min, remaining translocated for 20 min. DA withdrawal prolonged the effect of SP-induced translocation of PKC alpha- and beta-IR. Similar effects were detected when the catalytic activity of PKC in response to DA withdrawal was evaluated. Thus, DA washout redistributed PKC catalytic activity and prolonged the effect of SP on catalytical PKC translocation to the particulate fraction. Pretreatment of cells with the protein kinase A inhibitor, rp-adenosine-3',5'-cyclic monophosphothionate (rp-cAMP), reduced the amount of PKC alpha- and beta-IR redistributed after DA withdrawal. Furthermore, this treatment also reduced the DA withdrawal effect on SP-mediated translocation of PKC alpha- and beta-IR. Methoxyverapamil, a blocker of voltage-gated Ca2+ channels, completely inhibited the redistribution of PKC isozymes after DA withdrawal, but also reduced the potentiating effect of DA withdrawal on SP-induced redistribution of PKC isozyme-IR. In perifused enriched lactotrophs, DA withdrawal induced a release of Prl that lasted 45-55 min and prolonged the effect of SP on Prl secretion. rp-cAMP did not significantly affect Prl release due to DA removal, but the prolonging effect of DA withdrawal on SP-induced Prl secretion was abolished. Methoxyverapamil completely abolished the rebound release of Prl after DA withdrawal, and the potentiating effect of DA removal on SP-mediated Prl release was also diminished. Readdition of DA after DA withdrawal was able to suppress the translocation of PKC isozyme-IR and catalytic activity and to reduce the release of Prl to baseline levels. Moreover, readdition of DA reduced the potentiating effects of DA withdrawal on the same parameters after SP-stimulation of cells. On the basis of these results it is concluded that in resting cells following DA withdrawal prolactin is released and specific PKC isozymes and concomitant catalytic activity are translocated to the particulate fraction in enriched lactotrophs. While cAMP/PKA and influx of Ca2+ seem to work in concert in translocating PKC, influx of Ca2+ is the primary mechanism responsible for the rebound release of Prl after DA withdrawal. DA withdrawal exerts a potentiating effect on SP-induced PKC translocation and Prl release. It is suggested that the biochemical events involved in these processes are cAMP/PKA and Ca2+ influx.
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PMID:Effects of withdrawal of dopamine on translocation of protein kinase C isozymes and prolactin secretion in rat lactotroph-enriched pituitary cells. Modulation of substance P-mediated responses. 919 72

The inhibitory actions of prolactin on gonadal steroidogenesis have been reported in different species and under a variety of experimental approaches. In this study, the mechanisms of the in-vitro effects of human prolactin (hPRL) on human follicle stimulating hormone (hFSH)-induced aromatase activity were determined using cultured granulosa cells from diethylstilboestrol (DES)-primed immature rats. Human PRL caused a dose-dependent decrease in hFSH-induced 17 beta-oestradiol production, even when cells were cultured in the presence of a cAMP analogue (8-Br-cAMP). These effects of hPRL appeared to be specific, since addition of an anti-rat PRL receptor monoclonal antibody (mAb) mimicked the hPRL inhibitory effect upon steroidogenesis in rat granulosa cells. In order to assess the importance of tyrosine kinase and protein kinase-C activation in the hPRL inhibitory effects upon oestrogen biosynthesis, cells were cultured in the presence of kinase inhibitors. The results showed that addition of genistein or staurosporine (a tyrosine kinase and protein kinase-C antagonist respectively) to cultured granulosa cells resulted in potent inhibition of hPRL actions upon hFSH-induced aromatization in a dose-dependent manner. These observations suggest that tyrosine kinase and protein kinase-C activation are involved in the biochemical events leading to hPRL inhibitory effects at the gonadal level.
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PMID:The prolactin inhibition of follicle-stimulating hormone-induced aromatase activity in cultured rat granulosa cells is in part tyrosine kinase and protein kinase-C dependent. 923 89

p27Kip1 is a member of the family of cyclin-dependent kinase inhibitors (CKIs), which play critical roles in the regulation of cell cycle. To study the transcriptional regulation that controls the expression of p27, we have isolated the p27 promoter, defined its transcription initiation site, and performed various analyses for sequences upstream to 3 kb. Transient transfection assays using fusion reporters containing progressively truncated p27 promoter fragments showed that a region of 170 bp upstream of the start site is sufficient for maximal transcription activity. Detailed sequence analysis of this 170 bp region identified several GC-rich segments, putative sites of the transcription factor Sp1. Footprinting experiments revealed two Sp1-protected boxes, named BoxI and BoxII, which are located at positions -133 to -117 and -87 to -72, respectively. Binding of Sp1 to the two boxes was further demonstrated by gel mobility shift assays and supershift assays. Co-transfection studies in Drosophila Schneider line 2 cells showed that Sp1 indeed activates the p27 promoter constructs that harbor one or both of the GC-rich sequences. Furthermore, the GC-rich sequences could confer Sp1-dependent transactivation to a heterologous prolactin minimal promoter. Mutations in the GC-rich sequences abolished both binding and transactivation by Sp1. Taken together, our data strongly show that the p27 promoter is activated by the ubiquitously expressed transcription factor Sp1, which may provide a molecular mechanism for the constitutive nature of p27 transcription.
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PMID:Molecular characterization of the cyclin-dependent kinase inhibitor p27 promoter. 934 26

Progesterone is a key factor in regulating endometrial cell decidualization, but the signal transduction pathways involved in mediating the effects of progesterone are not known. A role of the cAMP pathway in decidualization has been suggested by in vitro studies demonstrating that cAMP agonists can stimulate decidualization, in the absence of sex steroids. In this article, we have used an in vitro culture model of progesterone-dependent decidualization of human endometrial stromal cells to examine whether progesterone-induced decidualization is associated with activation of the cAMP signal transduction pathway in which the prolactin gene expression is a marker of decidualization. Following a lag period of approx 3 d, progesterone induced prolactin secretion and elevated intracellular cAMP levels. By d 15, cAMP and prolactin levels were approx 10- and 60-fold greater, respectively, than those on d 3. Changes in cAMP levels showed a positive correlation with prolactin secretion. Prostaglandin E2 (PGE2), which enhances progesterone-dependent decidualization, also increased both prolactin secretion and cAMP levels approx two- to fourfold on d 15 compared with d 3, whereas PGE2 alone, which does not induce decidualization, did not stimulate prolactin secretion or intracellular cAMP accumulation. Conversely, all-trans retinoic acid, which attenuates progesterone-dependent decidualization, significantly (p < 0.05) decreased both prolactin secretion and cAMP levels. Furthermore, the protein kinase A (PKA) inhibitor, 8-bromoadenosine-3',5'-cyclic monophosphorothioate, significantly (p < 0.05) suppressed progesterone-dependent prolactin expression. Since activation of the PGE2 receptor subtype EP2 stimulates adenylate cyclase, reverse transcription-polymerase chain reaction (RT-PCR) analysis of endometrial cells was undertaken. Expression of EP2 mRNA was induced in cells treated with progesterone and estradiol alone or with PGE2, compared with untreated controls. The data suggest that the cAMP signal transduction cascade is activated during progesterone-dependent decidualization.
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PMID:Progesterone-dependent decidualization of the human endometrium is mediated by cAMP. 936 87

Fibroblast growth factors (FGFs) have been implicated in pituitary lactotroph tumorigenesis; however, little is known about the molecular mechanisms of FGF signal transduction. We used a transient transfection approach, in GH4 cells, to identify components of the FGF signaling pathway leading to activation of the rat prolactin (rPRL) promoter. Using dominant-negative constructs of p21(Ras), Raf-1 kinase, and mitogen-activated protein (MAP) kinase, we show that FGF activation of the rPRL promoter is independent of Ras and Raf-1 but requires MAP kinase. Furthermore, MAP kinase but not Raf-1 kinase catalytic activity is stimulated by FGFs. The rPRL promoter FGF response maps to two Ets binding sites, centered at -212 (FRE1) and -96 (FRE2), and co-transfection of dominant-negative Ets inhibits FGF activation. FRE1 co-localizes with a composite, Ets/GHF-1, Ras response element. However, overexpression of Ets-1 and GHF-1, which potentiate the Ras response, inhibits FGF stimulation of the rPRL promoter, implying that Ras and FGF signaling pathways target distinct factors to elicit their effects. These data suggest that Ets factors serve to sort and integrate MAP kinase-dependent growth factor signals, allowing highly specific transcriptional responses to be mediated via the interaction of distinct Ets proteins and cofactors at common response elements.
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PMID:Functional components of fibroblast growth factor (FGF) signal transduction in pituitary cells. Identification of FGF response elements in the prolactin gene. 938 30

We previously reported that a single intraperitoneal injection of prolactin (PRL) in female adult rats rapidly and transiently activates mitogen-activated protein kinase (MAPK) in the liver (Piccoletti et al., (1994) Biochem. J. 303, 429-423). Here we analysed the PRL signalling pathway that accounts for MAPK activation. We found that total liver MAPK kinase-1 phosphorylating activity and Raf-1 activity significantly increase after PRL treatment, following a time course that accounts for the activation of MAPK. We also identified a significant increase in the phosphotyrosine content of the 52 kDa Shc protein, accompanied by an increase in Shc coimmunoprecipitated Grb2, which suggests the Ras involvement by PRL. We found that Janus kinase (JAK)2 tyrosine kinase, which appears constitutively associated with the PRL receptor expressed in the liver, is activated and associated with Shc proteins after in vivo PRL treatment. Taken together our data provide evidence that in vivo PRL activates the Shc Ras Raf MAPK cascade in the liver by the involvement of JAK2 and suggests the possibility that the liver short form of PRL receptor plays a role in triggering this signalling pathway.
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PMID:Signal transduction pathway of prolactin in rat liver. 948 13

In the adenohypophysis, thyrotrophin-releasing hormone (TRH) is inactivated by pyroglutamyl peptidase II (PPII), a TRH-specific ectoenzyme localized in lactotrophs. TRH slowly downregulates surface PPII activity in adenohypophyseal cell cultures. Protein kinase C (PKC) activation mimics this effect. We tested the hypothesis that other hypothalamic factors controlling prolactin secretion could also regulate PPII activity in adenohypophyseal cell cultures. Incubation for 16 h with pituitary adenylate cyclase activator peptide 38 (PACAP; 10(-6) M) decreased PPII activity. Bromocryptine (10(-8) M), a D2 dopamine receptor agonist, or somatostatin (10(-6) M) stimulated enzyme activity and blocked the inhibitory effect of [3-Me-His2]-TRH, a TRH receptor agonist. Bromocryptine and somatostatin actions were suppressed by preincubation with pertussis toxin (400 ng ml(-1)). Because these hypophysiotropic factors transduce some of their effects using the cAMP pathway, we analysed its role on PPII regulation. Cholera toxin (400 ng ml(-1)) inhibited PPII activity. Forskolin (10(-6) M) caused a time-dependent decrease in PPII activity, with maximal inhibition at 12-16 h treatment; ED50 was 10(-7) M. 3-isobutyl-1-methylxanthine or dibutiryl cAMP, caused a dose-dependent inhibition of PPII activity. These data suggest that increased cAMP down-regulates PPII activity. The effect of PACAP was blocked by preincubation with H89 (10(-6) M), a protein kinase A inhibitor, suggesting that the cAMP pathway mediates some of the effects of PACAP. Maximal effects of forskolin and 12-O-tetradecanoylphorbol 13-acetate were additive. PPII activity, therefore, is independently regulated by the cAMP and PKC pathways. Because most treatments inhibited PPII mRNA levels similarly to PPII activity, an important level of control of PPII activity by these factors may be at the mRNA level. We suggest that PPII is subject to 'homologous' and 'heterologous' regulation by elements of the multifactorial system that controls prolactin secretion.
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PMID:Multiple hypothalamic factors regulate pyroglutamyl peptidase II in cultures of adenohypophyseal cells: role of the cAMP pathway. 957 8

We have previously shown that 10-12 kDa N-terminal fragments of rat proopiomelanocortin (POMC) and human POMC1-76 stimulate mitosis and/or differentiation in lactotrophs of early postnatal rat pituitary. A truncated form, POMC1-26, mimics the differentiation-inducing but not the mitogenic action of the former peptides. To further characterize these two biological responses, the present study compared changes in the intracellular free calcium concentration ([Ca2+]i) in response to POMC1-76 and POMC1-26 in isolated pituitary cells from 14-day-old female rats. Calcium (Ca2+) responses were also used as a guide to determine whether the responsive cells belong to the lactosomatotroph lineage. Application of POMC1-76 or POMC1-26 induced a maintained oscillating [Ca2+]i increase in a small population of cells. Increasing doses of the peptides did not affect the magnitude and the frequency of [Ca2+]i oscillations but clearly augmented the number of responding cells. Approximately 2% of the cells responded at 0.1 nM POMC1-76 or 5 nM POMC1-26, and 11-13% of the cells responded at 10 nM and 500 nM of the respective peptides. About one-third of the cells responsive to these peptides also showed a [Ca2+]i increase in response to growth hormone-releasing peptide-6 (GHRP-6) while, in a small number of responsive cells, [Ca2+]i was depressed by dopamine, suggesting that the former cells are somatotrophs and the latter lactotrophs. This interpretation was confirmed by immunocytochemical identification of prolactin and growth hormone (GH) in the cells. Of the cells showing Ca2+ response to POMC1-76, approximately one-third contained GH and another third prolactin. The remainder contained neither GH nor prolactin. Comparable results were obtained with POMC1-26. The rise of [Ca2+]i induced by the N-terminal POMC peptides persisted after depletion of intracellular Ca2+ stores by thapsigargin. Removal of Ca2+ from the extracellular medium or addition of cadmium completely abolished both the POMC1-76- and POMC1-26-induced [Ca2+]i increase. Nifedipine inhibited the Ca2+ response to both peptides, although only in 55% of the responsive cells. Depletion of some isoforms of protein kinase C by preincubation with the phorbol ester PMA for 24 h did not modify the Ca2+ responses. In contrast, blockade of the protein kinase A pathway with Rp-cAMPs partially inhibited the POMC1-76- or POMC1-26-induced [Ca2+]i increase. The present data show that, in immature pituitary cells, POMC1-76 induces an increase in [Ca2+]i through extracellular Ca2+ influx, possibly mediated in part by protein kinase A activation. The active domain of POMC1-76 seems to comprise its N-terminal moiety. The data support the hypothesis that POMC1-76 exerts a specific function in the development of different members of the lactosomatotroph lineage and that the peptide mobilizes different subsets of cells within this lineage, by a mechanism determined by its concentration.
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PMID:Stimulation of Ca2+ entry in lactotrophs and somatotrophs from immature rat pituitary by N-terminal fragments of proopiomelanocortin. 957 10

The process of decidualization involves the morphological and functional transformation of stromal fibroblasts to decidual cells. The objective of this study was to define appropriate in vitro culture conditions required for decidualization of baboon stromal cells. Parallel studies were also done with human endometrial stromal cells for comparative analysis. Human stromal cells produced prolactin and insulin-like growth factor-binding protein (IGFBP)-1 in response to hormones (estradiol-17beta [36 nM], medroxyprogesterone acetate [1 microM], and relaxin [100 ng/ml]), and production was enhanced in the presence of 0.1 mM dibutyryl cAMP (dbcAMP). By contrast, baboon cells did not produce any detectable levels of prolactin, even in the presence of hormones and dbcAMP. IGFBP-1 expression in baboon stromal cells was detectable by Day 6 of hormone and dbcAMP treatment and increased exponentially thereafter. In both human and baboon stromal cells, alpha smooth muscle actin (alphaSMA) expression, an early marker for decidualization in the baboon in vivo, was induced spontaneously under normal culture conditions. Furthermore, a decrease in alphaSMA expression was observed in cells producing high levels of IGFBP-1. Human cells produced significant levels of IGFBP-1 (p < or = 0.01) in response to short-term dbcAMP treatment (48 h) after 2 and 12 days of hormone treatment. However, baboon stromal cells required 17 days of hormonal treatment before cells became responsive to short-term dbcAMP treatment (p < or = 0.01). Finally, human endometrial stromal cells expressed the protein kinase A regulatory subunits RIalpha, RIbeta, RIIalpha, and RIIbeta whereas baboon stromal cells expressed RIalpha, RIIalpha, and RIIbeta. No difference in the mRNA expression of these isoforms was observed in decidualized or nondecidualized cells of either human or baboon endometrium. Our observations indicate that baboon stromal cells can be induced to decidualize in vitro and that this requires dbcAMP in addition to hormones. This is the first report demonstrating in vitro decidualization in a nonhuman primate.
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PMID:Comparative studies on the in vitro decidualization process in the baboon (Papio anubis) and human. 967 7


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