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J Rosen

Publications and source records attributed to J Rosen.

At least 73 records · Page 4Linked to original sources
PubMed1996

Determinants of promoter-specific activity by glucocorticoid receptor.

Glucocorticoid receptor (GR) is expressed at essentially equal levels in almost all tissues and cell types. Remarkably, glucocorticoids themselves regulate transcription in vivo in both a promoter- and tissue-specific manner. Thus, specific systems must be in place to regulate receptor action within certain cells and at certain promoters. To address two specific aspects of these systems, we have analyzed promoter-specific activity of GR using two different, well studied promoters (termed simple and composite promoters) from which GR activates transcription. The simple promoter depends only on the receptor for glucocorticoid-responsive transcriptional activation, while GR activity at the composite promoter depends on additional transcription factors. We have compared the action of several GR ligands at these promoters and demonstrate fundamental differences in the activities of these ligands on receptor activity. Furthermore, these compounds induce unique conformational changes in receptor, resulting in promoter-specific receptor function. We have identified critical amino acid residues within GR which, when mutated, genetically distinguish the action of GR at these promoters. Taken together, the data indicate that the presence of only the receptor and the ligand is not sufficient to allow activation of transcription. An additional system of regulation influences receptor action in both a tissue- and promoter-selective fashion, suggesting that multiple, regulated surfaces of the receptor respond to the cellular environment and determine the spectrum of GR activities. These functional surfaces may be induced or regulated by ligand binding, by the DNA sequence to which receptor is bound, or by the nonreceptor factors resident at the promoter or in the tissue.

Animals↗
PubMed1995

STAT protein complexes activated by interferon-gamma and gp130 signaling molecules differ in their sequence preferences and transcriptional induction properties.

Activation of members of the STAT (signal transducers and activators of transcription) family of latent transcription factors is an early event following the binding of many cytokines to their cognate receptors. Although the patterns of STATs activated by different cytokines are well described, the consequences of differential STAT activation are less well studied. We show by mutational analysis that STAT binding elements (SBEs) exist that discriminate between STAT complexes containing STAT1 alpha, STAT3 or both, and that these elements show altered cytokine responsiveness. We also show that in the context of a minimal promoter, single and multiple SBEs exhibit strikingly different patterns of transcriptional activation in response to IFN-gamma, IL-6, OSM or LIF. These differences in transcriptional activation are correlated with the differential ability of these cytokines to activate STAT1 alpha, STAT3 or both. Our results show that the pattern of STATs activated by a cytokine and the arrangement and sequence of the SBEs in the responding promoter have a profound effect on the ability of the cytokine to elicit a transcriptional response.

Animals↗
PubMed1995

Spacing of palindromic half sites as a determinant of selective STAT (signal transducers and activators of transcription) DNA binding and transcriptional activity.

Signal transducers and activators of transcription (STAT proteins) bind to palindromic sequence elements related to interferon gamma (IFN-gamma) activation sites, which were first identified in the promoters of IFN-gamma-inducible genes. Although the sequences of the natural palindromic STAT-binding elements vary considerably, they conform to the general structure TT(N)5AA. We have systematically examined the effects of the spacing between the TT and AA core half sites on the binding of the STAT complexes activated by IFN-gamma, interleukin (IL) 6, granulocyte-macrophage colony-stimulating factor, and IL-4. We show that (i) as suggested earlier, a core palindromic TT--AA motif with a 5-bp spacing displays general STAT binding, (ii) a palindromic motif with a spacing of 4 bp selectively binds to complexes containing Stat3, and (iii) a motif with a 6-bp spacing selectively binds the STAT complexes activated by IL-4. We have examined natural elements in the promoters of cytokine-responsive genes that differ in half-site spacing and found that they display binding properties predicted from the synthetic binding sites. Furthermore, the observed differential selective binding characteristics for the most part correlate with the ability to mediate transcriptional activation of transfected test genes in response to the cytokines tested. Our results thus demonstrate that the specificity of STAT-directed transcription in response to particular cytokines or cytokine families depends in part on the spacing of half sites within the conserved response element sequence.

Base Sequence↗
PubMed1995

Event-related potential and behavioral correlates of semantic processing in Alzheimer's patients and normal controls.

In normal young adults, N400 amplitude varies inversely with the extent to which a word has been primed by its preceding semantic context. Based on a series of behavioral studies, it appears that in Probable Alzheimer's patients (PAD) the organization of semantic memory is disrupted such that specific items within a category lose their distinction, although superordinate information remains relatively intact. The present study examined whether the N400 gradient which has been found with normal young adults would also reflect this loss of discriminability among semantically related items in PAD patients. Ten normal young adults, 10 normal elderly, and 6 "mild" PAD patients made speeded (but accurate) sense/nonsense decisions to the terminal words of a series of highly constrained sentence contexts. The terminal words belonged to one of four stimulus types which varied as a function of relatedness to a highly expected word. Counter to our predictions, N400 amplitude was identically responsive to semantic relatedness in the young normal and PAD groups, but was characterized differently in the normal elderly. Given the significantly greater number of errors committed by PAD patients, we concluded that their disruption in semantic processing occurs at some point between the elicitation of N400 and the generation of the reaction time response. The anomalous N400 pattern in the normal elderly appeared to be strategy related and superimposed upon an otherwise normal semantic network.

Adult↗
PubMed1995

Simple reaction time as a measure of global attention in Alzheimer's disease.

Alzheimer's disease (AD) is characterized by progressive decline in memory, language and other cognitive functions. Deficits in attentional processes have also been suggested. A simple reaction time (RT) task was used to assess global attention in AD. The length and consistency of a warning signal given prior to the response stimulus were manipulated to determine if patients with AD and age-matched controls benefit from predictability in RT tasks. Overall reaction time was slower in the AD group than in the and control group. Both groups demonstrated significant improvement in RT with long warning signals compared to short warning signals, but only the control group benefited from the consistency of the warning.

Aged↗
PubMed1995

Prospective cytochrome P450 phenotyping for neuroleptic treatment in dementia.

Older patients have more adverse experiences when treated with psychotropics than younger patients. Age-associated physiological changes, such as reductions in hepatic mass and blood flow, magnify genetic and acquired variations in drug metabolism. Cytochrome P450 2D6 (debrisoquine hydroxylase), which is responsible for the metabolism of several antidepressants and neuroleptics, is constitutionally deficient in up to 10 percent of the population. In this study of 45 elderly patients suffering from dementia and treated with perphenazine, 5 patients who were prospectively identified as poor P450 2D6 metabolizers had significantly greater side effects than the 40 extensive metabolizers.

Aged↗
PubMed1995

Clinical profile, comorbidity, and treatment history in 123 hair pullers: a survey study.

BACKGROUND: Trichotillomania, characterized by an irresistible urge to pull one's hair, may be more prevalent than previously believed. Despite increasing attention devoted to this topic in the recent literature, there are few studies based on large samples that are potentially generalizable to a community population. METHOD: Surveys addressing clinical profile, comorbidity, and treatment history were mailed to all responders to a nationally distributed magazine article on trichotillomania. Out of 772 surveys sent, 123 completed surveys were returned. RESULTS: While there was a predominance of females in the whole sample, female-to-male prevalence was lower in children than adults. Onset was predominantly in childhood (mean age = 11 years), most frequently in middle childhood and least frequently before age 6. Subjects pulled hair from a variety of sites, including scalp, eyelashes, eyebrows, pubic region, face, and body, but the highest incidence and severity involved scalp hair. Children under 6 were more likely than other age groups to pull scalp hair and possibly less likely to pull other hair. In adults, symptom profile was not associated with age at onset. While subjects reported high rates of comorbid conditions in both self and family, trichotillomania was reportedly formally diagnosed in only 40% of the subjects. Although subjects reported a range of treatments, the majority (58%) reported no treatment history. Finally, only minimal improvement was reported for all modalities, with no significant difference in response to psychotherapy, behavior therapy, clomipramine, or fluoxetine. CONCLUSION: Trichotillomania is a chronic illness that may be difficult to treat. Controlled studies on comorbidity, epidemiology, treatment-seeking patterns, and long-term treatment response are needed.

Adolescent↗
PubMed1995

Prolactin response to neuroleptic challenge in late-life psychosis.

Psychosis in the elderly is superimposed on both age-related and disease-specific declines in dopaminergic function. Though the prolactin (PRL) response to neuroleptic challenge has been used as an in vivo measure of dopaminergic function in midlife adults, it remains uninvestigated in late-life psychoses. We examined the PRL response to intravenous perphenazine (PZ) in 11 elderly patients with psychotic symptoms complicating either a major depression (MD-P) or a dementia. The magnitude of increase in prolactin after PZ divided patients into three non-overlapping groups: dementia patients had a bimodal response and MD-P patients fell between the dementia groups. Our findings suggest that the PRL response to PZ may provide an in vivo measure of dopaminergic function in elderly patients. This finding must be confirmed through correlation with other measures of dopaminergic function in late-life psychoses and with measures of neuroleptic response and neuroleptic-induced extrapyramidal effects.

Aged↗
PubMed1994

Rapid activation of the STAT3 transcription factor by granulocyte colony-stimulating factor.

Granulocyte colony-stimulating factor (G-CSF) is a glycoprotein that stimulates proliferation and differentiation of progenitor cells of neutrophils by signaling through its receptor (G-CSFR). Although the G-CSFR belongs to the cytokine receptor superfamily, which lacks an intracellular kinase domain, G-CSF-induced tyrosine phosphorylation of cellular proteins is critical for its biologic activities. We report here that JAK1 and JAK2 tyrosine kinases are tyrosine phosphorylated in response to G-CSF induction. We also demonstrate that the DNA-binding protein STAT3 (also called the acute-phase response factor [APRF], activated by interleukin-6) is an early target of G-CSF-induced tyrosine phosphorylation. G-CSF induces two DNA-binding complexes; the major complex contains tyrosine phosphorylated STAT3 protein and the minor complex appears to be a heterodimer of the STAT1 (previously p91, a component of DNA-binding complexes activated by interferons) and STAT3 proteins. Antiphosphotyrosine antibody interferes with the DNA binding activity of activated STAT3, indicating that tyrosine phosphorylation of STAT3 is important for the DNA binding activity. These results identify a signal transduction pathway activated in response to G-CSF and provide a mechanism for the rapid modulation of gene expression by G-CSF.

DNA↗
PubMed1994

Rapid activation of proteins that interact with the interferon gamma activation site in response to multiple cytokines.

Many cytokines and growth factors trigger rapid changes in gene expression upon binding to their receptors. In many cases, the mechanism by which these changes are affected is unknown. In this report, we show that interleukin-2 (IL-2), IL-3, IL-4, IL-6, leukemia inhibitory factor (LIF), erythropoietin (Epo), and granulocyte-macrophage colony-stimulating factor (GM-CSF) treatment of cells causes rapid activation of DNA-binding activities that recognize a DNA sequence element previously implicated in regulation of gene expression by interferon gamma (IFN gamma). The IL-4-, IL-6-, and GM-CSF-induced complexes can be distinguished from the recently characterized IFN gamma-activated protein p91 on the basis of mobility in polyacrylamide gels, sequence preferences, and lack of reactivity with an anti-p91 antiserum. The IL-4- and GM-CSF-induced complexes react with antiphosphotyrosine antibodies, demonstrating the presence of phosphotyrosine-containing proteins in these DNA-binding complexes. Transcriptional activation of a reporter gene linked to a synthetic IFN gamma-responsive promoter is observed in response to IFN gamma, IL-6, and LIF. These data suggest a pathway by which cytokines induce rapid changes in gene expression.

Base Sequence↗