Biomedical subjects

Jianming Xu

Publications and source records attributed to Jianming Xu.

At least 19 recordsLinked to original sources

PubMed2025

Rat somatic genome editing enables ER+ breast cancer modeling.

Genetically engineered mouse models have advanced cancer research but often fail to capture key features of certain human tumors. Rats, with distinct physiology and tumor biology, offer a powerful alternative, yet their use has been constrained by technical barriers to genome editing. Here, we report efficient somatic genome editing in rats, enabling both Indel and substitution mutations. We then apply this approach to model estrogen receptor (ER)-positive breast cancer, which accounts for ~70% of human cases but remains poorly represented in mice. The resulting rat tumors reproduce hallmarks of human ER+ breast cancer, including ductal histology, hormone responsiveness, and immune-microenvironmental features. By contrast, identical genetic alterations in mice failed to yield ER+ tumors, underscoring critical species differences in tumorigenesis. Together, this work establishes a versatile platform for rapid generation of clinically relevant rat tumor models, opening new avenues to dissect tumor biology, therapeutic response, and immune interactions in previously inaccessible cancer subtypes.

Journal Article↗

PubMed2006

Haploinsufficiency of the corepressor of estrogen receptor activity (REA) enhances estrogen receptor function in the mammary gland.

Estrogen receptor (ER)-mediated gene expression plays an essential role in mammary gland morphogenesis, function, and carcinogenesis. The repressor of ER activity (REA) is an ER-interactive protein that counterbalances estrogen-induced ER transcriptional activity. Our previous study showed that genetic deletion of both REA alleles resulted in embryonic lethality. This study demonstrates that REA and ERalpha are coexpressed in mammary epithelial cells. REA heterozygous (REA(+/-)) mutant mice exhibit faster mammary ductal elongation in virgin animals, increased lobuloalveolar development during pregnancy, and delayed mammary gland involution after weaning. These morphological phenotypes of REA(+/-) mice are associated with significantly increased cell proliferation and ER transcriptional activities, as indicated by the estrogen response element (ERE)-luciferase reporter in the WT/ERE-Luc and REA(+/-)/ERE-Luc bigenic mice and by the higher expression levels of estrogen-responsive genes such as progesterone receptor and cyclin D1 in the mammary gland. Our analysis also revealed that REA is an important repressor of ER transcriptional activity in the mammary gland under natural, as well as ovariectomized and estrogen-replaced, hormonal conditions. Our results indicate that REA is a physiological modulator of ER function in the mammary gland and that its correct gene dosage is required for maintenance of normal ER activity and normal mammary gland development. Consequently, a reduction or loss of REA function may cause overactivation of ER and increase breast cancer risk in humans.

Animals↗

PubMed2006

Stimulation of steroid receptor coactivator-3 (SRC-3) gene overexpression by a positive regulatory loop of E2F1 and SRC-3.

Steroid receptor coactivator 3 (SRC-3, amplified in breast cancer 1, or ACTR) is a transcriptional coactivator for nuclear receptors and certain other transcription factors such as E2F1. SRC-3 is overexpressed in breast cancers, and its overexpression is sufficient to cause mammary carcinomas in vivo. However, the mechanisms controlling endogenous SRC-3 overexpression are unknown. In this study, we identified the first exon and analyzed the 5' regulatory sequence of the SRC-3 gene. We found three evolutionarily conserved regions (ECRs) in the 5' SRC-3 regulatory sequence, and ECR2 makes a major contribution to the SRC-3 promoter activity. The ECR2 region (bp -250/+350) contains several specificity protein 1 (Sp1) binding sites and two E2F1 binding sites. We show that E2F1 can significantly activate the ECR2 promoter activity in a dose-dependent manner. Furthermore, overexpression of E2F1 significantly increases the promoter activity of the endogenous SRC-3 gene and boosts SRC-3 expression in vivo. Conversely, knockdown of E2F1 reduces SRC-3 expression. We demonstrate that the mechanism of E2F1 activity on SRC-3 promoter is independent of the E2F binding sites but relies on the Sp1 element located at bp +150/+160. Sp1, E2F1, and SRC-3 are specifically recruited to this Sp1 site and the interaction between E2F1 and Sp1 is essential to modulate SRC-3 expression. Moreover, SRC-3 coactivates E2F1 activity and thereby additively stimulates a further increase in SRC-3 expression in vivo. These results suggest that in cells with hyperactive E2F1, such as the case encountered in breast cancer cells, there is a positive feedback regulatory loop consisting of E2F1 and SRC-3 to maintain high levels of SRC-3 and E2F1 activity, which may partially interpret the oncogenic role of SRC-3 overexpression.

Amino Acid Motifs↗

PubMed2006

FK506-binding protein 52 is essential to uterine reproductive physiology controlled by the progesterone receptor A isoform.

FK506-binding protein 52 (FKBP52) is a tetratricopeptide repeat protein that associates with steroid receptors in complexes containing heat shock protein 90. To investigate the role of FKBP52 in steroid-regulated physiology, we generated FKBP52-deficient mice. FKBP52 (-/-) females are sterile due to a complete failure of implantation, a process that requires estrogen (ER) and progesterone receptors (PR). Because the uterus expresses two forms of PR, PR-A and PR-B, we investigated all three receptors as potential targets of FKBP52 action. FKBP52 (-/-) uteri showed a normal growth response to estradiol, and unaltered expression of genes controlled by ER and PR-B. In contrast, FKBP52 (-/-) uteri were neither able to express two PR-A-regulated genes, nor undergo decidualization in response to progesterone, suggesting that FKBP52 specifically regulates PR-A at this organ. Analysis of uterine PR heterocomplexes showed preferential association of FKBP52 with PR-A compared with PR-B. Loss of FKBP52 neither disrupted the PR-A/heat shock protein 90 interaction, nor impaired uterine PR-A hormone-binding function, demonstrating the essential role of FKBP52 in PR-A action to be downstream of the hormone-binding event. Transcription studies in +/+ and -/- mouse embryonic fibroblast cells showed a near-complete loss of PR-A activity at mouse mammary tumor virus and synthetic progesterone response element promoters, although partial reductions of ER and PR-B were also observed. Partial disruptions of ovulation and mammary development were also found in FKBP52 (-/-) females. Taken as a whole, our results show FKBP52 to be an essential regulator of PR-A action in the uterus, while being a nonessential but contributory regulator of steroid receptors in the mammary and ovary. These data may now provide the basis for selective targeting of steroid-regulated physiology through tetratricopeptide repeat proteins.

Animals↗

PubMed2006

Generalized models for prediction of pentachlorophenol dissipation dynamics in soils.

Dissipation of pentachlorophenol (PCP) in soil was investigated and the chemical relationships with soil properties were addressed. The results indicate that the dissipation of extractable PCP residues can be described using first-order kinetics equations, with a half-dissipation time (T(1/2)) ranging from 6.5 to 173.3d. The sharply different patterns of PCP dissipation in different soils were closely related to soil properties. Correlations of stepwise regression equations obtained were significant at 0.01 probability level between soil parameters and extractable PCP residues (R(2)=0.974**) as well as T(1/2) values (R(2)=0.882**). Using pH together with organic carbon content (OC) and soil particle size distribution, the dissipation dynamics of PCP in soil could be accurately predicted.

Carbon↗

PubMed2006

Sorption of phenanthrene by soils contaminated with heavy metals.

The fate of polycyclic aromatic hydrocarbons (PAHs) in soils with co-contaminants of heavy metals has yet to be elucidated. This study examined sorption of phenanthrene as a representative of PAHs by three soils contaminated with Pb, Zn or Cu. Phenanthrene sorption was clearly higher after the addition of heavy metals. The distribution coefficient (K(d)) and the organic carbon-normalized distribution coefficient (K(oc)) for phenanthrene sorption by soils spiked with Pb, Zn or Cu (0-1000 mg kg(-1)) were approximately 24% larger than those by unspiked ones, and the higher contents of heavy metals added into soils resulted in the larger K(d) and K(oc) values. The enhanced sorption of phenanthrene in the case of heavy metal-contaminated soils could be ascribed to the decreased dissolved organic matter (DOM) in solution and increased soil organic matter (SOM) as a consequence of DOM sorption onto soil solids. Concentrations of DOM in equilibrium solution for phenanthrene sorption were lower in the case of the heavy metal-spiked than unspiked soils. However, the decreased DOM in solution contributed little to the enhanced sorption of phenanthrene in the presence of metals. On the other hand, the sorbed DOM on soil solids after the addition of heavy metals in soils was found to be much more reactive and have far stronger capacity of phenanthrene uptake than the inherent SOM. The distribution coefficients of phenanthrene between water and the sorbed DOM on soil solids (K(ph/soc)) were about 2-3 magnitude larger than K(d) between water and inherent SOM, which may be the dominant mechanism of the enhanced sorption of phenanthrene by soils with the addition of heavy metals.

Adsorption↗

PubMed2006

Liver-specific overexpression of the insulin-like growth factor-I enhances somatic growth and partially prevents the effects of growth hormone deficiency.

The precise role of circulating IGF-I in somatic growth under normal and GH-deficient conditions remains unclear. To define the contribution of circulating IGF-I to the endocrine regulation of somatic growth and the GH/IGF-I axis, we constructed a transgene with the transthyretin (TTR) enhancer/promoter and the mouse IGF-I cDNA and generated TTR-IGF-I transgenic mice. The transgene was exclusively expressed in the liver, which resulted in a 50-60% increase in serum IGF-I, a decrease in serum GH, and an improved tolerance to glucose challenge. The body weight and lean mass of TTR-IGF-I mice were heavier compared with wild-type (WT) mice. The increase in lean mass was a result of increase in both number and thickness of skeletal muscle fibers. The femur, tibia, and body lengths of TTR-IGF-I mice also were longer. In WT mice, the GH antagonist pegvisomant (Peg) suppressed the transcription of endogenous IGF-I and acid-labile subunit (ALS) genes with no effect on IGF-binding protein 3 (IGFBP-3) mRNA. Consequently, Peg-induced GH deficiency in WT mice severely reduced ALS, IGF-I, and IGFBP-3 in the circulation and caused a severe growth deficit. In TTR-IGF-I mice, Peg reduced the mRNA of the endogenous IGF-I gene with no effect on the TTR-IGF-I transgene expression, leading to a blunted decrease in serum IGF-I levels. Interestingly, IGFBP-3 mRNA was elevated and circulating IGFBP-3 was less reduced in Peg-treated TTR-IGF-I mice. Peg-treated TTR-IGF-I mice also exhibited heavier body weight and longer body length than Peg-treated WT mice. Therefore, liver-expressed IGF-I can stimulate IGFBP-3 mRNA expression and stabilize IGFBP-3 under GH deficiency, leading to a better maintenance of IGF-I levels in the circulation. Higher circulating levels of IGF-I can stimulate somatic growth and lean mass and improve glucose tolerance.

Animals↗

PubMed2006

Assessment of toxicity of heavy metal contaminated soils by the toxicity characteristic leaching procedure.

The concentrations of Cu, Zn, Pb and Cd in soils near a lead-zinc mine located in Shangyu, Zhejiang Province, China, were determined and their toxicity was assessed using the toxicity characteristic leaching procedure (TCLP) developed by the United States Environmental Protection Agency. The TCLP method is a currently recognized international method for evaluation of heavy metal pollution in soils. The available levels of Cu, Zn, Pb and Cd were 8.2-36, 23-143, 6.4-1367 and 0.41-2.2 mg kg(-1), respectively, while the international standards were 15, 25, 5 and 0.5 mg kg(-1), respectively. Soils around the mine were more polluted with Zn and Pb, followed by Cd and Cu. Moreover, the levels of heavy metals in the soils extracted by TCLP indicated that extraction fluid 2 was more effective than extraction fluid 1 in extracting the heavy metals from the polluted soils and there was a positive correlation between fluids 1 and 2. Available heavy metal contents determined by TCLP were correlated with soil total heavy metal contents.

Cadmium↗

PubMed2006

Detailed sorption isotherms of pentachlorophenol on soils and its correlation with soil properties.

Insight into the sorption mechanism of pentachlorophenol (PCP) was gained by constructing highly detailed isotherms over the widest possible concentration range. Using the dual-mode model, sorption isotherms of PCP were accurately predicted, the sorption capacities were determined, and the mechanisms of adsorption (hole-filling) and partitioning were elucidated. Sorption-desorption hysteresis in the present study was manifested to some significant degree in 10 soils with different properties. Such hysteresis might result from the pore deformation and entrapment of PCP molecules within organic matter. Total nitrogen in soils also has its contribution in these kinds of processes. Correlations of stepwise regression equations obtained confirm that pH, soil organic carbon and organic carbon fractions, and particle size distribution are the main factors responsible for the sorption and desorption hysteresis processes. These factors worked in concert in influencing the fate of PCP sorption-desorption in soil. The empirical models developed in this study accurately predict PCP sorption and desorption hysteresis phenomena for the soils that were investigated.

Adsorption↗

PubMed2006

Potential contributions of clay minerals and organic matter to pentachlorophenol retention in soils.

Sorption of pentachlorophenol (PCP) by pure minerals and humic acids were measured to obtain additional perspective on the potential contributions of both clay minerals and soil organic matter (SOM) to contaminants retention in soils. Four types of common soil minerals and two kinds of humic acids (HAs) were tested. The sorption affinity for PCP conformed to an order of HAs >> K-montmorillonite >> Ca-montmorillonite >> goethite >> kaolinite. Such a difference in sorption capacity could be attributed to the crucial control of HAs. Clay minerals also had their contribution, especially K-montmorillonite, which played an important, if not dominant, role in the controlling process of PCP sorption. By removing 80% (on average) of the organic carbon from the soils with H(2)O(2), the sorption decreased by an average of 50%. The sorption reversibility had been greatly favored as well. Considering the uncharged mineral fractions in soil before and after H(2)O(2)-treated, the main variation in sorption behavior of the soil might thus be related to the removed organic carbon and the reduced pH. This testified rightly the interactive effect of SOM and clay minerals on PCP sorption as a function of pH.

Adsorption↗

PubMed2006

Regulation of insulin secretion and beta-cell mass by activating signal cointegrator 2.

Activating signal cointegrator 2 (ASC-2) is a transcriptional coactivator of many nuclear receptors (NRs) and other transcription factors and contains two NR-interacting LXXLL motifs (NR boxes). In the pancreas, ASC-2 is expressed only in the endocrine cells of the islets of Langerhans, but not in the exocrine cells. Thus, we examined the potential role of ASC-2 in insulin secretion from pancreatic beta-cells. Overexpressed ASC-2 increased glucose-elicited insulin secretion, whereas insulin secretion was decreased in islets from ASC-2+/- mice. DN1 and DN2 are two dominant-negative fragments of ASC-2 that contain NR boxes 1 and 2, respectively, and block the interactions of cognate NRs with the endogenous ASC-2. Primary rat islets ectopically expressing DN1 or DN2 exhibited decreased insulin secretion. Furthermore, relative to the wild type, ASC-2+/- mice showed reduced islet mass and number, which correlated with increased apoptosis and decreased proliferation of ASC-2+/- islets. These results suggest that ASC-2 regulates insulin secretion and beta-cell survival and that the regulatory role of ASC-2 in insulin secretion appears to involve, at least in part, its interaction with NRs via its two NR boxes.

Amino Acid Motifs↗

PubMed2005

Steroid receptor coactivator-1-deficient mice exhibit altered hypothalamic-pituitary-adrenal axis function.

Steroidogenic factor-1 (SF-1), has emerged as a critical nuclear receptor regulating development and differentiation at several levels of the hypothalamic-pituitary-steroidogenic axis. Although many coregulatory factors have been shown to physically and functionally interact with SF-1, the relative importance of these interactions in SF-1 target tissues has not been thoroughly established. In this study we assessed roles of steroid receptor coactivator-1 (SRC-1) in hypothalamic-pituitary-adrenal (HPA) axis function using SRC-1-deficient (SRC-1-/-) mice in the absence or presence of SF-1 haploinsufficiency. Surprisingly, SRC-1 deficiency did not alter baseline HPA axis function or the acute rise in corticosterone after ACTH administration and failed to exacerbate adrenocortical dysfunction in SF-1+/- mice. However, after exposure to paradigms of acute and chronic stress, SRC-1-/- mice exhibited an elevation in serum corticosterone despite normal (nonsuppressed) ACTH, suggesting an increase in adrenal sensitivity as well as a concomitant defect in glucocorticoid-mediated feedback inhibition of the HPA axis. An examination of potential compensatory mechanism(s) revealed an increase in adrenal weight, selective elevation of melanocortin 2 receptor mRNA, and a coincident increase in SRC-2 and SRC-3 expression in SRC-1-/- adrenals. A reduction in blood glucose was observed in SRC-1-/- mice after chronic stress, consistent with a generalized state of glucocorticoid resistance. Dexamethasone suppression tests confirmed a weakened ability of glucocorticoids to 1) elevate serum glucose levels and induce hepatic phosphoenolpyruvate carboxykinase transcription and 2) suppress pituitary proopiomelanocortin transcript levels in SRC-1-/- animals. Collectively, these data are consistent with an indispensable role for SRC-1 in mediating actions of glucocorticoids in pituitary and liver.

Adrenal Glands↗

PubMed2005

Characterizing the risk assessment of heavy metals and sampling uncertainty analysis in paddy field by geostatistics and GIS.

For many practical problems in environmental management, information about soil heavy metals, relative to threshold values that may be of practical importance is needed at unsampled sites. The Hangzhou-Jiaxing-Huzhou (HJH) Plain has always been one of the most important rice production areas in Zhejiang province, China, and the soil heavy metal concentration is directly related to the crop quality and ultimately the health of people. Four hundred and fifty soil samples were selected in topsoil in HJH Plain to characterize the spatial variability of Cu, Zn, Pb, Cr and Cd. Ordinary kriging and lognormal kriging were carried out to map the spatial patterns of heavy metals and disjunctive kriging was used to quantify the probability of heavy metal concentrations higher than their guide value. Cokriging method was used to minimize the sampling density for Cu, Zn and Cr. The results of this study could give insight into risk assessment of environmental pollution and decision-making for agriculture.

Cadmium↗

PubMed2005

Studies on the phosphorus sorption capacity of substrates used in constructed wetland systems.

Langmuir sorption isotherm was used to screen various substrates for use in removing phosphorus (P) in constructed wetlands (CW). The nine tested substrates included four sands, two soils, bentonite, and two industrial by-products of furnace slag and fly ash. Results showed that the furnace slag had the highest P sorption capacity (8.89 g Pk g(-1)), followed was the fly ash (8.81 g P kg(-1)), and that of sand II was the lowest. Different kinds of sands also showed varying P sorption capacity (0.13-0.29 g P kg(-1)). P sorption capacity was influenced by both the physico-chemical characteristics of the substrates and the amount of organic matter (OM) added. Lifetime of sand II for P sorption estimated by Langmuir P sorption maximum was up to only 9 months in full-scale systems, while that of furnace slag could be used for up to 22 yr. Furnace slag has great potential as a CW substrate, due to its high P sorption capacity. The expected lifetime of constructed wetlands for P removal is strongly influenced by the choice of adsorbing substrate.

Adsorption↗

PubMed2005

Application of 16S rDNA-PCR amplification and DGGE fingerprinting for detection of shift in microbial community diversity in Cu-, Zn-, and Cd-contaminated paddy soils.

Seven soils were sampled from farmland at different distances (0.01-5 km) from a copper and zinc smelter. The total contents of heavy metals in these soils ranged from 46 to 4895 mg Cu kg-1, 96 to 1133 mg Zn kg-1, and 6.9 to 28.8 mg Cd kg-1, respectively. The available fractions were highly correlated with total contents of the metals. In order to assess the impact of combined contamination of heavy metals on soil bacterial communities, denaturing gradient gel electrophoresis (DGGE) of polymerase chain reaction (PCR) amplicons of 16S rDNA sequence of bacteria in soil was used. Bacterial community structure was affected to some extent by heavy metals. The number of DGGE bands in soils increased with increasing distance from the copper and zinc smelter. Clustering analysis of the DGGE profiles showed that bacteria in the seven soils belonged to three clusters. Bacterial communities in three soils sampled at 0.01-0.60 km from the smelter belonged to one cluster, and those in three soils sampled at 0.8-1.2 km from the smelter belong to another cluster. Bacterial community in soil farthest from the smelter belonged to a single cluster. This study demonstrated that heavy metal contamination decreased both biomass and diversity of bacterial community in the soil.

Cadmium↗

PubMed2005

Mice lacking the amplified in breast cancer 1/steroid receptor coactivator-3 are resistant to chemical carcinogen-induced mammary tumorigenesis.

Amplified in breast cancer 1 (AIB1; steroid receptor coactivator-3, p/CIP, RAC3, ACTR, TRAM-1, or NCoA-3) is a transcriptional coactivator for nuclear receptors and certain other transcription factors and is a newly defined oncogene overexpressed in human breast cancer. Although the role and molecular mechanism of AIB1 in normal physiology and in breast cancer are currently under intensive investigation, the role of AIB1 in determination of the susceptibility of mammary gland to chemical carcinogens remains uncharacterized. In this study, we used back-crossed FVB wild-type (WT) and AIB1 mutant mice to assess the role of AIB1 in mammary gland development and in carcinogen-induced tumorigenesis. We show that mammary ductal growth was delayed in AIB1-/- mice with FVB strain background, and mammary ductal outgrowths emanating from the AIB1-/- mammary epithelial transplants in WT mice also were attenuated, indicating that the role of AIB1 in mammary ductal growth is a mammary epithelial autonomous function. In mice treated with the chemical carcinogen 7,12-dimethylbenz[a]anthracene (DMBA), AIB1 deficiency protected the mammary gland, but not the skin, from tumorigenesis. AIB1 deficiency suppressed the up-regulation of the insulin receptor substrate (IRS)-1 and IRS-2 and thereby inhibited the activation of Akt, expression of cyclin D1, and cell proliferation. The suppression of these components for insulin-like growth factor-I signaling might be partially responsible for the decreased DMBA-induced mammary tumor initiation and progression in AIB1-/- mice. Our results suggest that AIB1 may serve as a potential target for prevention of carcinogen-induced breast cancer initiation and for treatment of breast cancer progression.

9,10-Dimethyl-1,2-benzanthracene↗

PubMed2005

Steroid receptor coactivator (SRC)-1 and SRC-3 differentially modulate tissue-specific activation functions of the progesterone receptor.

The progesterone receptor (PR) and its coactivators and corepressors play an important role in female reproductive function. To investigate the functional interactions between PR and steroid receptor coactivators (SRCs) required for regulation of gene transcription in vivo, we crossed PR activity indicator (PRAI) mice with SRC-1(+/-) and SRC-3(+/-) mice to generate bigenic mice, PRAI-SRC-1(-/-) and PRAI-SRC-3(-/-). In the mammary gland, PR activity in the luminal epithelium of both wild-type and SRC-1(-/-) mice was induced by estrogen + progesterone treatment. In contrast, an increase in PR activity in the luminal epithelium was not detected in SRC-3(-/-) mice with the same treatment. In the uterus, PR activity in the stroma compartment of both wild-type and SRC-3(-/-) mice was induced by estrogen + progesterone treatment. However, the increased PR activity was not detected in SRC-1(-/-) mice. Taken together, our data indicate that the endogenous physiological function of PR in distinct tissues is modulated by different steroid receptor coregulators. SRC-3 is the primary coactivator for PR in breast and SRC-1 is the primary coactivator for PR in uterus.

Animals↗

PubMed2005

Roles of steroid receptor coactivator (SRC)-1 and transcriptional intermediary factor (TIF) 2 in androgen receptor activity in mice.

Genetic disruption of the steroid receptor coactivator (SRC)-1 and transcriptional intermediary factor (TIF)2/SRC-2 in mouse resulted in distinctive mutant phenotypes. To quantify their roles in the function of androgen receptor (AR) transcriptional activity in vivo, we generated a unique transgenic AR-reporter mouse and analyzed the cell-specific contributions of SRC-1 and TIF2 to the activity of AR in mouse testis. Transgenic AR-luciferase and transgenic AR-lacZ mice harbor a recombinant mouse AR gene, AR(GAL4DBD), which is functionally coupled with a upstream activation sequence-mediated reporter gene (AR activity indicator). After characterization of these mice in terms of AR function, we further derived bigenic mice by crossing AR activity indicator mice with the SRC-1-/- or TIF2+/- mutant mice. Analyses of the resultant bigenic mice by in vivo imaging and luciferase assays showed that testicular AR activity was decreased significantly in those with the TIF2+/- mutation but not in the SRC-1+/- background, suggesting that TIF2 serves as the preferential coactivator for AR in testis. Immunohistological analysis confirmed that AR and TIF2 coexist in mouse testicular Sertoli cell nuclei under normal conditions. Although SRC-1 concentrates in Sertoli cell nuclei in the absence of TIF2, nuclear SRC-1 is not able to rescue AR activity in the TIF2 mutant background. Interestingly, SRC-1 appears to negatively influence AR activity, thereby counterbalancing the TIF2-stimulated AR activity. Our results provide unique in vivo insights to the multidimensional cell-type-specific interactions between AR and coregulators.

Animals↗