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Biomedical subjects

Y J Topper

Publications and source records attributed to Y J Topper.

At least 19 recordsLinked to original sources
PubMed1988

Progesterone and prolactin are both required for suppression of the induction of rat alpha-lactalbumin activity.

Progesterone prevents lactation during pregnancy. This anti-lactogenic effect includes suppression of the advent of alpha-lactalbumin activity, an effect which prevents the formation of lactose. Alpha lactalbumin activity can be induced to some extent in pregnant rat mammary explants by insulin and hydrocortisone alone, and to a greater extent with prolactin in addition, or with EGF in addition. Physiological levels of progesterone markedly inhibit the induction in the presence of prolactin plus insulin and hydrocortisone, only weakly inhibit in the presence of insulin and hydrocortisone alone, and have no inhibitory effect in the presence of EGF plus insulin and hydrocortisone. Prolactin permits some inhibition in the presence of EGF. The results suggest that progesterone does not subvert the essential insulin or glucocorticoid signals. It also appears that transduction of the prolactin signal is required in order that progesterone effectively block induction of alpha-lactalbumin activity.

Animals↗
PubMed1988

Comparison of the regulation of the whey acidic protein gene with that of a hybrid gene containing the whey acidic protein gene promoter in transgenic mice.

The developmentally and hormonally regulated expression of the mouse whey acidic protein (WAP) gene and a hybrid gene containing the WAP gene promoter and a cDNA for human tissue plasminogen activator (tPA) were studied in a line of transgenic mice. During mammary gland development from the mature virgin state to the seventh day of lactation, the relative concentration of WAP mRNA increased about 10(4)-fold, the increase being most pronounced between days 14 and 16 of gestation. In mammary gland organ culture from virgin and midpregnant animals, the concerted actions of insulin, hydrocortisone, and PRL were required to increase WAP mRNA levels. Steady state levels of transcripts from the WAP-tPA hybrid gene increased about 100-fold during pregnancy; this occurred mainly around day 10 of gestation. Insulin, hydrocortisone, and PRL were necessary to maintain the levels of WAP-tPA RNA in explants from virgin and pregnant animals, but could not further elevate it. The results suggest that the WAP gene promoter and upstream region contains some, but perhaps not all elements conferring developmental and hormone regulated expression of the mouse WAP gene.

Animals↗
PubMed1987

Is EGF a physiological inhibitor of mouse mammary casein synthesis? Unphysiological responses to pharmacological levels of hormones.

It has been observed that EGF inhibits the induction of casein synthesis by mouse mammary tissue in vitro in addition to acting as a promoter of mammary epithelial proliferation. However, since the circulating level of EGF increases during lactation, and since functional EGF receptors are retained by the lactating cells, it seemed unlikely that EGF is an inhibitor of mammary differentiation in vivo. The current studies demonstrate, in fact, that EGF inhibits the induction of casein synthesis in vitro only when insulin is present in the culture medium at unphysiologically high concentrations. Other artifactual responses to high levels of hormones are described.

Animals↗
PubMed1987

Comparison of the roles of insulin and insulin-like growth factor I in casein gene expression and in the development of alpha-lactalbumin and glucose transport activities in the mouse mammary epithelial cell.

The concentration-activity profiles for insulin and insulin-like growth factor I (IGF-I; in the presence of and insulin-like growth factor I (IGF-I; in the presence of hydrocortisone and PRL) have been compared in terms of the accumulation of beta-casein mRNA, total casein synthesis, and alpha-lactalbumin and basal carrier-mediated glucose transport activities in mammary epithelial cells from midpregnant mice. For the accumulation of the casein mRNA and the induction of casein synthesis and alpha-lactalbumin activity, the insulin ED50 is 1-2 ng/ml, while that for IGF-I is 10- to 20-fold greater. The effects of insulin and IGF-I are not additive in these instances. For the induction of basal carrier-mediated glucose transport, the insulin ED50 is 8 ng/ml, and that for IGF-I is 16 ng/ml. Either factor can induce transport activity up to the level present in the cells from 2-day lactating mice. In this instance the effects are additive; insulin and IGF-I together can induce the transport up to the 10-day lactating level.

3-O-Methylglucose↗
PubMed1986

Transcriptional and post-transcriptional roles of glucocorticoid in the expression of the rat 25,000 molecular weight casein gene.

In the presence of hydrocortisone, plus insulin and prolactin, rat mammary explants transcribe the 25K casein gene, and the half-life of the transcript is about 20 h. The first detectable effect of the withdrawal of glucocorticoid is reduction of the half-life of the casein mRNA to about 1 h, with full retention of the rate of transcription of the casein gene. A later effect of the withdrawal of glucocorticoid is loss of the ability to transcribe the casein gene. Both aberrations can be rectified by hydrocortisone in vitro. The instability of the 25K casein mRNA in the absence of glucocorticoid appears to be related to degradation in the nucleus. Accumulation of actin mRNA in the nuclear fraction is not dependent on glucocorticoid. The results indicate that glucocorticoid exerts a profound, selective effect on the stabilization of rat 25K casein mRNA, and is essential for the transcription of the casein gene. These effects can be dissociated temporally from one another.

Adrenalectomy↗
PubMed1986

Changes in the rate of carrier-mediated glucose transport by mouse mammary epithelial cells during ontogeny: hormone dependence delineated in vitro.

Epithelial cells were isolated from mammary glands of mice in various physiological states, and the rate of carrier-mediated glucose transport was determined with 3-O-methylglucose. The basal rate (in the absence of exogenous insulin) increases about 40-fold as the animal of origin progresses from the virgin to the midlactating state and declines precipitously during involution. Insulin does not acutely stimulate carrier-mediated transport by cells isolated from virgin or lactating mice and evokes only about a 50% enhancement of this transport rate in the cells derived from pregnant and early postlactational animals. However, culture of mammary explants from pregnant mice in the presence of insulin, cortisol, and PRL before isolation of the epithelial cells results in a 400% increase in the basal rate of carrier-mediated glucose transport in the absence of exogenous hormones; this effect requires 3 days of incubation. The enhanced rate is equivalent to that in cells freshly isolated from animals in early lactation. Insulin-like growth factor I can mimic the chronic effect of insulin, but multiplication-stimulating activity, epidermal growth factor, and 20% fetal calf serum do not supplant insulin in this system. The maximum velocity, but not the Km, of 3-O-methylglucose transport is markedly increased during ontogeny; this is compatible with an increase in the number of functional transporters during development. The results suggest that insulin and/or insulin like growth factor I are implicated in development of the high basal rate of carrier-mediated glucose transport in mammary cells from lactating mice.

3-O-Methylglucose↗
PubMed1984

Effects of estrogen-depletion on rat casein gene expression.

Mammary tissue from rats that had been ovariectomized and adrenalectomized 4 weeks previously was compared to that from intact rats in terms of epithelial content and hormone-responsiveness in vitro. The endocrinectomy resulted in about a 30% enlargement of the gland, but led to a loss of only about 12% of the epithelium. This estrogen-depleted epithelium was able to acquire full responsiveness in vitro to insulin in terms of the accumulation of alpha-aminoisobutyric acid, and induction of glucose-6-phosphate and gluconate-6-phosphate dehydrogenases. It was also fully responsive to cortisol in relation to the induction of NADH-cytochrome C reductase, and to prolactin in terms of total RNA synthesis. However, estrogen-depletion led to an 82% loss in the ability of a unit amount of the epithelium to synthesize casein in response to these 3 hormones, and to a similar loss in relation to the accumulation of 25K casein mRNA. Estrogen administration in vivo could prevent and reverse the casein lesion. The disparity between constitutive and casein hormone-responsiveness in the absence of estrogen is discussed in relation to cell commitment.

Adrenalectomy↗
PubMed1984

Essential role of insulin in transcription of the rat 25,000 molecular weight casein gene.

Insulin is essential for the accumulation of rat casein messenger RNA (mRNA) in the presence of glucocorticoid and prolactin. The accumulation of certain mRNA's in other tissues has also been linked to insulin action. The present study shows that the accumulation effect on the 25,000 molecular weight rat casein mRNA does not reflect stabilization of the transcript by insulin. Rather, insulin is essential for its synthesis in the presence of glucocorticoid and prolactin.

Animals↗
PubMed1984

Prolactin-induced alpha-lactalbumin activity in mammary explants from pregnant rabbits. A role for epidermal growth factor and glucocorticoids.

Exogenous prolactin alone can induce alpha-lactalbumin activity in rabbit mammary explants. Under these conditions, exogenous corticosol has no effect. However, low levels of epidermal growth factor (EGF) can markedly inhibit the induction by prolactin, and this inhibitory effect, in turn, can be prevented by cortisol. The steroid can, in fact, convert EGF from a potent inhibitor into an agent which enhances the induction. None of the other growth factors tested inhibits induction of alpha-lactalbumin activity by prolactin, and no other type of steroid tested overcomes the effect of EGF. The results suggest that, under physiological conditions, glucocorticoid may be essential for induction of alpha-lactalbumin activity in the rabbit in order to override the effect of serum EGF.

Adrenal Cortex Hormones↗
PubMed1983

Selective enhancement of the induction of alpha-lactalbumin activity in rat mammary explants by epidermal growth factor.

Epidermal growth factor (EGF) enhances the induction of alpha-lactalbumin in mammary explants from pregnant and virgin rats in the presence of insulin (I), hydrocortisone (F) and prolactin (P). EGF also enhances the prolactin-independent induction of alpha-lactalbumin in tissue from pregnant rats and evokes prolactin-independent induction of alpha-lactalbumin in mammary tissue from virgin rats in the presence of I and F. Casein synthesis and galactosyltransferase activity are unaffected by EGF in the IFP-system, and are not induced in the IF-EGF-system. Multiplication stimulating activity, nerve growth factor, fibroblast growth factor and platelet-derived growth factor do not mimic the selective effects of EGF on rat alpha-lactalbumin. These influences of EGF on the differentiation of isolated rat mammary tissue are compared with those on mouse and rabbit tissue studied previously.

Animals↗
PubMed1983

Essentiality of insulin and prolactin for accumulation of rat casein mRNAs.

Fetal calf serum (20%) does not substitute for insulin in terms of enhanced accumulation of rat casein mRNAs, but it can sustain the mammary tissue in culture. This property of fetal calf serum was utilized to show that in the presence of cortisol and 1) insulin or 2) prolactin, the delayed addition of prolactin or insulin, respectively, produced similar enhancement of 25 K and 42 K casein mRNAs. The results indicate that both insulin and prolactin are required for accumulation of rat casein mRNAs, the accumulation is independent of the sequence of addition of these hormones, and that the response cannot be ascribed entirely to the hormone added last.

Animals↗
PubMed1983

A unique and essential role for insulin in the phenotypic expression of rat mammary epithelial cells unrelated to its function in cell maintenance.

Mammary explants from pregnant rats can be induced in regard to casein synthesis and alpha-lactalbumin activity when cultured in the presence of hydrocortisone, prolactin and levels of insulin approaching physiological concentrations. No detectable induction occurs in the absence of insulin. Although epidermal growth factor and multiplication stimulating activity, in the presence of hydrocortisone, can maintain the initial level of NADH-cytochrome c reductase as well as insulin, neither can substitute effectively for insulin in the induction of the milk proteins. Proinsulin, nerve growth factor, platelet-derived growth factor and fibroblast growth factor are also ineffective substitutes for insulin in this regard. Whereas prolonged tissue exposure to multiplication stimulating activity, hydrocortisone and prolactin does not result in induction of alpha-lactalbumin activity, subsequent addition of insulin leads to prompt response. The results suggest that the ability of insulin to function as a unique, essential factor in the induction of rat milk proteins is independent of its cell-maintenance activity. Thus, in addition to its well established functions in metabolic processes, insulin appears to play a vital role in certain developmental processes.

Animals↗
PubMed1983

An essential role for glucocorticoid in casein gene expression in rat mammary explants.

It is demonstrated that the accumulation of 42 K casein mRNA in mammary tissue from adrenalectomized, virgin rats is almost 20x higher in the presence of exogenous hydrocortisone than in its absence. Accumulation of 25 K casein mRNA in this tissue is totally dependent on the steroid. The results indicate a much greater dependency on hydrocortisone than was appreciated previously, and also show that this dependency does not reflect a loss of cell viability in the absence of the steroid.

Adrenalectomy↗
PubMed1983

Anti-insulin receptor serum mimics the developmental role of insulin in mouse mammary explants.

A number of growth factors can maintain hormonally-responsive epithelium in murine mammary explants as well as insulin, but only insulin can promote the synthesis of casein and alpha-lactalbumin, in the presence of glucocorticoid and prolactin. Anti-insulin receptor serum can elicit these effects of insulin on milk protein gene expression. The anti-serum is unique in its ability to mimic the developmental role of insulin in murine mammary epithelium.

Animals↗
PubMed1983

Deoxyribonucleic acid synthesis-dependent casein gene expression: species differences.

Mammary gland explants from mature virgin mice, rats, and rabbits exhibit an increased rate of both DNA and casein syntheses when cultured in the presence of specific combinations of insulin, hydrocortisone, and PRL. If cytosine arabinoside, a potent inhibitor of DNA synthesis, is added to the culture medium, casein synthesis is inhibited in explants from mice but not in those from rats or rabbits. This inhibition is at the level of accumulation of casein mRNA; an 89% reduction of stimulated levels was observed. The nature of this block was investigated further by examining the general response of mature virgin mouse mammary explants to hydrocortisone and PRL, hormones considered essential for casein gene expression in this species. Cytosine arabinoside did not prevent an increment in either hydrocortisone-induced NADH-cytochrome c-reductase or PRL-induced total RNA synthesis. Previous work has shown that certain insulin-induced responses are also unaffected. Taken collectively, these results suggest that the lesion induced by cytosine arabinoside inhibition of DNA synthesis is distal to the receptor for one or more of these hormones. The necessity for coupling DNA synthesis with overt differentiation in the mature virgin mouse, but not in the rat or rabbit, is one of numerous examples of species variation in regard to the interaction of hormones with the mammary gland.

Animals↗
PubMed1982

Effect of vitamin A deprivation on maintenance of rat mammary tissue and on the potential of the epithelium for hormone-dependent milk protein synthesis.

Mammary tissue from rats severely deficient in vitamin A was compared with that from control animals. Glands from the deficient animals weighed only about 60% as much as those from control rats, a reflection largely of loss of material from the mammary fat pad. By contrast, vitamin A-deficient glands had as much epithelium as control glands. Furthermore, explants from the deficient glands were as responsive to insulin, glucocorticoid, and PRL as explants from control glands, in terms of the induction of casein synthesis and the alpha-lactalbumin and galactosyltransferase activities. It appears that vitamin A does not have a physiological role either in the maintenance of rat mammary epithelium or in its potential for hormone-dependent phenotypic expression. The results suggest that the anticarcinogenic activity of retinoids on rat mammary gland reported previously may lie outside the purview of these aspects of the mammary cell.

Animals↗