Randal Jaffe - Academia.edu (original) (raw)

Papers by Randal Jaffe

Biology of Reproduction, 1998

Journal of Steroid Biochemistry, 1986

These results clearly illustrate that the chronic administration of P decreases the uterine conce... more These results clearly illustrate that the chronic administration of P decreases the uterine concentration of its own receptor, and suggests that P decreases the E, receptor system by a selective action within the nucleus which diminishes their ability to retain EnR.

Endocrine, 2006

In the human and non-human primate the major secretory product of the uterine glandular epithelia... more In the human and non-human primate the major secretory product of the uterine glandular epithelial cells is glycodelin. The expression of glycodelin is associated with elevated progesterone levels as its production peaks during the late luteal phase of the menstrual cycle and in early pregnancy. Consistent with our previous studies, we found that the majority of the progestin responsiveness of the baboon glycodelin promoter was retained in the-20/+48 region, a region devoid of progestin-and Sp1-response elements. Using serial 5' and 3' deletions of 10 basepairs of the promoter within the pGL3Basic vector, we identified the 5' and 3' limits required for progestin responsiveness as-22 and +18, respectively. When the same regions were cloned into the pGL3Promoter vector, a construct that contains the heterologous SV40 promoter, progestin did not enhance expression. Mutation of the DNA binding domain of the progesterone receptor, which disrupts its ability to activate the progesterone response element, does not obliterate its ability to induce expression via the baboon glycodelin promoter. Inhibitors of protein tyrosine kinases, genistein and AG18, blocked the progestin-mediated induction as did an inhibitor of MEK, PD98059, but not an inhibitor of p38 MAP kinase, SB202190. These findings imply that glycodelin induction in response to progestins involves a nongenomic mechanism through the ERK1/2 branch of the MAP kinase pathway. The ultimate target may be a factor involved in the initiation of glycodelin gene transcription.

Journal of Pharmacy and Pharmacology, 1978

Consumption of an ethanol-containing diet by mice resulted in a significant increase in circulati... more Consumption of an ethanol-containing diet by mice resulted in a significant increase in circulating concentrations of corticosterone which was maintained for 8 days. There were no changes in the concentrations of plasma corticosterone binding globulin. Ethanol withdrawal symptoms followed the removal of ethanol from the diet and circulating corticosterone concentrations were further increased. There was no correlation between blood ethanol and glucocorticoid concentrations during the chronic ethanol treatment. Stress related to ethanol consumption may be of greater importance than the circulating ethanol concentrations in producing the elevation in plasma glucocorticoids.

Biology of Reproduction, 2003

Insulin-like growth factor binding protein-1 (IGFBP-1) is abundantly expressed in the liver and d... more Insulin-like growth factor binding protein-1 (IGFBP-1) is abundantly expressed in the liver and decidualized endometrium. FKHR, a FOXO forkhead transcription factor, stimulates IGFBP-1 promoter activity in liver cells through the insulin response sequences (IRSs). HOXA10, a homeobox transcription factor, is important in the decidualization process. Here we show that FKHR and HOXA10 are expressed in baboon endometrium during the menstrual cycle and pregnancy. Levels are lowest during the follicular phase and highest in pregnancy. Reporter gene studies reveal that FKHR stimulates both baboon and human IGFBP-1 promoter activity, whereas HOXA10 alone has a relatively weak effect. When FKHR and HOXA10 are expressed together, promoter activity is markedly up-regulated, which is indicative of cooperativity. A DNA binding-deficient FKHR mutant fails to stimulate promoter activity, even in the presence of HOXA10, and deletion or mutation of IRSs also disrupts the effect of FKHR and cooperativity with HOXA10. Conversely, the IRS region placed upstream of the 31 base pair IGFBP-1 minimal promoter is sufficient to mediate effects of FKHR and cooperativity with HOXA10. Pull-down studies reveal physical association between GST-FKHR and 35 S-HOXA10. These studies show that FKHR and HOXA10 interact directly and can function cooperatively to stimulate IGFBP-1 promoter activity in endometrial cells and perhaps in other settings.

Biochimica et Biophysica Acta (BBA) - General Subjects, 1975

The binding of progesterone-receptor complexes to chromatin from target and nontarget tissues was... more The binding of progesterone-receptor complexes to chromatin from target and nontarget tissues was studied in vitro. Chromatin from both ta~;et and nontarget tissues responds in a similar manner to saly and cofactors and has the same K D (approx. 3 • 10-9 M) for the progesterone-receptor complex. The only observed difference in the binding of the progesterone-receptor complex to target and nontarget chromatins is the difference in total number of acceptor sites. Oviduct chromatin has approx. 1300 sites/pg DNA, spleen chromatin has approx. 840 sites/pg DNA, and erythrocyte chromatin has about 330 sites/pg DNA. The K n and number of acceptor sites for progesterone-receptor complex binding to oviduct chromatin remains the same even after extensive purification of the progesterone-receptor complex. Activation of cytosol labeled with [3H]progesterone by preincubation at 25°C, analogous to that required for maximal nuclear binding, occurs if the binding studies to chromatin are performed in 0.025 M salt. The absence of an observable temperature effect when the studies are performed at 0.15 M salt is due to the activation of the receptor by salt. The dissociation of the progesterone-receptor complex from chromatin exhibits a single dissociation rate and the initial event is the appearance of free progesterone rather than a progesterone-receptor complex. Lastly, the treatment of chromatin with an antibody prepared against either single-stranded DNA or double-stranded DNA does not alter the extent of binding of the progesterone-receptor complex. Similarly, pretreatment of chromatin with a single-stranded nuclease does not inhibit the capacity of chromatin to bind the hormone-receptor complex.

Journal of Steroid Biochemistry, 1979

ABSTRACT

Molecular and Cellular Endocrinology, 1977

The binding of triiodothyronine by Rana catesbeiana tadpole liver and tail fin cytoplasmic protei... more The binding of triiodothyronine by Rana catesbeiana tadpole liver and tail fin cytoplasmic proteins was studied using protamine sulfate to separate bound and free hormone. The number of binding sites and the dissociation constant for triiodothyronine in liver cytosol did not differ between tissue taken from animals of stage I to V (premetamorphic) and tissue from tadpoles of stage XX (metamorphic climax). The same was true for the binding of triiodothyronine to tail fin cytosol from animals of the two stages. There were, however, significant differences between the liver and tail fin cytosol of tissue from animals of stage I to V for the number of binding sites for triiodothyronine (2.0 X 10-l 1 mol/mg protein vs. 6.2 X 10-l 1 mol/mg protein) and the dissociation constant (4.6 X 10Fs M vs. 1.6 X lo@ M). Similarly, significant differences between liver and tail fin cytosol from tadpoles of stage XX in the number of binding sites (1.9 X 10-l 1 mol/mg protein vs. 7.6 X 10-l 1 mol/mg protein) and dissociation constant (3.0 X 10es M vs. 1.3 X lo-* M) were observed. No distinctive differences were noted in the rate of dissociation of triiodothyronine from cytoplasmic proteins from the two tissues (tl/Z from liver cytosol of 31.5 min vs. t1/2 from tail fin cytosol of 24.0 min) or in the relative binding of various thyroid hormone analogs. Of interest was the observation that L-thyroxine is a lOOO-fold weaker competitor than L-triiodothyronine for displacement of labeled triidothyronine in view of the observation that thyroxine is only a lo-fold weaker inducer of metamorphosis.

Steroids, 1985

In the endometrium of the spay cat, estradiol treatment causes a drastic reduction in glycogen co... more In the endometrium of the spay cat, estradiol treatment causes a drastic reduction in glycogen content. The initiation of simultaneous progesterone treatment causes a replenishment of glycogen with the levels surpassing those observed in the spayed animal. The effect of the hormones on glycogen synthetase I follows the same pattern as the changes in glycogen content, while the effect on phosphorylase a is the mirror image. The total content of glycogen synthetase and phosphorylase do not show appreciable changes with the same hormone treatment. The possible reproductive role of these changes in glycogen content are discussed.

Advances in shock research, 1981

Thermal injury often results in the development of compromised host defense mechanisms against in... more Thermal injury often results in the development of compromised host defense mechanisms against infections (eg, increased incidence of pulmonary sepsis in postburn animals has been attributed to impaired cellular defenses in the lung). Recent reports have demonstrated that high dose glucocorticoid therapy used in the treatment of inflammatory diseases and shock also results in an increased susceptibility of the host to pulmonary sepsis. Although several defense mechanisms are available to the respiratory tract combating bacterial challenges, the major cellular defense is the alveolar macrophage, which phagocytizes infectious agents and potentially toxic particulate matter that infiltrate the lower respiratory tract. Recent evidence has demonstrated that high doses of cortisol in vivo impair both functional and metabolic activities of the alveolar macrophage. However, there is little information regarding whether alterations in endogenous levels of glucocorticoids following systemic i...

The American journal of anatomy, 1979

Oviducts were obtained from women who elected to undergo sterilization either during a normal men... more Oviducts were obtained from women who elected to undergo sterilization either during a normal menstrual cycle, after the first trimester of pregnancy, or in the puerperium. The percent of ciliated cells, cell height and morphology of the fimbria and ampulla were determined and correlated with the stage of the reporductive cycle and plasma levels of the ovarian steroids. Mature ciliated and secretory cells were observed only at mid-cycle. Atrophy, deciliation and loss of secretory activity coincided with elevated levels of serum progesterone. These degenerative processes continued during pregnancy. Ciliation, hypertrophy, and restoration of secretory activity occurred when serum progesterone was essentially undetectable and estradiol relatively low. During each menstrual cycle the secretory cells were observed to undergo a complete cycle of dedifferentiation-differentiation, whereas 10--12% of the ciliated cells lost and regenerated their celia. Ciliogenic cells were frequently prese...

Molecular Endocrinology, 1990

Thyroid hormones are responsible for the specific biochemical and structural changes that occur d... more Thyroid hormones are responsible for the specific biochemical and structural changes that occur during amphibian metamorphosis. In this study we screened a series of cDNAs from a. library constructed from T 4-treated premetamorphic tadpole liver poly(A) + RNA in order to identify a clone that could be used to study the influence of T 3 on liverspecific gene expression during Rana catesbeiana metamorphosis. The cDNA from one clone exhibited a greater degree of hybridization to liver RNA from thyroid hormone-treated tadpoles than untreated tadpoles and no hybridization to RNA from tail fins of tadpoles of either group. On Northern blots, the mRNA to which the cDNA hybridized was 2.3 kilobases in size. The pattern of hybridization to genomic DNA digested by various restriction enzymes was consistent with the presence of a single gene. Using slot blot analysis we found that the mRNA levels first rose above basal levels only after 5 days of immersion of tadpoles in 12.5 M9/liter T 3. The mRNA levels increased approximately 10-fold after 7 and 9 days of treatment. Frog livers had mRNA levels that were intermediate between those in untreated tadpoles and tadpoles immersed in T 3 for 7 days. Sequence analysis revealed a significant degree of homology to serum albumin and a-fetoprotein. While it is known that serum albumin levels rise dramatically during metamorphosis in Rana species, presumably playing a critical role in maintaining water and electrolyte balance during the animals' terrestrial phase, the molecular basis of the induction has not been fully explained. (Molecular Endo

Molecular and Cellular Endocrinology, 1978

The segmentation velocity, gel filtration properties and pattern of elution from ion exchange gei... more The segmentation velocity, gel filtration properties and pattern of elution from ion exchange geis of the cytoplasmic trfodothyronine (T3) binding protein from Rana catesbeiana liver and tall fin cytosol were determined. The T3 binding protein in liver cytosol had a sedimentation coeftlcient of 4.4s on suerose gradients and a Stokes radius from Sephadex gel filtration of 38.2 f 4.2 A. From these two values a molecular weight of 71,700 * 4100 and a frictional ratio of 1.28 f 0.05 for the TJ binding protein from tadpole liver has been calculated. The liver T3 binding protein was eluted from DEAE-Sephadex gels at a salt concentration of 0.233 f 0.017 M NaCl. The sedimen~tion coefficient, Stokes radius and salt requirement for elution from DEAE-Sephadex of the T3 binding protein from tail tin cytosol were essentially identical (4.4S, 35.2 t 4.2 A. and 0.213 i 0.015 M NaCt respectively). The calculated molecular weight is 66,100 f 7900 and the frictional ratio is 1.21 f 0.10 for the tail fin T3 binding protein. The great similarity in the physicochemic~ properties of the T3 binding protein from the liver and tail fin implies that the T3 binding protein in each tissue is similar if not identical. The possible reason for the differences in the dissociation constants previously reported for the binding of T3 in the two tissues is discussed.

Molecular and Cellular Endocrinology, 1987

The binding of triiodothyronine (Ts) to tadpole liver, intestine, and tail fin nuclei was consist... more The binding of triiodothyronine (Ts) to tadpole liver, intestine, and tail fin nuclei was consistent with a single class of binding sites. The K, for the binding of Ts to isolated nuclei from the liver (1.02 nM), intestine (1.40 nM), and tail fin (0.831 nM) nuclei were not significantly different. The number of binding sites for T) in the nuclei isolated from each tissue were also not significantly different. Sucrose gradient centrifugation of the salt-extracted nuclear TX-receptor complex revealed that the s*,,~ was not significantly different for the complex from the liver (3.7 S), intestine (3.9 S), or tail fin (3.9 S). Similarly, the Stokes radii of the complex from the liver (3.65 nm), intestine (3.84 mn), and tail fin (3.99 nm) were not significantly different. Molecular weights of 57 000, 64 000, and 67 000 were calculated from the sedimentation coefficients and Stokes radii for the T,-receptor complex from the liver, intestine, and tail fin, respectively. The similarity of the physicochemical properties of the T,-receptor complex from each of the tissues studied is consistent with the hypothesis that the same receptor is capable of inducing tissue-specific biochemical changes.

Lung, 1979

The presence of specific, high affinity, low capacity glucocorticoid binding was demonstrated in ... more The presence of specific, high affinity, low capacity glucocorticoid binding was demonstrated in resident and activated rabbit lung macrophage suspensions. The binding of [3H]-dexamethasone reached a plateau after 2 h at 30 ° C. Scatchard analysis revealed only a single class of binding sites in both activated and nonactivated macrophages. There was no significant difference in the dissociation constants for the binding of dexamethasone to nonactivated and activated macrophages (4.39 + 2.53 x 10 .9 vs. 1.08 + 0.36 x 10-9 M). The number of binding sites in activated macrophages (15,900 + 1,710 binding sites per cell), however, was significantly greater than the number of binding sites in nonactivated macrophages (5,260+490 binding sites per cell). The relative binding activities of steroids for the receptor were dexamethasone ~ triamcinolone acetonide > cortisol > corticosterone > progesterone ~ testosterone > 17/3-estradiol. Thus, a specific glucocorticoid receptor exists in nonactivated and activated lung macrophages. The presence of activation is associated with a large increase in the number of specific glucocorticoid binding sites per cell.

Journal of Molecular Endocrinology, 2007

During the late luteal phase of the menstrual cycle and early pregnancy, the major secretory prod... more During the late luteal phase of the menstrual cycle and early pregnancy, the major secretory product of the uterine glandular epithelial cells in humans and non-human primates is glycodelin. Previous studies using Ishikawa cells, a human endometrial cell line, have shown that a chimeric plasmid containing the baboon glycodelin promoter responds to progestins but the response is modest compared with the induction of glycodelin seen in vivo and in gene array analysis. A recent report indicating that the histone deacetylase inhibitor trichostatin A (TSA) promoted glycodelin expression prompted us to examine its mechanism of action. In Ishikawa cells transfected with the baboon glycodelin promoter, TSA and the synthetic progestin medroxyprogesterone acetate both stimulated expression of the reporter and the combined treatment produced a synergistic effect. The effect of TSA and progestin was absent when the same promoter constructs were transfected into COS-1 cells, a kidney cell line, ...

The Journal of Clinical Endocrinology & Metabolism, 1980

In LiIO 3 and BBO crystals the wave-matching conditions for femtosecond noncollinear parametric l... more In LiIO 3 and BBO crystals the wave-matching conditions for femtosecond noncollinear parametric light generation at l 390 nm pumping wavelength are investigated. In the LiIO 3 crystal simultaneous phase-and groupvelocity-matching angles are determined. Parametric generation occurred at 0.45-2.9-mm wavelengths by pumping with the second harmonic of 150-fs Ti:sapphire laser pulses and is in qualitative agreement with calculated directions in both crystals.

Human Reproduction, 1999

One of the most remarkable processes associated with the establishment of pregnancy in the primat... more One of the most remarkable processes associated with the establishment of pregnancy in the primate is the process of decidualization. This transformation of a stromal fibroblast to a fully differentiated decidual cell is required for implantation and embryo survival in early pregnancy. Although the morphological and biochemical characteristics of the primate decidual cell have been extensively studied, the precise cellular, biochemical and molecular signals required for this transformation have yet to be elucidated. During decidualization, stromal cells first proliferate and then differentiate. Based on our extensive in-vivo and ongoing in-vitro studies, we have suggested that the process of decidualization in the baboon can be divided into two distinct phases. The initial proliferative phase is characterized by the expression of the cytoskeletal protein a smooth muscle actin (otSMA) in the stromal fibroblasts and is independent of the presence of the conceptus. The second phase of differentiation is characterized by the expression of insulin-like growth factor binding protein-1 (IGFBP-1) and the downregulation of ocSMA in the decidualized stromal fibroblast. The expression of IGFBP-1 is dependent on the presence of the conceptus in vivo and is regulated by hormones and cAMP in vitro. We have postulated that, during the initial phase of stromal cell differentiation, aSMA expression is regulated by the interaction between stromal cell integrins with the secreted extracellular matrix proteins (ECM). In response to pregnancy a trophoblast 'factor', mediated by cAMP signal transduction, induces IGFBP-1 expression in decidualizing stromal fibroblasts. This induction of IGFBP-1 is associated with the disappearance of ocSMA and denovo protein synthesis. Our comparative studies suggest that the process of decidualization in the human and baboon involve similar mechanisms. However, the metabolic pathways required for decidualization in the two species appear to differ in their degree of sensitivity to external stimuli. This review focuses on the cellular events that may potentially regulate decidualization in the primate and its role in regulating trophoblast migration.

General and Comparative Endocrinology, 1974

General and Comparative Endocrinology, 1984

The binding of the synthetic glucocorticoid dexamethasone (dex) to Rana catesbeiana tadpole liver... more The binding of the synthetic glucocorticoid dexamethasone (dex) to Rana catesbeiana tadpole liver, intestine, and tailfin cytosol during both spontaneous and triiodothyronine (T&induced metamorphosis has been examined. No change was observed in the dissociation constant (K,) in the liver or intestine during either spontaneous or T,-induced metamorphosis compared with liver and intestine cytosol from the frog. The binding capacity (N) in liver cytosol of premetamorphic tadpoles (14.33 x lo-l4 mol dexfmg protein) was not significantly different from that found during prometamorphosis (stage XVIII) (11 SO x lo-l4 mol dex/mg protein) and in the adult frog (19.24 x lo-l4 mol dex/mg protein). Following the onset of metamorphic climax, however, there were significant reductions in N in liver cytosol, reaching a nadir at stage XXIV (0.38 x lo-l4 mol dex/mg protein). Binding capacity in premetamorphic tadpole intestine (19.60 x lo-l4 mol dex/mg protein) was significantly reduced following premetamorphosis. Values did not return to premetamorphic values in the frog intestine (6.54 x lo-l4 mol dexlmg protein) as occurred in the frog liver, nor were values significantly reduced following the onset of metamorphic climax (10.43 x lo-l4 mol dexfmg protein) when compared with prometamorphosis (11.58 x lo-l4 mol dexl mg protein). The binding capacity in the tailfin cytosol did not deviate from premetamorphic tadpole values (11.61 x lo-l4 mol dex/mg protein) through stage XXI (9.68 x lo-l4 mol dex/mg protein), the last stage in which sufficient tissue was available for analysis.