The associations between social support and mental health among Chinese immigrant pregnant and parenting women.

BACKGROUND: While it is recognized that social support can alleviate mental health symptoms, this relationship is not well-understood among Chinese pregnant and parenting immigrants in the United States. This study aims to bridge this gap by exploring the relationships between different types of social support and women's anxiety and depression, and examining how these associations vary with pregnancy status. METHODS: Data were obtained from a cross-sectional survey conducted in Simplified Chinese or Mandarin between March-June 2021 among 526 women who were pregnant and/or parenting a child under five years. The Patient-Reported Outcomes Measurement Information System (PROMIS) Anxiety, Depression, and Social Support scales were used to measure anxiety, depression, and social support levels. Descriptive statistics, t-tests, chi-square tests, and Pearson's correlations were employed for analysis. Hierarchical regression was conducted to investigate the main and interaction effects of social support types and pregnancy status on mental health outcomes. RESULTS: Compared to non-pregnant women, pregnant women reported higher mean scores for anxiety (non-pregnant: 55, pregnant: 59, p < 0.01) and depression (non-pregnant: 54, pregnant: 56, p = 0.02). Instrumental support displayed a significant main effect in relation to anxiety (ß=-0.13, p = 0.01) and depression (ß=-0.16, p < 0.01); emotional support exhibited a significant main effect solely on depression (ß=-0.13, p = 0.01). Notably, the interaction effects between pregnancy status and both instrumental (ß=-0.28, p = 0.01) and emotional support (ß=-0.42, p < 0.01) were significant for anxiety. In contrast, informational support did not exhibit a significant impact on either anxiety or depression. CONCLUSIONS: The findings indicate that tailoring support to the cultural context is crucial, especially for pregnant women in this Chinese immigrant community, with instrumental and emotional support being particularly beneficial in mitigating maternal anxiety.

Self-Reported Speeding Among New York City Adult Drivers, 2015-2016.

Motor vehicle crashes are a leading cause of injury related deaths. Urban areas accommodate multiple road users and pedestrians account for a larger share of traffic fatalities. Speed reduction has been one component of New York City's multidisciplinary approach to reduce traffic fatalities-Vision Zero. Data from the New York City (NYC) Community Health Survey 2015-2016 were used to document population-based estimates of self-reported speeding (defined as driving ten miles per hour or more over the posted speed limit in the past 30 days) among NYC adult drivers collected soon after the adoption of Vision Zero in 2014. Self-reported speeding is common, with nearly two-thirds (63%) of adult drivers indicating they ever sped and 13% often speeding. In adjusted multivariable models, often speeding was more common among younger drivers vs. older drivers (adjusted prevalence ratio: 2.77; 95%CI 1.93-3.98), males vs. females (adjusted prevalence ratio: 1.59; 95%CI 1.35-1.87), wealthier drivers vs. poorer drivers (adjusted prevalence ratio: 1.37; 95%CI 1.10-1.70) and those reporting worse perceived social cohesion vs. better perceived social cohesion (adjusted prevalence ratio 1.51; 95%CI 1.09-2.10). Population-based health surveys facilitate exploration of a range of potential influences on health behaviors.

Lessons Learned in Developing and Testing a Methotrexate Case Study for Pharmacy Education.

This article describes the development, implementation, and evaluation of a complex methotrexate ethics case used in teaching a Pharmacy Law and Ethics course. Qualitative analysis of student reflective writings provided useful insight into the students' experience and comfort level with the final ethics case in the course. These data demonstrate a greater student appreciation of different perspectives, the potential for conflict in communicating about such cases, and the importance of patient autonomy. Faculty lessons learned are also described, facilitating adoption of this methotrexate ethics case by other healthcare profession educators.

Matrix adhesion polarizes heart progenitor induction in the invertebrate chordate Ciona intestinalis.

Cell-matrix adhesion strongly influences developmental signaling. Resulting impacts on cell migration and tissue morphogenesis are well characterized. However, the in vivo impact of adhesion on fate induction remains ambiguous. Here, we employ the invertebrate chordate Ciona intestinalis to delineate an essential in vivo role for matrix adhesion in heart progenitor induction. In Ciona pre-cardiac founder cells, invasion of the underlying epidermis promotes localized induction of the heart progenitor lineage. We found that these epidermal invasions are associated with matrix adhesion along the pre-cardiac cell/epidermal boundary. Through targeted manipulations of RAP GTPase activity, we were able to manipulate pre-cardiac cell-matrix adhesion. Targeted disruption of pre-cardiac cell-matrix adhesion blocked heart progenitor induction. Conversely, increased matrix adhesion generated expanded induction. We were also able to selectively restore cell-matrix adhesion and heart progenitor induction through targeted expression of Ci-Integrin ß2. These results indicate that matrix adhesion functions as a necessary and sufficient extrinsic cue for regional heart progenitor induction. Furthermore, time-lapse imaging suggests that cytokinesis acts as an intrinsic temporal regulator of heart progenitor adhesion and induction. Our findings highlight a potentially conserved role for matrix adhesion in early steps of vertebrate heart progenitor specification.

Emulsion oil droplet size significantly affects satiety: A pre-ingestive approach.

Previous research has demonstrated that the manipulation of oil droplet size within oil-in-water emulsions significantly affects sensory characteristics, hedonics and expectations of food intake, independently of energy content. Smaller oil droplets enhanced perceived creaminess, increased Liking and generated greater expectations of satiation and satiety, indicating that creaminess is a satiety-relevant sensory cue within these systems. This paper extends these findings by investigating the effect of oil droplet size (d4,3: 2 and 50 µm) on food intake and appetite. Male participants (n = 34 aged 18-37; BMI of 22.7 ± 1.6 kg/m(2); DEBQ restricted eating score of 1.8 ± 0.1.) completed two test days, where they visited the laboratory to consume a fixed-portion breakfast, returning 3 h later for a "drink", which was the emulsion preload containing either 2 or 50 µm oil droplets. This was followed 20 min later with an ad libitum pasta lunch. Participants consumed significantly less at the ad libitum lunch after the preload containing 2 µm oil droplets than after the 50 µm preload, with an average reduction of 12% (62.4 kcal). Despite the significant differences in intake, no significant differences in sensory characteristics were noted. The findings show that the impact that an emulsion has on satiety can be enhanced without producing significantly perceivable differences in sensory properties. Therefore, by introducing a processing step which results in a smaller droplets, emulsion based liquid food products can be produced that enhance satiety, allowing covert functional redesign. Future work should consider the mechanism responsible for this effect.

Rsr1 focuses Cdc42 activity at hyphal tips and promotes maintenance of hyphal development in Candida albicans.

The extremely elongated morphology of fungal hyphae is dependent on the cell's ability to assemble and maintain polarized growth machinery over multiple cell cycles. The different morphologies of the fungus Candida albicans make it an excellent model organism in which to study the spatiotemporal requirements for constitutive polarized growth and the generation of different cell shapes. In C. albicans, deletion of the landmark protein Rsr1 causes defects in morphogenesis that are not predicted from study of the orthologous protein in the related yeast Saccharomyces cerevisiae, thus suggesting that Rsr1 has expanded functions during polarized growth in C. albicans. Here, we show that Rsr1 activity localizes to hyphal tips by the differential localization of the Rsr1 GTPase-activating protein (GAP), Bud2, and guanine nucleotide exchange factor (GEF), Bud5. In addition, we find that Rsr1 is needed to maintain the focused localization of hyphal polarity structures and proteins, including Bem1, a marker of the active GTP-bound form of the Rho GTPase, Cdc42. Further, our results indicate that tip-localized Cdc42 clusters are associated with the cell's ability to express a hyphal transcriptional program and that the ability to generate a focused Cdc42 cluster in early hyphae (germ tubes) is needed to maintain hyphal morphogenesis over time. We propose that in C. albicans, Rsr1 "fine-tunes" the distribution of Cdc42 activity and that self-organizing (Rsr1-independent) mechanisms of polarized growth are not sufficient to generate narrow cell shapes or to provide feedback to the transcriptional program during hyphal morphogenesis.

Multiple aspects of amyloid dynamics in vivo integrate to establish prion variant dominance in yeast.

Prion variants are self-perpetuating conformers of a single protein that assemble into amyloid fibers and confer unique phenotypic states. Multiple prion variants can arise, particularly in response to changing environments, and interact within an organism. These interactions are often competitive, with one variant establishing phenotypic dominance over the others. This dominance has been linked to the competition for non-prion state protein, which must be converted to the prion state via a nucleated polymerization mechanism. However, the intrinsic rates of conversion, determined by the conformation of the variant, cannot explain prion variant dominance, suggesting a more complex interaction. Using the yeast prion system [PSI+ ], we have determined the mechanism of dominance of the [PSI+ ]Strong variant over the [PSI+ ]Weak variant in vivo. When mixed by mating, phenotypic dominance is established in zygotes, but the two variants persist and co-exist in the lineage descended from this cell. [PSI+ ]Strong propagons, the heritable unit, are amplified at the expense of [PSI+ ]Weak propagons, through the efficient conversion of soluble Sup35 protein, as revealed by fluorescence photobleaching experiments employing variant-specific mutants of Sup35. This competition, however, is highly sensitive to the fragmentation of [PSI+ ]Strong amyloid fibers, with even transient inhibition of the fragmentation catalyst Hsp104 promoting amplification of [PSI+ ]Weak propagons. Reducing the number of [PSI+ ]Strong propagons prior to mating, similarly promotes [PSI+ ]Weak amplification and conversion of soluble Sup35, indicating that template number and conversion efficiency combine to determine dominance. Thus, prion variant dominance is not an absolute hierarchy but rather an outcome arising from the dynamic interplay between unique protein conformations and their interactions with distinct cellular proteostatic niches.

Enhancing immigrant families' mental health through the promotion of structural and community-based support.

Immigrant communities in the United States are diverse and have many assets. Yet, they often experience stressors that can undermine the mental health of residents. To fully promote mental health and well-being among immigrant communities, it is important to emphasize population-level policies and practices that may serve to mitigate stress and prevent mental health disorders. In this paper, we describe the stressors and stress experienced by immigrant families, using Sunset Park, Brooklyn as an example. We discuss ways to build structures and policies in support of equitable environments that promote mental health at the population level and enable families and their children to thrive.

The Effectiveness of Pain Science Education on Caregiver and Children's Knowledge, Beliefs, Attitudes, and Behaviors-A Systematic Review and Meta-Analysis.

Pain science education (PSE) can be used as part of treatment and prevention for chronic pain in children. We assessed the effectiveness of PSE on knowledge, beliefs, attitudes, and behaviors in children and the people that care for children. We set a minimum criterion for education to address pain biology knowledge. We included studies aimed at both treatment and prevention of chronic pain. We conducted searches using 5 databases. We assessed the risk of bias using the Cochrane Risk of Bias 2 tool. Data were pooled using a random-effects meta-analysis or assessed using a narrative synthesis. The certainty of evidence was assessed using the Grading of Recommendations, Assessment, Development and Evaluation. We screened 14,505 records and included 7 studies involving 351 caregivers and 1,285 children. Four studies were included in meta-analyses. We found low-certainty evidence that PSE has a large beneficial effect on caregiver knowledge and beliefs compared with alternative education (standardized mean difference = 1.14 [95% confidence interval: .88-1.42]; I2 = 0%). We found no difference in functional disability in children with chronic pain after PSE (Functional Disability Inventory score mean difference = .73 [95% confidence interval: -.81 to 2.27; I = 0%]). Narrative syntheses showed low-certainty evidence for improved knowledge and beliefs in children with preventative and treatment effects. Overall, we found few studies, and along with high risk of bias, this significantly contributed to the low certainty of findings. The effect of learning pain science for both preventative and treatment effects in children, carers, and the child/carer dyad remains mostly unknown. This review was prospectively registered with The international Prospective register of systematic reviews (CRD42022344382) on July 22, 2022. PERSPECTIVE: This review examines the effect of PSE on pain-related knowledge, beliefs, attitudes, and behaviors in children and the people that care for children (0-18). The findings contribute to knowledge about pain treatments and health promotion for caregivers and their children with and without chronic pain.

Rax2 is important for directional establishment of growth sites, but not for reorientation of growth axes, during Candida albicans hyphal morphogenesis.

Hyphae of filamentous fungi maintain generally linear growth over long distances. In Candida albicans, hyphae are able to reorient their growth in the direction of certain environmental cues. In previous work, the C. albicans bud-site selection proteins Rsr1 and Bud2 were identified as important for hyphae to maintain linear growth and were necessary for hyphal responses to directional cues in the environment (tropisms). To ask if hyphal directional responses are general functions of all yeast bud-site selection proteins, we studied the role of Rax2, ortholog of the Saccharomyces cerevisiae bud-site selection protein Rax2, in C. albicans hyphal morphogenesis. Rax2-YFP localized to the hyphal cell surface in puncta and at the hyphal tip in a crescent. Strains lacking Rax2 had hyphal morphologies that did not differ from control strains. In non-cued growth conditions, rax2 mutant strains had defects in both yeast (bud) and hyphal (branch) site selection and mutant hyphae exhibited non-linear growth trajectories as compared to control hyphae. In contrast, when encountering a directional environmental cue, hyphae lacking Rax2 retained the ability to reorient growth in response to both topographical (thigmotropism) and electric-field (galvanotropism) stimuli but exhibited a reduced ability to establish hyphal growth in the direction of a cathodal stimulus. In conclusion, these results indicate that C. albicans Rax2 is important for establishing sites of emergence of yeast and hyphal daughters and for maintaining the linearity of hyphal growth. In contrast to Rsr1 and Bud2, Rax2 is not involved in responses that require a reorientation of the direction of already established hyphal growth (tropisms). Thus, it appears that some hyphal directionality responses are separable in that they are mediated by a different set of polarity proteins.

Preventive dental care among New York City children, 2009.

This study aims to describe the prevalence of preventive dental care among New York City (NYC) children, including disparities by race/ethnicity or poverty and to identify health care utilization factors associated with these outcomes. Data were obtained from the 2009 NYC Child Community Health Survey. Descriptive statistics were calculated for preventive dental visits in the past 12 months among children aged 2-12 years (n = 2,435) and receipt of sealants among children aged 6-12 years (n = 1,416). Multivariable logistic regression was used to compute adjusted prevalence ratios (aPRs). One in four (23.3 %) NYC children aged 2-12 years, including 57.3 % of 2-3-year olds, had no preventive dental visit in the past 12 months. Lack of preventive visits was more prevalent among Asian/Pacific Islander children compared with non-Hispanic white children (aPR 1.42 [95 % CI 1.07-1.89]), and among children living in poorer households compared with wealthier households (aPR 1.47 [95 % CI 1.13-1.92]). Two-thirds (64.5 %) of children aged 6-12 years never had sealants. Compared with non-Hispanic white children, Asian/Pacific Islander (aPR 1.26 [95 % CI 1.01-1.56]), non-Hispanic black (aPR 1.24 [95 % CI 1.06-1.46]), and Hispanic (aPR 1.21 [95 % CI 1.04-1.41]) children were more likely not to have sealants, as were children without a personal health care provider compared with children with a provider (aPR 1.33 [95 % CI 1.14-1.56]). Disparities in preventive dental care exist by race/ethnicity, poverty, and health care utilization. Personal health care providers may improve children's oral health by linking them to preventive dental care and promoting sealant application.

Barriers and enablers of older adults initiating a deprescribing conversation.

OBJECTIVE: To examine older adults' perceptions and identify barriers and enablers to initiating a conversation about stopping medication(s) with their healthcare provider. METHODS: We conducted one focus group (n = 3) and in-depth, face-to-face, individual interviews (n = 6) using an interview guide. Older adults aged ≥65 years in a retirement community who were taking ≥5 medications were recruited. Focus groups and interviews were audio-recorded and transcribed verbatim. Both a deductive analysis, informed by the Theoretical Domains Framework, and an inductive analysis were conducted. RESULTS: Five themes and fourteen sub-themes were identified. Theme 1, 'older adult-related barriers', discusses limited or varying self-efficacy, past unsuccessful deprescribing experiences and limited familiarity with medications/deprescribing. Theme 2, 'provider-related barriers', discusses trust, short office visits, lack of communication and multiple providers. Theme 3, 'environmental/social-related barriers', involves limited availability of resources and access to telehealth/internet. The remaining themes (Themes 4-5) identified enablers including strategies to promote older adults' self-efficacy and improved healthcare communication. CONCLUSION: Consumer-centric tools could improve older adults' self-efficacy to initiate deprescribing conversations. PRACTICE IMPLICATIONS: Removing barriers and implementing enablers may empower older adults to initiate deprescribing conversations with providers to take fewer medications. Ultimately, this could be a catalyst for increased translation of deprescribing in practice.

Two regions within the proximal steroidogenic factor 1 promoter drive somatic cell-specific activity in developing gonads of the female mouse.

Targets of steroidogenic factor 1 (SF1; also known as NR5A1 and AD4BP) have been identified within cells at every level of the hypothalamic-pituitary-gonadal and -adrenal axes, revealing SF1 to be a master regulator of major endocrine systems. Mouse embryos express SF1 in the genital ridge until Embryonic Day 13.5 (E13.5). Thereafter, expression persists in the male and is substantially lower in the female gonad until birth. We hypothesize that the sexually dimorphic expression of Sf1 during gonadogenesis is mediated by sex-specific regulation of its promoter. To investigate dimorphic regulation within the fetal gonad, we developed an experimental strategy using transient transfection of E13.5 gonad explant cultures and evaluated various Sf1 promoter constructs for sexually dimorphic DNA elements. The proximal Sf1 promoter correctly targeted reporter activity to SF1-expressing cells in both XY and XX gonads. Stepwise deletion of sequences from the Sf1 promoter revealed two regions that affected regulation within female gonads. Mutation of both sequences together did not cause further disruption of reporter activity, suggesting the two sites might work in concert to promote activity in female somatic cells. Results from gel mobility shift assays and fetal gonad-chromatin immunoprecipitation showed that TCFAP2 binds to one of the two female-specific sites within the proximal promoter of Sf1. Together, we show that transient transfection experiments performed within developing testes and ovaries are a powerful tool to uncover elements within the Sf1 promoter that contribute to sex-specific expression.

Overreporting of deaths from coronary heart disease in New York City hospitals, 2003.

INTRODUCTION: New York City has one of the highest reported death rates from coronary heart disease in the United States. We sought to measure the accuracy of this rate by examining death certificates. METHODS: We conducted a cross-sectional validation study by using a random sample of death certificates that recorded in-hospital deaths in New York City from January through June 2003, stratified by neighborhoods with low, medium, and high coronary heart disease death rates. We abstracted data from hospital records, and an independent, blinded medical team reviewed these data to validate cause of death. We computed a comparability ratio (coronary heart disease deaths recorded on death certificates divided by validated coronary heart disease deaths) to quantify agreement between death certificate determination and clinical judgment. RESULTS: Of 491 sampled death certificates for in-hospital deaths, medical charts were abstracted and reviewed by the expert panel for 444 (90%). The comparability ratio for coronary heart disease deaths among decedents aged 35 to 74 years was 1.51, indicating that death certificates overestimated coronary heart disease deaths in this age group by 51%. The comparability ratio increased with age to 1.94 for decedents aged 75 to 84 years and to 2.37 for decedents aged 85 years or older. CONCLUSION: Coronary heart disease appears to be substantially overreported as a cause of death in New York City among in-hospital deaths.

An internal polarity landmark is important for externally induced hyphal behaviors in Candida albicans.

Directional growth is a function of polarized cells such as neurites, pollen tubes, and fungal hyphae. Correct orientation of the extending cell tip depends on signaling pathways and effectors that mediate asymmetric responses to specific environmental cues. In the hyphal form of the eukaryotic fungal pathogen Candida albicans, these responses include thigmotropism and galvanotropism (hyphal turning in response to changes in substrate topography and imposed electrical fields, respectively) and penetration into semisolid substrates. During vegetative growth in C. albicans, as in the model yeast Saccharomyces cerevisiae, the Ras-like GTPase Rsr1 mediates internal cellular cues to position new buds in a prespecified pattern on the mother cell cortex. Here, we demonstrate that Rsr1 is also important for hyphal tip orientation in response to the external environmental cues that induce thigmotropic and galvanotropic growth. In addition, Rsr1 is involved in hyphal interactions with epithelial cells in vitro and its deletion diminishes the hyphal invasion of kidney tissue during systemic infection. Thus, Rsr1, an internal polarity landmark in yeast, is also involved in polarized growth responses to asymmetric environmental signals, a paradigm that is different from that described for the homologous protein in S. cerevisiae. Rsr1 may thereby contribute to the pathogenesis of C. albicans infections by influencing hyphal tip responses triggered by interaction with host tissues.

Interaction of estrogen receptor alpha with proliferating cell nuclear antigen.

The ability of estrogen receptor alpha (ERalpha) to modulate gene expression is influenced by the recruitment of a host of co-regulatory proteins to target genes. To further understand how estrogen-responsive genes are regulated, we have isolated and identified proteins associated with ERalpha when it is bound to DNA containing the consensus estrogen response element (ERE). One of the proteins identified in this complex, proliferating cell nuclear antigen (PCNA), is required for DNA replication and repair. We show that PCNA interacts with ERalpha in the absence and in the presence of DNA, enhances the interaction of ERalpha with ERE-containing DNA, and associates with endogenous estrogen-responsive genes. Interestingly, rather than altering hormone responsiveness of endogenous, estrogen-responsive genes, PCNA increases the basal expression of these genes. Our studies suggest that in addition to serving as a platform for the recruitment of DNA replication and repair proteins, PCNA may serve as a platform for transcription factors involved in regulating gene expression.

Strategies to optimize medication use in the physician group practice: the role of the clinical pharmacist.

OBJECTIVES: To (1) describe the role of clinical pharmacists in providing population-based pharmaceutical care as employees of a physician group practice, (2) describe the strategies used by pharmacists to optimize medication use, (3) quantify improvements in care, and (4) illustrate the calculations used to quantify cost savings. SETTING: Community-based, multispecialty, physician group practice located in the north Puget Sound area between 2003 and 2007. PRACTICE DESCRIPTION: Using four cornerstones (evidence-based medicine, therapeutic interchange, academic detailing, and a local pharmacy and therapeutics committee), the pharmacists provided population-based pharmaceutical care, leading generic switches, target drug programs, and prescription to over-the-counter medication switches. They also led disease management programs, managed drug recalls, implemented electronic health records, negotiated budgets with health plans, and led patient assistance programs and prior authorization programs to improve patient satisfaction. PRACTICE INNOVATION: Implementing these strategies from the vantage point of a physician group presents a seldom-realized employment opportunity for pharmacists. MAIN OUTCOME MEASURES: The impact of these strategies is measured by process, use, and clinical outcomes metrics. These, in turn, are linked to incentive payments in the pay-for-performance environment or to a lowered per member, per month cost in the capitated environment. RESULTS: In 2006-2007, 71% of our hypertensive patients received generic agents compared with a network average for receiving generic agents of 43%, while the proportion of patients with controlled blood pressure increased from 45% to 60%. We saved $450,000 in inpatient costs for deep venous thrombosis. CONCLUSION: Clinical pharmacists employed in a physician group practice can optimize medication use, improve care, and reduce costs.

Isolation of novel coregulatory protein networks associated with DNA-bound estrogen receptor alpha.

BACKGROUND: DNA-bound transcription factors recruit an array of coregulatory proteins that influence gene expression. We previously demonstrated that DNA functions as an allosteric modulator of estrogen receptor alpha (ERalpha) conformation, alters the recruitment of regulatory proteins, and influences estrogen-responsive gene expression and reasoned that it would be useful to develop a method of isolating proteins associated with the DNA-bound ERalpha using full-length receptor and endogenously-expressed nuclear proteins. RESULTS: We have developed a novel approach to isolate large complexes of proteins associated with the DNA-bound ERalpha. Purified ERalpha and HeLa nuclear extracts were combined with oligos containing ERalpha binding sites and fractionated on agarose gels. The protein-DNA complexes were isolated and mass spectrometry analysis was used to identify proteins associated with the DNA-bound receptor. Rather than simply identifying individual proteins that interact with ERalpha, we identified interconnected networks of proteins with a variety of enzymatic and catalytic activities that interact not only with ERalpha, but also with each other. Characterization of a number of these proteins has demonstrated that, in addition to their previously identified functions, they also influence ERalpha activity and expression of estrogen-responsive genes. CONCLUSION: The agarose gel fractionation method we have developed would be useful in identifying proteins that interact with DNA-bound transcription factors and should be easily adapted for use with a variety of cultured cell lines, DNA sequences, and transcription factors.

The role of retinoblastoma-associated proteins 46 and 48 in estrogen receptor alpha mediated gene expression.

The differential recruitment of coregulatory proteins to the DNA-bound estrogen receptor alpha (ERalpha) plays a critical role in mediating estrogen-responsive gene expression. We previously isolated and identified retinoblastoma-associated proteins 46 (RbAp46) and 48 (RbAp48), which are associated with chromatin remodeling, histone deacetylation, and transcription repression, as proteins associated with the DNA-bound ERalpha. We now demonstrate that RbAp46 and RbAp48 interact with ERalphain vitro and in vivo, associate with ERalpha at endogenous, estrogen-responsive genes, and alter expression of endogenous, ERalpha-activated and -repressed genes in MCF-7 breast cancer cells. Our findings reveal that RbAp48 limits expression of estrogen-responsive genes and that RbAp46 modulates estrogen responsiveness in a gene-specific manner. The ability of RbAp46 and RbAp48 to interact with ERalpha and influence its activity reveals yet another role for these multifunctional proteins in regulating gene expression.

The deoxyribonucleic acid repair protein flap endonuclease-1 modulates estrogen-responsive gene expression.

The ligand-occupied estrogen receptor alpha (ERalpha) initiates changes in gene expression through its interaction with target DNA. The capacity of ERalpha to modulate gene expression is influenced by the association of the receptor with a variety of coregulatory proteins. To further understand the role of these coregulatory proteins in ERalpha-mediated transcription, we have isolated and identified proteins associated with ERalpha when it is bound to the consensus estrogen response element. One of the proteins identified in this complex, flap endonuclease-1 (FEN-1), is required for DNA replication and repair. We show that FEN-1 interacts directly with ERalpha and enhances the interaction of ERalpha with estrogen response element-containing DNA. More importantly, chromatin immunoprecipitation and RNA interference assays demonstrate that endogenously expressed FEN-1 associates with the native pS2 gene in MCF-7 cells and influences estrogen-responsive gene expression. Interestingly, estrogen differentially regulates expression of FEN-1 in mouse uterine epithelial, stromal, and myometrial cells. Together, our studies help to elucidate the functional consequence of the ERalpha-FEN-1 interaction and increase our understanding of the elaborate regulatory mechanisms that drive estrogen-responsive gene expression and DNA repair.