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PubMed2000

Tyrosine kinase effects on adrenoceptor-stimulated cyclic AMP accumulation in preoptic area and hypothalamus of female rats: modulation by estradiol.

These studies examined the functional interactions between adrenergic G-protein coupled receptors and protein tyrosine kinases in the preoptic area and hypothalamus, brain regions that regulate reproductive function in female rats, and evaluated whether in vivo treatment with estradiol for 2 days modulates the cross-talk between these two signaling pathways. In hypothalamic slices genistein, a general tyrosine kinase inhibitor, enhances norepinephrine-stimulated cAMP synthesis independent of estradiol treatment. Genistein appears to act by increasing beta-adrenoceptor signaling. At high norepinephrine concentrations, estradiol potentiates genistein enhancement of the cAMP response in hypothalamic slices. This interaction between estradiol and genistein appears to involve modification of alpha(2)-adrenoceptor signaling mechanisms. In preoptic area slices, genistein enhancement of norepinephrine-stimulated cAMP synthesis is only observed in estradiol-treated rats. In this brain region, genistein enhances cAMP accumulation by modifying alpha(1)- and/or alpha(2)-adrenoceptor rather than beta-adrenoceptor signaling. Genistein amplification of norepinephrine-stimulated cAMP synthesis is not mediated by interactions with estrogen receptors, or by regulation of adenylyl cyclase or phosphodiesterase activities. At the concentration used, genistein inhibits tyrosine phosphorylation in slices from both brain regions. Daidzein, an inactive analogue of genistein, fails to enhance the norepinephrine-stimulated cAMP response in either brain region independent of hormone treatment. These results suggest that protein tyrosine kinases regulate adrenergic responses in the hypothalamus and preoptic area. Moreover, the functional interaction between adrenergic G-protein coupled receptor signaling and protein tyrosine kinases is modified in a brain region and receptor subtype specific manner by estradiol.

Adrenergic alpha-Agonists↗
PubMed2001

Estradiol tends to improve inhibitory avoidance performance in adrenalectomized male rats and reduces pyknotic cells in the dentate gyrus of adrenalectomized male and female rats.

Estradiol or vehicle was administered daily to gonadectomized, adrenalectomized (ADX) male (experiment 1) and female (experiment 2) Long-Evans rats. Four and 5 days after ADX, respectively, animals were trained and tested in an inhibitory avoidance task. Male and female ADX rats had shorter cross over latencies on the test day than did nonADX rats. In males, estradiol administration to ADX rats improved inhibitory avoidance performance to levels that were comparable to nonADX, estradiol-administered male rats. No effects of estradiol were seen on inhibitory avoidance performance of female rats. In both males and females, ADX increased the number of pyknotic cells in the dentate gyrus compared to nonADX rats; estradiol also reduced pyknotic cell number compared to vehicle administration. These findings suggest that estradiol's effects on inhibitory avoidance and pyknosis in the dentate gyrus may be independent of each other.

Adrenalectomy↗
PubMed1983

A simple ultrafiltration method for determining unbound estradiol in serum.

The Amicon MPS-1 centrifugal ultrafiltration device and the YMT membrane were used to measure free estradiol in serum. Two independent assays were required. The first measured total estradiol-17 beta and the second ultrafiltrable fraction. The unbound fraction was determined by counting [3H]estradiol-17 beta in 0.15-0.3 mL ultrafiltrates of 0.5 to 1 mL of serum that had been equilibrated with [3H]estradiol-17 beta at 37 degrees C. The assay is rapid (1 h), practicable (requires 0.6 mL serum) and reproducible (CV 4.6% within assay and 6.5% between assays). Samples from apparently healthy men and women and from pregnant women gave results that agreed with those obtained by equilibrium dialysis. The percentages of free serum estradiol-17 beta were similar during both early and late follicular phases of the menstrual cycle. Samples from women with hirsutism gave values for total and free estradiol-17 beta which were not significantly different from those of normal females when no consideration was given to the phase of the menstrual cycle. The means for both of these female groups were significantly different from those of males.

Adult↗
PubMed1996

Sex differences in the effects of 17 beta-estradiol on vascular adrenergic responses.

The in vitro effects of 17 beta-estradiol on vascular responses to adrenergic nerve stimulation were studied in perfused tail arteries from age-matched male and female rats. Nerve stimulation resulted in vasoconstriction that was greater in male arteries. Addition of 17 beta-estradiol (3 x 10(-5) M) reduced the vasoconstrictor responses in both male and female arteries, but the reduction was significantly greater in the females. Gonadectomy of the animals for 1 month prior to the experiment did not alter the in vitro responses to 17 beta-estradiol in either males or females. 17 beta-Estradiol (10(-6) - 3 x 10(-5) M) also relaxed perfused tail arteries precontracted with KCl (50 mM); however the relaxation was not different between males and females, either intact or gonadectomized. Stimulation-evoked release of noradrenaline from adrenergic nerves of perfused tail arteries was measured, but no differences were found between males and females, nor was release modified by in vitro exposure to 17 beta-estradiol (10(-5) M). These results suggest that 17 beta-estradiol acts directly on postjunctional mechanisms to relax tail arteries of either sex. The effect of the hormone on arteries constricted by adrenergic nerve stimulation, however, is greater in females compared to males.

Animals↗
PubMed1998

Inhibition of striatal dopamine transporter activity by 17beta-estradiol.

Striatal synaptosomes from ovariectomized rats were prepared to examine the effect of 17beta-estradiol on [3H]dopamine uptake. Estradiol inhibited [3H]dopamine uptake in a dose-dependent manner, with an IC50 of 7.2 microM. Use of identical concentrations of progesterone had no effect on [3H]dopamine uptake. The effects of estradiol were exerted by decreasing the affinity of the transporter for dopamine, as revealed by a dose-dependent increase in the Km. The Km values for 0 (control), 10, and 100 microM estradiol were 108+/-11 258+/-44 and 415+/-40 nM, respectively, with each of the three concentrations tested being significantly different among each other. No statistically significant differences were obtained for the Vmax, with values for the three increasing doses being 9.2+/-0.8, 8.3+/-0.5 and 7.3+/-0.8 pmol/min per mg protein. These results demonstrate that estradiol, but not progesterone, inhibits striatal dopamine uptake by decreasing the affinity of the transporter for dopamine. Such a mechanism may serve as one of the bases for the modulatory effects of estradiol upon the nigrostriatal dopaminergic system.

Animals↗
PubMed1977

Effect of metal ions on the binding of 17beta-estradiol to human endometrial cytosol.

The influence of zinc and other metal ions on the binding of 3H-17beta-estradiol to human endometrial cytosol was studied. Zn2+ began to interfere with estrogen binding when its concentration in the cytosol exceeded 50 micronM. At a concentration of 5 mM, all of the specific binding of 17beta-estradiol, including more than 50% of the nonspecific binding of the hormone, was destroyed. Analysis of the binding data revealed that one possible site of action of the cations on the binding protein might be the sulfhydryl group(s) of the 17beta-estradiol binding site. The inhibition of 17beta-estradiol binding brought about by Zn2+ was partially abolished by dithiothreitol. Among the metal ions tested, Cu2+ was found to be the most potent inhibitor, followed by Cd2+, Zn2+, and Pb2+. At 1 mM, Mn2+, Ba2+, Ca2+, and Mg2+ had little effect, but at 5 mM, their inhibitory action became more appreciable. K+ and Na+ had no effect on 17beta-estradiol binding. The stimulatory effect of 5 mM Zn2+, Ca2+, Mg2+, and K+ on the binding of 3H-17beta-estradiol to a macromolecular fraction from bovine endometrium was not observed in human endometrial cytosol.

Barium↗
PubMed1981

A comparison of cytoplasmic and nuclear estradiol and progesterone receptors in human fallopian tube and endometrial tissue.

Quantitative and qualitative aspects of the in vitro binding of 3H-estradiol and 3H-progesterone to receptor components from human endometrium and fallopian tube cytoplasmic and nuclear fractions were studied. The steroid binding macromolecules formed in vitro could be extracted from nuclei by 0.4 M KCl and detected by glycerol gradient centrifugation. Both estradiol- and progesterone-binding compounds formed only one peak (under high ionic strength conditions) with a sedimentation coefficient of about 4-5 S. The number of cytoplasmic and nuclear binding sites for both estradiol and R5020 varied dramatically throughout the menstrual cycle: the estradiol and progesterone receptor concentrations were highest during the proliferative phase and were very significantly lower in the second half of the menstrual cycle. Furthermore, measurement of both receptors in the cytosol revealed differences among the anatomic segments of the fallopian tube. The highest estradiol and progesterone binding could be detected in the ampullary region; significantly lower levels of estradiol and progesterone receptors were seen in the infundibulum and the isthmus.

Cell Nucleus↗
PubMed2001

Different role of endothelium/nitric oxide in 17beta-estradiol- and progesterone-induced relaxation in rat arteries.

The present study was aimed to examine the different role of endothelium/nitric oxide in relaxation induced by two female sex hormones, 17beta-estradiol and progesterone in rat isolated aortas and mesenteric arteries. The isometric force of each ring was measured with Grass force-displacement transducers in the organ bathes. 17beta-Estradiol induced both endothelium-dependent and -independent relaxation in the rat aortas but only the endothelium-independent relaxation in the rat mesenteric arteries. In contrast. progesterone induced both endothelium-dependent and -independent relaxation in the rat mesenteric arteries but only endothelium-independent relaxation in rat aortas. N(G)-Nitro-L-arginine methyl ester and methylene blue attenuated the relaxant response to 17beta-estradiol in the aortic rings or to progesterone in the mesenteric arteries. Pretreatment with L-arginine antagonized the effect of N(G)-nitro-L-arginine methyl ester on sex hormone-induced relaxation. The endothelium contribution to relaxation seems to only relate to lower concentrations of 17beta-estradiol and progesterone. In summary, the present results clearly demonstrate a different role of the functional endothelium in the relaxant response to 17beta-estradiol or progesterone in the conduit vessel (aorta) and the resistance vessels (mesenteric artery). Nitric oxide contributes largely to the endothelium-dependent relaxation induced by 17beta-estradiol in the isolated aortas or by progesterone in the mesenteric arteries.

Animals↗
PubMed2002

Effect of treatment with different doses of 17-beta-estradiol on the insulin receptor.

The mechanism for the development of insulin resistance in normal pregnancy is complex and is associated with serum levels of sex hormones. However, the influence of these hormones on the early steps of insulin action has not been extensively studied, although the potentially beneficial effect of estradiol on glucose homeostasis has been reported. In this paper, we attempted to determine the effect of 17-beta-estradiol on the insulin receptor of ovariectomized rats treated with different doses of hormones. Our results showed a tissue-dependent response to estradiol. We found that low doses of estradiol increased the amount of insulin receptors in liver and muscle on days 6 and 11 of treatment but not in adipose tissue, and after 16 days only the muscle responsed in this way. On the other hand, high doses of estradiol significantly decreased the amount of insulin receptors, at least in muscle and adipose tissue. We believe that the low concentrations of 17-beta-estradiol (similar to early pregnancy) could be responsible for the increase in insulin sensitivity by increasing the amount of insulin receptors in peripheral tissues. When the hormone levels were high (similar to late pregnancy) the amount of insulin receptors decreased in peripheral tissues, and insulin sensitivity is diminished just as in late pregnancy. The specific molecular mechanism for this action is as yet unknown.

Adipose Tissue↗
PubMed1997

Transient effects of MK-801 administration on secretion of luteinizing hormone and prolactin in ovariectomized and estradiol-treated sheep.

The neuroendocrine role of endogenous ligands for the excitatory amino acid receptor subtype known as the NMDA receptor was investigated by administering the NMDA receptor antagonist MK-801 to ovariectomized (ovx) and estradiol-treated sheep. Repetitive administration of MK-801 at intravenous (iv) dosages of 0.1 mg/kg to untreated ovx ewes did not affect the episodic profiles of luteinizing hormone (LH) release, but each injection of MK-801 abruptly stimulated release of prolactin (PRL) demonstrating the effectiveness of the dosage. Injection of estradiol-17beta (50 microg/ewe) to ovx ewes produced the expected biphasic LH response; an initial suppression followed by a surge-like LH increase together with an elevated basal secretion of PRL. Injections of MK-801 occurring 9 and 11 h after estradiol-17beta injection rapidly and transiently increased serum LH in a very unexpected response. However, these same MK-801 injections also resulted in decreased serum LH 14-17 h after estradiol-17beta by delaying the onset of the surge-like release of LH. Estradiol-17beta administration itself elevated basal release of PRL to serum concentrations observed after repetitive MK-801, and further injection of MK-801 no longer transiently increased serum PRL as it had done prior to estradiol-17beta treatment. In summary, antagonizing the endogenous excitatory amino acid ligands of the NMDA receptor with MK-801 did not alter either the timing or magnitude of the putative episodic discharges of gonadotropin-releasing hormone (GnRH) which in turn cause the episodic releases of pituitary LH in ovx sheep. Estrogen administration created a transient neuroendocrine environment in which antagonism of these endogenous ligands was stimulatory to abrupt discharge of GnRH and thereby to acute release of LH. Antagonism of NMDA receptors in untreated ovx ewes stimulated release of PRL suggesting that the endogenous NMDA ligands were probably stimulatory to the release of a PRL-inhibiting neurohormone such as dopamine.

Animals↗
PubMed1998

Estradiol implants in the arcuate nucleus induce lactogenesis in virgin rats. Role of progesterone.

The aim of this study was to determine the effect of the centrally administered estradiol, and the effects of the consequent hypersecretion of prolactin (PRL) and progesterone, on lactogenesis as evaluated by mammary accumulation of casein and lactose. Bilateral cannulae containing 17beta-estradiol or cholesterol were implanted in the arcuate nucleus of virgin rats on the day of estrus (Day 0). In the first experiment different groups of rats were killed on Days 6, 9, 15, 17, or 19. Trunk blood was collected and abdominal mammary glands were taken. In the second experiment, estradiol-implanted rats received the progesterone antagonist mifepristone or vehicle at 14.00 h on Day 8 or 16 post-implant, and were killed 28 or 48 h later. Serum PRL and progesterone and mammary casein were measured by RIA and lactose was determined by an enzymatic assay. Estradiol-implanted rats showed a significant increase in both milk components at all time points after implant compared to controls. On Day 9 after estradiol implant, mifepristone had no effect on mammary content of casein or lactose. By contrast, on Day 16, mifepristone markedly increased both casein and lactose contents without modifying serum PRL and progesterone concentrations. In conclusion, 17beta-estradiol implants in the arcuate nucleus of virgin rats results in hyperprolactinaemia and stimulates mammary accumulation of casein and lactose in the absence of feto-placental units. Despite the prolonged luteal activation, the sustained high levels of circulating progesterone become inhibitory to lactogenesis after a relatively long period after implant.

Animals↗
PubMed1999

The role of beta 2-adrenergic vascular receptors in the peripheral vasodilation caused by 17 beta-estradiol in anesthetized pigs.

It has been previously shown in anesthetized pigs that intravenous infusion of 2 microg/h of 17beta-estradiol primarily dilated renal, iliac and coronary circulations, while higher doses of the hormone were required to cause vasodilation also in the mesenteric vascular bed. In the same experimental model, a tonic beta2-adrenoceptor mediated vasodilation, which could be argued to attenuate the vasodilator effect of 17beta-estradiol, has been described. The present study was planned to investigate the role of beta2-adrenergic receptors in the hemodynamic responses of renal and mesenteric vascular beds to 17beta-estradiol. Changes in flow caused by intravenous infusion of 2 microg/h of the hormone at constant heart rate and aortic blood pressure in the left renal and superior mesenteric arteries were assessed using electromagnetic flowmeters. In six pigs, infusion of 17beta-estradiol caused an increase in renal blood flow, which averaged 12.1% of the control values, without affecting mesenteric blood flow. In the same pigs, after hemodynamic variables had returned to the baseline values, blockade of beta2-adrenergic receptors with butoxamine caused an increase in aortic blood pressure and an increase in renal and mesenteric resistance. The subsequent infusion of 17beta-estradiol elicited increases in renal and mesenteric blood flow which respectively averaged 19.6% and 12.8%. Therefore, the present study in anesthetized pigs have shown that the vasodilator responses of the renal and mesenteric circulations to 17beta-estradiol were attenuated and even masked by a tonic beta2-adrenoceptor mediated vasodilation. This indicates that some vasodilator effects elicited by normally used replacement doses of the hormone may not be apparent.

Adrenergic beta-Antagonists↗
PubMed1996

Urinary excretion of testosterone and estradiol in Chinese men and relationships with serum lipoprotein concentrations.

Urinary excretion of total and free testosterone and estradiol was measured in 46 healthy Chinese men, along with serum concentrations of total testosterone and estradiol and the calculated free (unbound) concentrations. Associations with serum concentrations of total, low-density lipoprotein (LDL), high-density lipoprotein-2 (HDL2), and HDL3 cholesterol, apolipoproteins (apos) A-I and B, lipoprotein(a) [Lp(a)] were studied. Serum total and free testosterone concentrations were positively correlated with HDL and HDL2 cholesterol and apo A-I. Serum total and free estradiol levels showed borderline-significant negative associations with total and LDL cholesterol levels. Among urinary variables, total estradiol excretion was negatively associated with apo B levels and showed borderline-significant associations with total and LDL cholesterol. Adjustment for potential confounders, including age, body mass index (BMI), and waist to hip ratio (WHR), strengthened the associations between urinary total estradiol and serum total cholesterol, LDL cholesterol, and apo B. Urinary free estradiol showed a significant correlation with HDL3 cholesterol. Urinary excretion of total testosterone was significantly negatively associated with serum cholesterol and LDL cholesterol levels only after controlling for confounding variables. There were no significant associations between hormone variables and Lp(a) values. This study suggests that variation in sex hormone production accounts for some of the variation in serum lipid levels.

Adult↗
PubMed2002

Protective effects of estradiol against amyloid beta protein-induced inhibition of neuronal Cl(-)-ATPase activity.

Low concentrations of amyloid beta proteins (Abetas, 1-10 nM) were recently demonstrated to reduce Cl(-)-ATPase activity in parallel with an increase in the intracellular Cl(-) concentration ([Cl(-)]i) and decreases in plasma membrane phosphorylated phosphatidylinositol (PIP and PIP2) levels in cultured rat hippocampal neurons. In this study, 17 beta-estradiol (estradiol) at a therapeutic concentration (1.8 nM) for Alzheimer's disease was found to block these Abeta (Abeta25-35)-induced changes. This protective effect of estradiol on Cl(-)-ATPase activity was antagonized by a pure estrogen receptor antagonist, ICI182780 and inhibitors for cyclic GMP-dependent protein kinase (PKG) (KT5823), Ca(2+)-calmodulin-dependent protein kinase II (CaMKII) (KN62) and phosphatidylinositol (PI) 4-kinase (wortmannin and quercetin). Estradiol recovered Abeta-induced decreases in plasma membrane phosphoinositide (PIP and PIP2) levels, this effect being inhibited by KT5823 and KN62. Glutamate toxicity was augmented in neurons with elevated [Cl(-)]i either by Abeta-treatment or carbachol+KCl+LiCl-treatment. The increased glutamate toxicity in the Abeta-treated neurons was attenuated by estradiol. Thus, a therapeutic concentration of estradiol protected Abeta-treated neurons against inhibition of Cl(-)-ATPase activity and an increase in [Cl(-)]i through its receptor, probably via PKG- and CaMKII(-)mediated recovery of PI4P formation. Elevated [Cl(-)]i may be related to enhancement of glutamate toxicity.

Adenosine Triphosphatases↗
PubMed2002

High levels of estradiol impair spatial performance in the Morris water maze and increase 'depressive-like' behaviors in the female meadow vole.

The present study investigated sex differences and the effect of a high level of estradiol in the female meadow vole on performance in the forced swim test (FST) and the Morris water maze in meadow voles. Female meadow voles were ovariectomized (OVX) and administered either vehicle (sesame oil) or estradiol for 2 days prior to performing the FST. Four days following the FST, all animals were run in the Morris water maze. Results indicated that estradiol-injected female meadow voles showed more 'depressive-like' behaviors in the FST (greater time spent immobile and less time spent swimming) than vehicle-treated female or male meadow voles. In addition, estradiol-treated females had impaired performance (greater latencies and distance swam to reach the hidden platform) than both vehicle-treated female and male meadow voles, consistent with previous data. Despite the fact that estradiol administration increased 'depressive-like' behaviors in the FST and impaired performance in the Morris water maze, there was no correlation between the two behaviors indicating that 'depressive-like' behaviors did not account for the differences seen in spatial performance in the Morris water maze. To our knowledge, this is the first demonstration in rodents indicating that estradiol-mediated changes in behavior in the FST is not indicative of subsequent performance in the Morris water maze.

Animals↗
PubMed1981

Boron estrogens: synthesis, biochemical and biological testing of estrone and estradiol-17 beta 3-carboranylmethyl ethers.

Synthesis, biochemical and biological testing of the first carborane derivatives of estrogens are described. Estrone 3-carboranylmethyl ether was synthesized in two steps from estrone. Reduction of estrone 3-carboranylmethyl ether with sodium borohydride provided estradiol-17 beta 3-carboranylmethyl ether. Enzyme kinetic measurements showed that estrone 3-carboranylmethyl ether is a substrate for human placental 17 beta-hydroxysteroid dehydrogenase with Km = 5 x 10(-6)M, and Vmax = 0.016 mumol min-1 microgram -1. The relative affinity constant of estradiol-17 beta 3-carboranylmethyl ether for rat uterine estrogen receptor was 0.5 (compared with a value of 100 for estradiol-17 beta). Consistent with its low affinity for estrogen receptor, the dose-dependent uterotropic response to estradiol-17 beta 3-carboranylmethyl ether in castrated female rats was one sixtieth that of estradiol-17 beta. None of the tested rats had a toxic reaction to estradiol-17 beta 3-carboranylmethyl ether. These results demonstrate that exceptionally stable carborane derivatives of estrogens can be synthesized with preservation of their biochemical and biological properties. Boron-containing estrogens may be useful for thermal neutron capture therapy of cancers with estrogen receptors to concentrate boron in the cell nucleus.

17-Hydroxysteroid Dehydrogenases↗
PubMed2004

Effects of estradiol and progesterone on radial maze performance in middle-aged female rats fed a low-calcium diet.

There is increasing evidence that ovarian steroids and calcium ions are involved in learning and memory. To examine the effect of ovarian steroids on learning and memory under a low-calcium condition, middle-aged female rats were fed either a low-calcium (0.02% Ca) or a normal-calcium (1.25% Ca) diet. All rats were ovariectomized (OVX), and these animals were divided into eight groups: 1) an OVX group with a normal-calcium diet (OVX-normal-Ca group), 2) an OVX group with 17beta-estradiol treatment and a normal-calcium diet (E2 group), 3) an OVX with progesterone treatment and a normal-calcium diet (P4 group), 4) an OVX with 17beta-estradiol and progesterone treatments and a normal-calcium diet (E2 + P4 group), 5) an OVX group with a low-calcium diet (OVX-low-Ca group), 6) an OVX group with 17beta-estradiol treatment and a low-calcium diet (LE2 group), 7) an OVX group with progesterone treatment and a low-calcium diet (LP4 group), and 8) an OVX group with 17beta-estradiol and progesterone treatments and a low-calcium diet (LE2 + LP4). Seventy-seven days after the OVX operation, the learning and memory abilities of the rats were examined by using an eight-arm radial maze task. E2 and E2 + P4 groups learned in fewer trials, and performed better in the radial maze and the working memory task than the other groups under the normal-calcium condition. Rats in the LE2 group learned in fewer trials, and performed better in the maze and working memory task than the other low-calcium groups, but in combination with progesterone under the low-calcium condition (LE2 + LP4 group), the facilitative effect of estradiol in all the tasks was inhibited. Treatment with progesterone alone did not inhibit the learning and memory task performance. These results suggest the possibility that treatment with estradiol under low-calcium conditions cannot improve impaired learning and memory when progesterone is applied simultaneously, and that the intake of adequate calcium may be necessary and effective for patients with learning and memory hypofunction receiving hormone replacement therapy.

Animals↗
PubMed2000

Bone morphogenetic protein-2 induces cyclin kinase inhibitor p21 and hypophosphorylation of retinoblastoma protein in estradiol-treated MCF-7 human breast cancer cells.

The biologic effects and mechanisms by which bone morphogenetic proteins (BMPs) function in breast cancer cells are not well defined. A member of this family of growth and differentiation factors, BMP-2, inhibited both basal and estradiol-induced growth of MCF-7 breast tumor cells in culture. Flow cytometric analysis showed that in the presence of BMP-2, 62% and 45% of estradiol-stimulated MCF-7 cells progressed to S-phase at 24 h and 48 h, respectively. Estradiol mediates growth of human breast cancer cells by stimulating cyclins and cyclin-dependent kinases (CDKs). BMP-2 significantly increased the level of the cyclin kinase inhibitor, p21, which in turn associated with and inactivated cyclin D1. BMP-2 inhibited estradiol-induced cyclin D1-associated kinase activity. Also estradiol-induced CDK2 activity was inhibited by BMP-2. This inhibition of CDK activity resulted in hypophosphorylation of retinoblastoma protein thus keeping it in its active form. These data provide the first evidence by which BMP-2 inhibits estradiol-induced proliferation of human breast cancer cells.

Bone Morphogenetic Protein 2↗