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Query: UNIPROT:P06889 (Mol)
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The effects of prolactin (PRL), alone and as a modulator of human chorionic gonadotropin (hCG) action, on steroidogenesis and cAMP accumulation in rat luteal cell cultures were examined. Cultured rat luteal cells were prepared from immature rats primed with pregnant mare serum gonadotropin and hCG. In vitro treatment was performed with 0.1 and 0.2 IU/ml hCG and 1-100 ng/ml PRL. Cultures were incubated for 48 h for evaluation of progesterone (P4) secretion and for 1 h for measurement of cAMP accumulation. The same doses of hormones and incubation periods were also used in preovulatory rat granulosa cell cultures and found to cause a significant, dose-dependent inhibition in estradiol, P4 and cAMP accumulation. In luteal cell cultures, on the other hand, P4 secretion was significantly elevated, in a dose-dependent manner, by PRL. Moreover, identical doses of PRL caused a significant, dose-dependent stimulation of cAMP accumulation. Basal levels of P4 were also significantly elevated by PRL alone, but no such stimulation by PRL was detected in basal levels of cAMP. Addition of the phosphodiesterase inhibitor, 3-isobutyl-1-methylxanthine, increased the stimulation of P4 and cAMP by hCG + PRL in a manner dependent on PRL concentrations. The overall data therefore demonstrate divergent effects of PRL on cAMP accumulation and steroidogenesis in the ovary: inhibitory in the preovulatory and stimulatory in the postovulatory state. Moreover, these findings suggest a possible common mechanism linking the effects of PRL before and after ovulation: inhibition of cAMP accumulation via enhanced breakdown of the nucleotide.
Mol Cell Endocrinol 1989 Aug
PMID:Effects of prolactin on steroidogenesis and cAMP accumulation in rat luteal cell cultures. 247 49

The single-copy gene encoding the alpha subunit of glycoprotein hormones is expressed in the pituitaries of all mammals and in the placentas of only primates and horses. We have systematically analyzed the promoter-regulatory elements of the human and bovine alpha-subunit genes to elucidate the molecular mechanisms underlying their divergent patterns of tissue-specific expression. This analysis entailed the use of transient expression assays in a chorionic gonadotropin-secreting human choriocarcinoma cell line, protein-DNA binding assays, and expression of chimeric forms of human or bovine alpha subunit genes in transgenic mice. From the results, we conclude that placental expression of the human alpha-subunit gene requires a functional cyclic AMP response element (CRE) that is present as a tandem repeat in the promoter-regulatory region. In contrast, the promoter-regulatory region of the bovine alpha-subunit gene, as well as of the rat and mouse genes, was found to contain a single CRE homolog that differed from its human counterpart by a single nucleotide. This difference substantially reduced the binding affinity of the bovine CRE homolog for the nuclear protein that bound to the human alpha CRE and thereby rendered the bovine alpha-subunit promoter inactive in human choriocarcinoma cells. However, conversion of the bovine alpha CRE homolog to an authentic alpha CRE restored activity to the bovine alpha-subunit promoter in choriocarcinoma cells. Similarly, a human but not a bovine alpha transgene was expressed in placenta in transgenic mice. Thus, placenta-specific expression of the human alpha-subunit gene may be the consequence of the recent evolution of a functional CRE. Expression of the human alpha transgene in mouse placenta further suggests that evolution of placenta-specific trans-acting factors preceded the appearance of this element. Finally, in contrast to their divergent patterns of placental expression, both the human and bovine alpha-subunit transgenes were expressed in mouse pituitary, indicating differences in the composition of the enhancers required for pituitary- and placenta-specific expression.
Mol Cell Biol 1989 Nov
PMID:Expression of the glycoprotein hormone alpha-subunit gene in the placenta requires a functional cyclic AMP response element, whereas a different cis-acting element mediates pituitary-specific expression. 248 Dec 30

In the hamster, DNA polymerase-alpha (Pol-alpha) in follicles at stages 1-4 (1-4 layers granulosa cells and no theca) increased significantly during the proestrous (P) gonadotropin surges, remained high on estrus (E) and then declined to low levels by 09.00 h, proestrus (P). However, Pol-alpha in stages 5-8 (large preantral to small antral stages) remained steady throughout the cycle. Hypophysectomy on metestrus decreased Pol-alpha by 17 h which was reversed by 2.5 micrograms follicle stimulating hormone (FSH) but not by luteinizing hormone (LH) (2.5 micrograms) or human chorionic gonadotropin (hCG) (1 IU). Hypophysectomy on E resulted 72 h later in a fall in Pol-alpha in stages 1-6; FSH (2.5 micrograms) or LH (2 micrograms) restored enzyme activity within 5 h to stages 1-6 and 5-6, respectively. Thus, Pol-alpha in the smallest preantral follicles is induced by FSH; however, for large preantral and antral follicles, steady levels are maintained by tonic FSH and LH resulting in no apparent change in enzyme activity during active DNA synthesis.
Mol Cell Endocrinol 1989 Feb
PMID:Deoxyribonucleic acid polymerase-alpha activity in hamster follicles during the estrous cycle: roles of follicle stimulating hormone and luteinizing hormone. 249 57

It is the objective of the experiments reported herein to examine the possible relevance of transforming growth factor-beta (TGF beta) to theca-interstitial cell function, and to further characterize the established interaction of TGF beta with the granulosa cell. In examining the interaction of TGF beta (10 ng/ml) with murine theca-interstitial cells, no significant effect was observed on either basal or human chorionic gonadotropin (hCG)-stimulated androsterone accumulation. In contrast, given murine granulosa cells, TGF beta (10 ng/ml) produced dose- and time-dependent augmentation of follicle-stimulating hormone (FSH)-supported aromatase activity with a minimal and median effective doses of 20 +/- 3 and 123 +/- 24 pg/ml, respectively and a minimal time requirement of less than or equal to 48 h. The ability of TGF beta to augment FSH hormonal action could not be accounted for by alteration(s) of specific FSH binding (13965 +/- 298 and 12614 +/- 694 cpm/4 X 10(5) cells for FSH and FSH + TGF beta). However, TGF beta proved capable of exerting a direct upregulatory effect on stimulatable adenylate cyclase activity, further enhancement occurring at site(s) distal to cAMP generation (dibutyryl cyclic AMP (Bt2cAMP) = 1.4 +/- 0.2 ng/culture; Bt2cAMP + TGF beta = 4.1 +/- 0.6 ng/culture). Taken together, our findings are in keeping with the notion that TGF beta, possibly of intraovarian origin, comprises the central signal of autocrine or paracrine loop(s) capable of amplifying gonadotropin action at the level of the granulosa, but not theca-interstitial cell.
Mol Cell Endocrinol 1989 Feb
PMID:Ovarian transforming growth factor-beta (TGF beta): cellular site(s), and mechanism(s) of action. 249 58

Pituitary-determined hormones regulate the expression of hepatic cytochromes P-450 through processes involving both negative and positive controls. Accordingly, protein levels of several P-450 forms are elevated in rat liver following hypophysectomy [P-450 forms designated 2a (gene IIIA2), RLM2 (gene IIA2), and PB-4 (gene IIB1)], whereas protein levels of others are suppressed [e.g., P-450 2c (gene IIC11)]. In the present study, microsomal steroid hydroxylase activities associated with these same P-450 forms were found to be decreased by hypophysectomy, despite elevations in protein levels for several of them. Studies were, therefore, undertaken to determine the biochemical basis for this decrease in microsomal P-450 enzyme specific activity. In vivo treatment of hypophysectomized rats with gonadotropin, under conditions that restore heme to testis P-450, and heme reconstitution experiments carried out with liver homogenates indicated that a deficiency in P-450-associated heme is unlikely to account for the observed decreases in liver P-450 enzyme specific activity. Analysis of the flavoprotein P-450 reductase, however, revealed that the reductase protein and its associated cytochrome c reductase activity are decreased by 50 to 75% in liver microsomes isolated from hypophysectomized rats. Moreover, supplementation of isolated liver microsomes with exogenous purified P-450 reductase stimulated microsomal steroid hydroxylase activity preferentially in the hypophysectomized rats, to levels consistent with the observed changes in P-450 protein levels. Thus, a deficiency in P-450 reductase, which is a rate-limiting component for many P-450-dependent hydroxylation reactions, appears to be responsible for the decrease in steroid hydroxylase specific activity in the hypophysectomized rats. Although growth hormone, adrenocorticotropic hormone, and chorionic gonadotropin were each ineffective at restoring hepatic P-450 reductase when administered to hypophysectomized rats, substantial restoration of P-450 reductase levels could be achieved by treatment of the hypophysectomized rats with thyroxine. Thyroxine treatment of these rats also elevated the microsomal steroid hydroxylase activities associated with the individual hepatic P-450 forms to levels commensurate with their respective P-450 protein levels. These results establish that hepatic P-450 reductase is subject to hormonal controls that are distinct from those governing cytochrome P-450 expression and further demonstrate the complexity of endocrine control of hepatic steroid hormone metabolism.
Mol Pharmacol 1989 Apr
PMID:Hypophysectomy differentially alters P-450 protein levels and enzyme activities in rat liver: pituitary control of hepatic NADPH cytochrome P-450 reductase. 249 35

Rat cytochrome P450 2c (P450 gene IIC11) is a constitutive, male-specific hepatic enzyme which is suppressed greater than 90% by treatment with 3,4,5,3',4',5'-hexachlorobiphenyl (HCB) [H. N. Yeowell et al. (1987) Mol. Pharmacol. 32, 340-347]. HCB also decreases serum testosterone levels in adult male rats (greater than 98% loss). The present study assesses whether the suppression of P450 2c by HCB is a direct result of its effects on serum testosterone levels. Further, the site along the hypothalamic-pituitary-testicular axis at which HCB acts to depress testosterone secretion was examined. Administration of the synthetic androgen methyltrienolone to HCB-treated rats failed to prevent the suppression of P450 2c mRNA and its associated microsomal steroid 16 alpha-hydroxylase activity under conditions where it effectively reversed the large decrease in P450 2c mRNA and steroid 16 alpha-hydroxylase activity produced by castration. Hepatic steroid 6 beta-hydroxylase activity, which is catalyzed primarily by P450 2a (P450 gene IIIA2), was also suppressed by HCB and was not protected by methyltrienolone. Administration of either human chorionic gonadotropin, an analog of pituitary-derived luteinizing hormone, or the hypothalamic luteinizing hormone releasing hormone elevated serum testosterone levels to a much smaller extent in HCB-treated rats than in control rats. These results indicate that the effects of HCB on serum testosterone levels reflect its effects on testicular function rather than the pituitary or hypothalamus. However, the present study demonstrates that the consequential reduction in serum testosterone levels in HCB-treated rats is not causally related to the reduction in hepatic P450 2c levels. Thus, HCB must also act on some other regulatory mechanism involved in the expression of this protein.
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PMID:Suppression of male-specific cytochrome P450 2c and its mRNA by 3,4,5,3',4',5'-hexachlorobiphenyl in rat liver is not causally related to changes in serum testosterone. 249 61

A growing body of evidence indicates that substances released by activated immune cells can directly influence the functions of various endocrine cells. In the present study, the direct in vitro effects of interleukins (IL) 1, 2, and 3 on follicle-stimulating hormone (FSH)-stimulated steroidogenesis and luteinizing hormone/human chorionic gonadotropin (LH/hCG) receptor induction in granulosa cells were examined. In the absence of FSH, none of the interleukins stimulated steroid production or LH/hCG receptor induction during a 2-day culture period. However, in the presence of FSH, both IL-1 alpha and IL-1 beta inhibited, in a dose-dependent manner, progesterone and estrogen production as well as LH/hCG receptor induction in response to FSH. In contrast, both agents augmented 20 alpha-hydroxy-4-pregnen-3-one (20 alpha-OH-P) production stimulated by FSH. In all cases, less IL-1 beta than IL-1 alpha was required to produce a comparable effect. IL-2 slightly, but significantly, enhanced both FSH-stimulated progesterone and 20 alpha-OH-P production but had no effect on FSH-stimulated estrogen production or LH/hCG receptor induction. IL-3 potentiated the 20 alpha-OH-P response to FSH by up to 65% but had no effect on FSH-stimulated progesterone or estrogen production or LH/hCG receptor induction. These data suggest that the interleukins, which are key mediators of immune responses, may affect mechanisms crucial for the maturation and differentiation of granulosa cells and thus may also play a regulatory role in reproductive function.
Mol Cell Endocrinol 1989 Mar
PMID:Effects of interleukins 1, 2 and 3 on follicle-stimulating hormone-induced differentiation of rat granulosa cells. 250 Nov 21

The effects of biologic response modifiers such as interferon-gamma, tumor necrosis factor alpha (TNF), and retinoic acid on the human chorionic gonadotropin (hCG) secretion of cultured choriocarcinoma cells (JAR) and term placenta have been studied. Although the proliferation of JAR cells was not inhibited by these agents, retinoic acid and TNF markedly increased both the intracellular levels as well as the secreted amounts of hCG. In the case of the term placenta, only retinoic acid increased the hCG secretion into the culture medium, whereas interferon-gamma and TNF both markedly reduced secretion. The cytostatic agent etoposide (VP-16) was able to augment the hCG secretion on the choriocarcinoma cells but did not alter its production on term placenta. The The data presented indicate different mechanisms of regulation of hCG secretion in the normal and malignant trophoblast.
Mol Biother 1989
PMID:Modulation of secretion of human chorionic gonadotropin by biologic response modifiers on term placenta and choriocarcinoma cells. 251 40

By using immature porcine Leydig cells cultured in defined medium as a model, transforming growth factor-beta (TGF beta) was shown to exert a dramatic inhibitory effect on their basal and human chorionic gonadotropin (hCG) (or 8-bromo-cyclic AMP) stimulated dehydroepiandrosterone secretion, in the presence or absence of saturating concentrations of exogenous (low density lipoprotein) cholesterol substrate. In contrast, TGF beta exerted both a stimulating and inhibitory effect on testosterone secretion: while hCG-stimulated testosterone secretion was enhanced by low doses of TGF beta (0.06-0.4 ng/ml, 48 h), it was decreased with higher concentrations of TGF beta (2.5-10 ng/ml, 48 h). The data obtained show that the inhibitory action of TGF beta on testicular steroidogenesis was related to a decrease in pregnenolone formation by affecting a step(s) distal to cyclic AMP formation but before cholesterol association with cytochrome P-450 side-chain cleavage. As for the stimulatory effect of TGF beta on testosterone formation, this was mainly related to an increase (about 2-fold) in 3 beta-hydroxysteroid dehydrogenase/isomerase activity (ED50 0.05 ng/ml, 2 X 10(-13) M). The results indicate that the (short-term) steroidogenic stimulatory action of luteinizing hormone (LH)/hCG is antagonized by high concentrations of TGF beta by decreasing pregnenolone formation while it is enhanced by the stimulating action of low concentrations of TGF beta exerted on 3 beta-hydroxy steroid dehydrogenase/isomerase activity.
Mol Cell Endocrinol 1989 Dec
PMID:On the mechanisms involved in the inhibitory and stimulating actions of transforming growth factor-beta on porcine testicular steroidogenesis: an in vitro study. 253 15

To elucidate further the seminiferous tubule-Leydig cell interaction we studied the effect of spent medium from 20 h rat seminiferous tubule cultures (STCM) on cyclic adenosine monophosphate (cAMP) and testosterone (T) production of Percoll-purified Leydig cells. 8% of STCM inhibited the human chorionic gonadotropin (hCG)-stimulated cAMP production by 30% in a 3 h, and 33% of STCm by 60% in a 20 h incubation. Likewise, a 40% decrease was found in the presence of 8% of STCM in the hCG-stimulated T production in a 3 h incubation. A similar inhibitory activity could be demonstrated in steroid-free rat interstitial fluid. STCM did not affect the viability of the Leydig cells (90-95% after a 20 h incubation) as judged by trypan blue exclusion and the adenosine triphosphate (ATP) content of the cells. Heating (80 degrees C for 10 min) abolished the inhibiting activity, and fractionation with Millipore Ultrafree filters showed that the inhibiting factor had an Mr of 30,000-100,000. When media from different stages of the seminiferous epithelial cycle were analyzed, only stages IX-I showed inhibition of T production (P less than 0.05). The cAMP production inhibiting activity was present in all stages, but stages IX-I showed significantly (P less than 0.05) greater inhibition than stages II-VI. STCM (16%) also inhibited cholera toxin- and forskolin-stimulated cAMP formation (approximately 50 and 60%, respectively; P less than 0.01), and the inhibitory activity persisted after a 3 h preincubation of Leydig cells with 100 micrograms/l pertussis toxin.(ABSTRACT TRUNCATED AT 250 WORDS)
Mol Cell Endocrinol 1989 Aug
PMID:A rat seminiferous epithelial factor that inhibits Leydig cell cAMP and testosterone production: mechanism of action, stage-specific secretion, and partial characterization. 255 Feb 94


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