Biomedical subjects

J Dupont

Publications and source records attributed to J Dupont.

At least 19 recordsLinked to original sources

PubMed2006

Peroxisome proliferator-activated receptors in reproductive tissues: from gametogenesis to parturition.

Peroxisome proliferator-activated receptors (PPARalpha, PPARbeta/delta and PPARgamma) are a family of nuclear receptors that are activated by binding of natural ligands, such as polyunsaturated fatty acids or by synthetic ligands. Synthetic molecules of the glitazone family, which bind to PPARgamma, are currently used to treat type II diabetes and also to attenuate the secondary clinical symptoms frequently associated with insulin resistance, including polycystic ovary syndrome (PCOS). PPARs are expressed in different compartments of the reproductive system (hypothalamus, pituitary, ovary, uterus and testis). Conservative functions of PPARs in mammalian species could be suggested through several in vivo and in vitro studies, especially in the ovary and during placental development. Several groups have described a strong expression of PPARgamma in ovarian granulosa cells, and glitazones modulate granulosa cell proliferation and steroidogenesis in vitro. All these recent data raise new questions about the biologic actions of PPARs in reproduction and their use in therapeutic treatments of fertility troubles such as PCOS or endometriosis. In this review, we first describe the roles of PPARs in different compartments of the reproductive axis (from male and female gametogenesis to parturition), with a focus on PPARgamma. Secondly, we discuss the possible molecular mechanisms underlying the effect of glitazones on PCOS. Like other 'insulin sensitizer' molecules, such as metformin, glitazones may in fact act directly on ovarian cells. Finally, we discuss the eventual actions of PPARs as mediators of environmental toxic substances for reproductive function.

Corpus Luteum↗

PubMed2005

Phase I trial of bortezomib and carboplatin in recurrent ovarian or primary peritoneal cancer.

PURPOSE: To determine the maximum-tolerated dose, pharmacodynamics, and safety of the combination of bortezomib and carboplatin in recurrent ovarian cancer. PATIENTS AND METHODS: Fifteen patients were treated with a fixed dose of carboplatin (area under the curve [AUC] 5) and increasing doses of bortezomib (0.75, 1, 1.3, and 1.5 mg/m2/dose). Patients must have received upfront chemotherapy and up to two prior chemotherapy regimens for recurrent disease. Neurologic evaluation was performed at baseline and after every two cycles by the Functional Assessment of Cancer Therapy/Gynecologic Oncology Group neurotoxicity questionnaire and examination by an attending neurologist. All patients received carboplatin alone in cycle 1 to establish baseline pharmacodynamics for nuclear factor-kappa B (NF-kB). Starting with cycle 2, patients were treated with carboplatin on day 1 and bortezomib on days 1, 4, 8, and 11. RESULTS: Diarrhea, rash, neuropathy, and constipation (with colonic wall thickening on computed tomography) were dose-limiting toxicities, occurring in the two patients treated at the 1.5 mg/m2/dose level. The Functional Assessment of Cancer Therapy/Gynecologic Oncology Group neurotoxicity questionnaire was helpful in guiding the need for dose reductions. Neurotoxicity was manageable through six cycles, with appropriate dose reductions. Carboplatin had no effect on bortezomib pharmacodynamics as measured by percent inhibition of the 20S proteasome. Bortezomib decreased carboplatin-induced NF-kB. The overall response rate to this combination was 47%, with two complete responses (CR) and five partial responses, including one CR in a patient with platinum-resistant disease. CONCLUSION: The recommended phase II dose of bortezomib administered in combination with carboplatin (AUC 5) is 1.3 mg/m2/dose.

Aged↗

PubMed2005

Estimation of critical loads of acidity for lakes in northeastern United States and eastern Canada.

The New England Governors and Eastern Canadian Premiers (NEG/ECP) adopted the Acid Rain Action Plan in June 1998, and issued a series of action items to support its work toward a reduction of sulfur dioxide (SO(2)) and nitrogen oxide (NO(x)) emissions in northeastern North America. One of these action items was the preparation of an updated critical load map using data from lakes in the NEG/ECP area. Critical load maps provide a more complete index of the surface water sensitivity to acidification. Combined sulfur and nitrogen critical loads and deposition exceedances were computed using Henriksen's Steady-State Water Chemistry (SSWC) model. Results show that 28% of all 2053 lakes studied have a critical load of 20 kg/ha/year or less, making them vulnerable to acid deposition. Emission reductions, and more specifically SO(2) emission reductions have proven beneficial because critical loads were exceeded in 2002 for 12.3% of all studied lakes. Those lakes are located in the more sensitive areas where geology is carbonate-poor. Of these lakes, 2.9% will never recover even with a complete removal of SO(4) deposition. Recovery from acidification for the remaining 9.4% of the lakes will require additional emission SO(2) reductions.

Acid Rain↗

PubMed2005

Internal transcribed spacer rRNA gene-based phylogenetic reconstruction using algorithms with local and global sequence alignment for black yeasts and their relatives.

Sequences of rRNA gene internal transcribed spacer (ITS) of a standard set of black yeast-like fungal pathogens were compared using two methods: local and global alignments. The latter is based on DNA-walk divergence analysis. This method has become recently available as an algorithm (DNAWD program) which converts sequences into three-dimensional walks. The walks are compared with, or fit to, each other generating global alignments. The DNA-walk geometry defines a proper metric used to create a distance matrix appropriated for phylogenetic reconstruction. In this work, the analyses were carried out for species currently classified in Capronia, Cladophialophora, Exophiala, Fonsecaea, Phialophora, and Ramichloridium. Main groups were verified by small-subunit rRNA gene data. DNAWD applied to ITS2 alone enabled species recognition as well as phylogenetic reconstruction reflecting clades discriminated in small-subunit rRNA gene phylogeny, which was not possible with any other algorithm using local alignment for the same data set. It is concluded that DNAWD provides rapid insight into broader relationships between groups using genes that otherwise would be hardly usable for this purpose.

Algorithms↗

PubMed2004

Calibration of the impedance method for rapid quantitative estimation of Escherichia coli in live marine bivalve molluscs.

AIM: Calibration of impedance measurement was performed vs the Association Françoise de Normalisation (AFNOR) MPN method with a view to rapid enumeration of Escherichia coli in live marine bivalve molluscs. METHODS AND RESULTS: Linear regression models between log10 MPN and detection time (DT) were adjusted for several shellfish types, growth media, and impedance instruments (BacTrac and Malthus systems). Escherichia coli concentrations could be estimated from DT using a single regression line for BacTrac 4100 with M1 medium (R2 = 87.8%) and Malthus with M2 medium (R2 = 86.7%), and two regression lines for BacTrac 4110 with M2 medium (R2 = 86.4 and 88.2%). The uncertainty of the predicted bacterial concentration was around +/-0.43 log unit for duplicate sample analysis. The impedance signal was attributable to E. coli in 99% of cases. All cultures containing E. coli produced an impedance signal with BacTrac 4100 and BacTrac 4110, whereas 5.6% did not exhibit a signal with Malthus. CONCLUSIONS: Impedance measurement is a possible alternative to the MPN method for rapid quantitative estimation of E. coli in live bivalve shellfish. SIGNIFICANCE AND IMPACT OF THE STUDY: The impedance method reduces analysis handling time considerably and is much easier to use than the MPN method. Moreover, results can be obtained within 5-10 h, allowing rapid intervention to ensure public health protection in case of shellfish contamination.

Animals↗

PubMed2004

Molecular basis of bone morphogenetic protein-4 inhibitory action on progesterone secretion by ovine granulosa cells.

We have recently reported that bone morphogenetic protein-4 (BMP-4) can inhibit progesterone production by ovine granulosa cells (GCs). Here, we have investigated the underlying mechanisms of this effect in basal as well as in FSH-induced conditions. We have confirmed that treatment with BMP-4 decreased basal GC progesterone secretion and totally abolished FSH-stimulating action. This inhibitory action was associated with a decrease in the expression of cAMP-regulated genes, steroidogenic acute regulatory protein (StAR) and P450 side-chain cleavage (P450 scc) at mRNA and protein levels. However, BMP-4 did not alter basal cAMP production by GCs. In contrast, BMP-4 decreased by half the FSH-induced cAMP production and strongly inhibited cAMP-induced progesterone production. Thus, the inhibitory effect of BMP-4 was exerted both upstream and downstream of cAMP signalling. We next examined the downstream effect, focusing on cAMP-dependent transcription factors, steroidogenic factor-1 (SF-1) and CREB, through the BMP factor signalling intermediary, Smad1. As expected, BMP-4 induced phosphorylation and transcriptional activity of Smad1 in ovine GCs. BMP-4-activated Smad1 did not affect CREB activity but inhibited the transcriptional activity of SF-1 on the canonical SF-1 responsive element. Interestingly, this transcriptional inhibitory mechanism occurred on transfected StAR and P450 scc promoter. Based on these results, we propose that SF-1 is a key target in the inhibitory mechanism exerted by BMP-4 on progesterone synthesis by ovine GCs in culture. Because SF-1 plays an essential role in the differentiation of GCs, our findings could have new implications in understanding the role of BMP family members in the control of ovarian folliculogenesis.

Animals↗

PubMed2004

Activin and inhibin receptor gene expression in the ewe pituitary throughout the oestrous cycle.

In mammals, activin and inhibin are important regulators of FSH secretion. Previous studies have demonstrated that primary ovine pituitary cells express different activin receptor subtypes: activin receptor-like (ALK)2, ALK4, activin type II receptor A (ActRIIA), ActRIIB and Smad proteins in vitro. Here, we have carried out physiological studies to investigate the pattern of mRNA expression of the activin receptor subunits in the ewe pituitary throughout the oestrous cycle. The oestrous cycles of ewes were synchronized with progestagen sponges. The animals were killed 36 h (before the preovulatory surge, n=4), 48 h (during the preovulatory surge, n=4), 72 h (during the second surge of FSH, n=6) and 192 h (during the luteal phase, n=4) after sponge removal. Using Northern blots, we have shown that the levels of ALK2, ALK4 and ActRIIB mRNA were significantly higher before the preovulatory surge and during the secondary surge of FSH as compared with both during the preovulatory surge and the luteal phase, whereas the level of the ActRIIA mRNA was similar throughout the oestrous cycle. Using Western blots we have also demonstrated that the level of phospho-Smad2 did not vary during the reproductive cycle. Inhibin binding protein (InhBP/p120) and the transforming growth factor-beta type III receptor, betaglycan, have been identified as putative inhibin co-receptors. In this study, we cloned a fragment of both InhBP/p120 and betaglycan cDNAs in the ewe and showed by Northern blot that pituitary betaglycan and InhBP/p120 mRNA levels did not fluctuate across the oestrous cycle nor did they correlate with serum FSH levels.

Activin Receptors↗

PubMed2003

Association between lower optic nerve laser Doppler blood volume measurements and glaucomatous visual field progression.

AIM: To perform a preliminary assessment of the relation between optic nerve circulatory parameters and glaucomatous visual field progression. METHODS: This study included 29 eyes of 23 patients with open angle glaucoma that had typical glaucomatous nerve fibre bundle visual field defects and increased cup to disc ratios. Laser Doppler flowmetry (Oculix) was used to measure relative optic nerve blood volume (Vol), velocity (Vel) and flow in the superior temporal (ST) and inferior temporal (IT) neuroretinal rim of the optic nerve. After blood flow measurements patients were followed for 6-62 months (mean 33 (SD 17) months) and 2-11 Humphrey visual fields (4.7 (2.6) fields) were obtained. Progression of glaucoma was assessed by the slope of the corrected pattern standard deviation (CPSD) values versus time, which was calculated manually for each eye using regression analysis. RESULTS: A significant negative correlation was observed between Vol in the IT rim and the CPSD slope (r=-0.56, p=0.002); patients with lower Vol tended to show faster progression of glaucomatous field damage than those with higher Vol. When the eyes were arbitrarily divided into two groups according to lower Vol (0.32 (0.06) arbitrary units, AU, n=15) or higher Vol (0.49 (0.06) AU, n=14), those with lower Vol had significantly worse mean CPSD slopes (0.50 (0.48) dB/year) than those with higher Vol (-0.67 (1.38) dB/year; Student's t test, p=0.009). CONCLUSIONS: In the IT rim, the area most prone to develop glaucomatous field damage, lower Vol is associated with subsequently faster CPSD progression. These measurements suggest that circulatory abnormalities may have a role in the development of glaucoma.

Adult↗

PubMed2001

NiCl(2)(PCy(3))(2): a simple and efficient catalyst precursor for the Suzuki cross-coupling of aryl tosylates and arylboronic acids.

NiCl(2)(PCy(3))(2) associated with PCy(3) promotes the selective cross-coupling of aryltosylates with arylboronic acids under relatively mild reaction conditions, and a variety of functional groups are tolerated in both arenes. This is one of the simplest and most efficient experimental procedures for the coupling of arylboronic acids with aryl tosylates reported to date. Reaction: see text.

Journal Article↗

PubMed2001

Functional inactivation of the IGF-I and insulin receptors in skeletal muscle causes type 2 diabetes.

Peripheral insulin resistance and impaired insulin action are the primary characteristics of type 2 diabetes. The first observable defect in this major disorder occurs in muscle, where glucose disposal in response to insulin is impaired. We have developed a transgenic mouse with a dominant-negative insulin-like growth factor-I receptor (KR-IGF-IR) specifically targeted to the skeletal muscle. Expression of KR-IGF-IR resulted in the formation of hybrid receptors between the mutant and the endogenous IGF-I and insulin receptors, thereby abrogating the normal function of these receptors and leading to insulin resistance. Pancreatic beta-cell dysfunction developed at a relative early age, resulting in diabetes. These mice provide an excellent model to study the molecular mechanisms underlying the development of human type 2 diabetes.

Aging↗

PubMed2001

Insulin-like growth factor 1 (IGF-1)-induced twist expression is involved in the anti-apoptotic effects of the IGF-1 receptor.

In this study we investigated the molecular mechanisms whereby insulin-like growth factor 1 (IGF-1) induced Twist gene expression and the role of Twist in the anti-apoptotic actions of the IGF-1 receptor. In NIH-3T3 fibroblasts overexpressing the human IGF-1 receptor (NWTb3), treatment with IGF-1 (10(-8) m) for 1 and 4 h increased the level of Twist mRNA as well as protein by 3-fold. In contrast, insulin at physiological concentrations did not stimulate Twist expression in NIH-3T3 fibroblasts overexpressing the human insulin receptor. The IGF-1 effect was specific for the IGF-1 receptor since, in cells overexpressing a dominant negative IGF-1 receptor, IGF-1 failed to increase Twist expression. Pre-incubation with the ERK1/2 inhibitor U0126 or expression of a dominant negative MEK-1 abolished the effect of IGF-1 on Twist mRNA expression in NWTb3 cells, suggesting that Twist induction by IGF-1 occurs via the mitogen-activated protein kinase signaling pathway. In vivo, IGF-1 injection increased the mRNA level of Twist in mouse skeletal muscle, the major site of Twist expression. Finally, using an antisense strategy, we demonstrated that a reduction of 40% in Twist expression decreased significantly the ability of IGF-1 to rescue NWTb3 cells from etoposide-induced apoptosis. Taken together, these results define Twist as an important factor involved in the anti-apoptotic actions of the IGF-1 receptor.

3T3 Cells↗

PubMed2001

Effect of sildenafil citrate (Viagra) on the ocular circulation.

PURPOSE: Sildenafil citrate induces vasodilation by enhancing the smooth muscle relaxant effects of nitric oxide. We have previously reported that nitrate compounds, a different group of nitric oxide-mediated vasodilators used mainly for the treatment of ischemic cardiac diseases, produce an increase in optic nerve head circulation and retinal venous vasodilation. The purpose of the present investigation was to evaluate the effect of sildenafil on ocular circulation. METHODS: In a double-blind, randomized, crossover trial, 15 healthy male volunteers received 100-mg doses of sildenafil citrate (Viagra; Pfizer, Inc, New York, New York) or matching placebo on 2 separate days. Laser Doppler flowmetry was used to assess foveolar choroidal and optic nerve rim circulatory parameters. Measurements were obtained in one eye at baseline, 1 hour, and 5 hours after dosing. Blood pressure and intraocular pressure were monitored, and perfusion pressure was calculated. RESULTS: Mean optic nerve head blood flow measurements at baseline, 1 hour, and 5 hours were 11.6 +/- 2.2 arbitrary units (+/- SD), 12.5 +/- 2.8, and 12.1 +/- 2.4 after sildenafil and 11.9 +/- 2.5, 12.6 +/- 3.1, and 13.0 +/- 3.0 after placebo, respectively. When compared with placebo, no significant change in mean blood pressure, intraocular pressure, perfusion pressure, or choroidal or optic nerve circulatory parameters were observed after sildenafil treatment. The power to detect a 20% change in optic nerve head and choroidal blood flow after sildenafil was approximately 90%. CONCLUSIONS: In comparison with placebo, no significant change in optic nerve rim or foveolar choroidal blood flow was observed after treatment with sildenafil. This suggests that nitrate compounds and sildenafil may differentially affect ocular circulation. Furthermore, no significant effects on intraocular pressure, systemic blood pressure, or ocular perfusion pressure were detected after sildenafil treatment.

Adult↗

PubMed2001

Optic nerve blood flow is diminished in eyes of primary open-angle glaucoma suspects.

PURPOSE: The purpose of this study was to evaluate optic nerve blood flow in primary open-angle glaucoma suspect eyes with normal automated visual fields, in an attempt to elucidate how early in the glaucomatous disease process changes in optic nerve blood flow become apparent. METHODS: Twenty-one eyes (21 patients) suspected of having primary open-angle glaucoma were studied prospectively and compared with a previously reported cohort of 22 eyes (22 patients) with primary open-angle glaucoma and 15 eyes (15 subjects) of age-matched controls. Primary open-angle glaucoma suspect eyes had untreated intraocular pressure greater than 21 mm Hg and normal visual fields using Humphrey program 24-2 or 30-2 with a full threshold strategy. Laser Doppler flowmetry was used to measure optic nerve head blood velocity, volume, and flow at four quadrants in the optic nerve, in the cup, and in the foveola of one eye of each patient. The mean flow from the superotemporal rim, inferotemporal rim, and cup was calculated (Flow(3)) and identified as the main outcome measure. Measurements from primary open-angle glaucoma suspect eyes were compared with corresponding measurements from controls and eyes with primary open-angle glaucoma; a Student t test was employed with a Bonferroni corrected P value of.025 to account for comparisons of primary open-angle glaucoma suspects both to controls and to eyes with primary open-angle glaucoma. RESULTS: Compared with controls, Flow(3) was 24% lower in primary open-angle glaucoma suspect eyes (P <.0003). In primary open-angle glaucoma suspect eyes, flow was 16% lower in the superotemporal rim (P <.007), 35% lower in the cup (P <.007), and 22% lower in the inferotemporal neuroretinal rim (P <.029) compared with controls. No significant difference between primary open-angle glaucoma suspect and control eyes was seen in the inferonasal rim, superonasal rim, or foveola. No significant difference was detected at any location between primary open-angle glaucoma suspect eyes and eyes with primary open-angle glaucoma. CONCLUSIONS: Laser Doppler flowmetry detected circulatory abnormalities in primary open-angle glaucoma suspects who did not have any manifest visual field defect. Decreases in flow in glaucoma suspects were similar in magnitude to those of subjects with primary open-angle glaucoma. These data suggest that impaired optic nerve blood flow develops early in the glaucomatous process and does not develop solely as a result of glaucoma damage.

Blood Flow Velocity↗

PubMed2001

Acute effects of sldenafil ctrate (Viagra) on intraocular pressure in open-angle glaucoma.

PURPOSE: To assess the acute effects of sildenafil citrate (VIAGRA) on the intraocular pressure (IOP) of patients with chronic open-angle glaucoma. DESIGN: This was a double-blind, randomized, placebo-controlled, crossover study, in which 15 patients received a single oral dose of sildenafil 100 mg or matching placebo on two separate occasions. METHODS: Fifteen subjects aged 63 +/- 14 years (mean +/- SD) with bilateral chronic open-angle glaucoma were administered a single oral dose of sildenafil 100 mg or matching placebo on two separate occasions at least 3 days apart. IOP was measured in both eyes by Goldmann ap-planation tonometry at baseline and then at 1-5 hours after dosing. Brachial artery systolic and diastolic blood pressures were determined by sphygmomanometry, and heart rate was also monitored at baseline and 1-5 hours after dosing. RESULTS: Compared with placebo, no statistically or clinically significant change in IOP was detected after a single dose of sildenafil 100 mg (P =.20). Moreover, no significant change in mean systemic blood pressure (P =.12) or heart rate (P =.72) was detected after treatment with sildenafil. CONCLUSION: At the maximum therapeutic dose of 100 mg, sildenafil did not produce any significant acute change in IOP in men with chronic open-angle glaucoma. This information is of importance for patients with glaucoma receiving sildenafil for treatment of erectile dysfunction.

3',5'-Cyclic-GMP Phosphodiesterases↗

PubMed2001

Insulin-like growth factor 1 and oestradiol promote cell proliferation of MCF-7 breast cancer cells: new insights into their synergistic effects.

In MCF-7 breast cancer cells, the insulin-like growth factor 1 receptor (IGF-1R) and the oestrogen receptor (ER) are coexpressed and the two signalling systems are engaged in a crosstalk that results in synergistic growth. However, coupling between the signalling cascades is poorly understood. Oestradiol enhances IGF-1R signalling by inducing the expression of insulin receptor substrate 1 (IRS-1), a substrate of the IGF-1R. Oestradiol induced expression of IRS-1 results in enhanced tyrosine phosphorylation of IRS-1 after IGF-1 stimulation, followed by enhanced mitogen activated protein kinase, phosphoinositide 3' kinase, and Akt activation. Oestradiol can also potentiate the effect of IGF-1 on the expression of cyclin D1 and cyclin E, and on the phosphorylation of the retinoblastoma protein (RB). These effects are greatly diminished in SX13 cells, which exhibit a 50% reduction in IGF-1R expression but few functional IGF-1Rs at the surface. Oestradiol and IGF-1 regulate the expression of two cyclin dependent kinase inhibitors, p21 and p27, differently. Whereas IGF-1 increases p21 expression and reduces p27 expression, oestradiol has no effect on p21. In summary, in MCF-7 cells, oestrogen potentiates the effect of IGF-1 on IGF-1R signalling and its effects on certain cell cycle components.

Breast Neoplasms↗

PubMed2001

Insulin and insulin-like growth factor I receptors: similarities and differences in signal transduction.

The insulin receptor (IR) and the insulin-like growth factor I receptor (IGF-IR) belong to the same subfamily of receptor tyrosine kinases with two extracellular alpha-subunits and two transmembrane beta-subunits. They share a high similarity of structure and intracellular signalling events. However, the IR and the IGF-IR mediate different effects on metabolism, cell proliferation, apoptosis and differentiation. Although some of the variation can be attributed to a different tissue distribution or subcellular localization, it can also be explained by structural differences in the beta-subunit, which may result in activation of specific substrates and signal pathways.

Animals↗

PubMed2001

Insulin and IGF-1 induce different patterns of gene expression in mouse fibroblast NIH-3T3 cells: identification by cDNA microarray analysis.

The IGF-1 receptor and the related insulin receptor are similar in structure and activate many of the same postreceptor signaling pathways, yet they mediate distinct biological functions. It is still not understood how the specificity of insulin vs. IGF-1 signaling is controlled. In this study, we have used cDNA microarrays to monitor the gene expression patterns that are regulated by insulin and IGF-1. Mouse fibroblast NIH-3T3 cells expressing either the wild-type human IGF receptor or the insulin receptor were stimulated with either IGF-1 or insulin, respectively. Thirty genes, 27 of which were not previously known to be IGF-1 responsive, were up-regulated by IGF-1 but not by insulin. Nine genes, none of which was previously known to be insulin responsive, were up-regulated by insulin but not by IGF-1. The IGF- and insulin-induced regulation of 10 of these genes was confirmed by Northern blot analysis. Interestingly, more than half of the genes up-regulated by IGF-1 are associated with mitogenesis and differentiation, whereas none of the genes specifically up-regulated by insulin are associated with these processes. Our results indicate that under the conditions used in this study, IGF-1 is a more potent activator of the mitogenic pathway than insulin in mouse fibroblast NIH-3T3 cells.

3T3 Cells↗

PubMed2000

The potentiation of estrogen on insulin-like growth factor I action in MCF-7 human breast cancer cells includes cell cycle components.

To gain insight into the mechanisms involved in the cross-talk between IGF-1 receptor (IGF-1R) and estrogen receptor signaling pathways, we used MCF-7-derived cells (SX13), which exhibit a 50% reduction in IGF-1R expression. Growth of NEO cells (control MCF-7 cells) was stimulated by both IGF-1 and estradiol (E2), and the addition of both mitogens resulted in a synergistic response. Estrogen enhanced IGF-1R signaling in NEO cells, but this effect was markedly diminished in SX13 cells. Estrogen was also able to potentiate the IGF-1 effect on the expression of cyclin D1 and cyclin E and on the phosphorylation of retinoblastoma protein in control but not in SX13 cells. IGF-1 increased the protein level of p21 and the luciferase activity of the p21 promoter, whereas it only reduced the protein level of p27 without affecting p27 promoter activity. Estrogen did not affect the p21 inhibitor, but it decreased the protein level of p27 and the p27 promoter luciferase activity. These effects of both mitogens were also observed at the level of association of both cyclin-dependent kinase inhibitors with CDK2 suggesting that IGF-1 and E2 affect the activity of both p21 and p27. Taken together, these data suggest that in MCF-7 cells, estrogen potentiates the IGF-1 effect on IGF-1R signaling as well as on the cell cycle components. Moreover, IGF-1 and E2 regulate the expression of p21 and p27 and their association with CDK2 differently.

Breast Neoplasms↗