Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:4.6.1.1 (adenylate cyclase)
 19,190 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Intracellular cAMP regulates cell proliferation as a second messenger of extracellular signals in a number of cell types. We investigated, by pharmacological means, whether an increase in intracellular cAMP levels changes proliferation rates of lactotrophs in primary culture, whether there are interactions between signal transduction pathways of cAMP and the growth factor insulin, and where the dopamine receptor agonist bromocriptine acts in the cAMP pathway to inhibit lactotroph proliferation. Rat anterior pituitary cells, cultured in serum-free medium, were treated with cAMP-increasing agents, followed by 5-bromo-2'-deoxyuridine (BrdU) to label proliferating pituitary cells. BrdU-labeling indices indicative of the proliferation rate of lactotrophs were determined by double immunofluorescence staining for PRL and BrdU. Treatment with forskolin (an adenylate cyclase activator) or (Bu)2cAMP (a membrane-permeable cAMP analog) increased BrdU-labeling indices of lactotrophs in a dose- and incubation time-dependent manner. The cAMP-increasing agents were also effective in increasing BrdU-labeling indices in populations enriched for lactotrophs by differential sedimentation. The stimulatory action of forskolin was observed, regardless of concentrations of insulin that were added in combination with forskolin. Inhibition of the action of endogenous cAMP by H89 or KT5720, a protein kinase A inhibitor, attenuated an increase in BrdU-labeling indices by insulin treatment. On the other hand, the specific mitogen-activated protein kinase inhibitor PD98059, which was effective in blocking the mitogenic action of insulin, markedly suppressed the forskolin-induced increase in BrdU-labeling indices. (Bu)2cAMP antagonized not only inhibition of BrdU labeling indices but also changes in cell shape induced by bromocriptine treatment, although forskolin did not have such an antagonizing effect. These results suggest that: 1) intracellular cAMP plays a stimulatory role in the regulation of lactotroph proliferation; 2) cAMP and insulin/mitogen-activated protein kinase signalings require each other for their mitogenic actions; and 3) the antimitogenic action of bromocriptine is, at least in part, caused by inhibition of cAMP production.
 ...
PMID:Mitogen-activated protein kinase-dependent stimulation of proliferation of rat lactotrophs in culture by 3',5'-cyclic adenosine monophosphate. 1034 77

Membrane functions in tumorous cells are different from those in healthy cells. The aim of the present study was to investigate the changes in pituitary cell membrane functions and hormone secretion after tumor induction in vivo and in vitro. Prolactinomas were induced in vivo in female Wistar rats with estrone acetate. Normal anterior pituitaries and prolactinomas of female Wistar rats were dissociated enzymatically and mechanically, then cultured on collagen-treated plastic dishes. Some normal anterior pituitary cultures were treated with benz(c)acridines as tumorigenic agents in vitro. Intracellular 3',5'-cyclic-adenosine monophosphate (cAMP) levels were determined by a competitive binding technique, membrane fluidity was assayed by fluorescence anisotropy, and ATP-ase activities were estimated via ATP loss. The results indicated decreased membrane fluidity in tumorous cell cultures. However, in vitro benz(c)acridine treatment exerted more pronounced effects than those observed after in vivo estrone treatment. The ATP-ase activities were highly increased in benz(c)acridine-treated cells and in estrogen-induced prolactinoma cells, more strongly so in the former ones. The intracellular cAMP levels were higher than normal in both of them. The results concerning the ACTH, alpha-MSH, PRL and GH levels of normal and tumorous cell cultures were published in our previous study. Our findings show that the tumorous transformation of pituitary cells can cause significant changes in functional membrane parameters and hormone secretion. Decreased membrane fluidity was accompanied by an increased exocytosis (hormone release) and adenylate cyclase activity in tumorous cells.
 ...
PMID:Functional membrane changes due to tumor induction in rat pituitary cell cultures. 1127 34

Hypothalamic hormones, including dopamine, regulate critical functions of pituitary cells via the cAMP-protein kinase A (PKA) pathway. The PKA-downstream transcription factor cAMP response element (CRE)-binding protein (CREB) is an integrating molecule that is also activated by many other protein kinase pathways. We investigated the involvement of CREB in the regulation of cell proliferation and the PRL promoter of rat lactotrophs in primary cell culture. Recombinant adenoviruses were used for efficient gene delivery into pituitary cells. Bromocriptine, a dopaminergic agonist known to decrease intracellular cAMP concentrations, caused inhibition of PRL promoter activity and lactotroph proliferation, which was accompanied by decreases in CRE-mediated transcription and CREB phosphorylation in lactotrophs. Expression of a dominant-negative form of CREB (MCREB), which was effective in suppressing CRE-mediated transcription induced by the adenylate cyclase activator forskolin, inhibited basal and forskolin-induced PRL promoter activity and PRL mRNA expression. MCREB expression lowered basal proliferative levels and blocked forskolin-induced proliferation of lactotrophs. Insulin-like growth factor I (IGF-I), a potent mitogen in lactotrophs, did not affect intracellular cAMP concentrations but transiently increased lactotroph CREB phosphorylation. MCREB expression also inhibited IGF-I-induced lactotroph proliferation. These results suggest that CREB is involved in the regulation of cell proliferation and the PRL promoter in normal lactotrophs and that dopamine inhibition of these lactotroph functions is at least in part due to inhibition of the cAMP-PKA-CREB pathway.
 ...
PMID:Involvement of cAMP response element-binding protein in the regulation of cell proliferation and the prolactin promoter of lactotrophs in primary culture. 1792 56

Angiotensin II (AII) and thyreoliberin (TRH) have recently been shown to stimulate intracellular cAMP formation in rat lactotroph cells, in addition to their already documented coupling to phospholipase C. The effect on intracellular cAMP is unaffected by pertussis toxin (PTX) and is not due to a direct coupling to adenylate cyclase (AC); it results instead from a protein kinase C (PKC)-dependent process. In contrast, when tested in membrane preparations, AII, but not TRH, induces a PTX-sensitive inhibition of AC. The present work indicates that AII, but not TRH, is also able to inhibit intracellular cAMP formation in mixed as well as in lactotroph-enriched cells. Two conditions are required to reveal this effect: desensitization of PKC by prior exposure to TPA and concomitant stimulation of CAMP level. This effect is observed only in the presence of vasoactive intestinal peptide, whose receptor is directly coupled to AC, but not in the presence of other AC-stimulating agents such as cholera toxin and forskolin. This AII inhibitory effect is dose dependent and sensitive to PTX as is AII membrane inhibition of AC activity. PTX also reverses DA inhibition of AC, on both membrane preparations and intact cells. However different G proteins seem to be involved in the negative coupling of AII and DA receptors, since both effects do not exhibit the same PKC sensitivity in entire cells and GTP dependency in membrane preparations. An inhibitory coupling of the AII receptor with AC thus exists in intact cells but is masked by PKC interactions. Under specific conditions, this AII inhibition of intracellular cAMP formation might be implicated in the regulation of PRL secretion.
 ...
PMID:PKC modulation of inhibitory coupling of angiotensin II receptors with adenylate cyclase in lactotroph cells. 1991 54

We have previously characterized PRL production in human myometrial tissue maintained in explant culture. Here we describe PRL gene expression and its regulation in smooth muscle cells isolated from normal human myometrium. Onset of PRL secretion occurred spontaneously after several days in culture and increased over time without exogenous stimulation. PRL secretion could be further simulated by the addition of PGE(2) or relaxin, both of which were also shown to increase cAMP formation in smooth muscle cells. Likewise, treatment with 8-Br-cAMP led to an elevation of PRL secretion. By reverse transcription/polymerase chain reaction, we demonstrate that smooth muscle cells transcribe the PRL gene from the alternative decidual-type dPRL promoter, located upstream of the pituitary promoter. Treatment with PGE(2), relaxin, and 8-Br-cAMP resulted in an increase in dPRL transcript abundancy. The effect of cAMP was transcriptional as shown by the induction of transfected dPRL promoter/reporter gene fusion constructs. A fragment of 332 bp flanking the dPRL transcription start site was sufficient to mediate cAMP inducibility. In parallel with the increase in PRL secretion, we detected an increase in cAMP formation and PGE(2) secretion in cultured smooth muscle cells. We propose the presence of a paracrine positive feedback mechanism that may reflect the physiological situation in vivo where an increase in myometrial adenylate cyclase activity throughout pregnancy has been reported.
 ...
PMID:Prolactin gene expression in human myometrial smooth muscle cells is induced by cyclic adenosine 3',5'-monophosphate. 2115 74


<< Previous 1 2 3 4 5 6