Colin R. Jefcoate's research while affiliated with University of Wisconsin–Madison and other places

Publications (246)

Article
Full-text available
Polycyclic aromatic hydrocarbon (PAH) pollutants and microbiome products converge on the aryl hydrocarbon receptor (AhR) to redirect selective rapid adherence of isolated bone marrow (BM) cells. In young adult mice, Cyp1b1-deficiency and AhR activation by PAH, particularly when prolonged by Cyp1a1 deletion, produce matching gene stimulations in the...
Article
Full-text available
Cytochrome P450 (CYP) 1B1 belongs to the superfamily of heme-containing monooxygenases. Unlike other CYP enzymes, which are highly expressed in the liver, CYP1B1 is predominantly found in extrahepatic tissues, such as the brain, and ocular tissues including retina and trabecular meshwork. CYP1B1 metabolizes exogenous chemicals such as polycyclic ar...
Article
STARD1 stimulates cholesterol transfer to mitochondrial CYP11A1 for conversion to pregnenolone. A cholesterol-binding START domain is guided by an N-terminal domain in a cell selective manner. Fetal and adult Leydig cells (FLC, ALC) show distinct Stard1 regulation. sm- FISH microscopy, which resolves individual molecules of Stard1 mRNA, shows unifo...
Article
Two specialized functions of cholesterol during fetal development include serving as a precursor to androgen synthesis and supporting hedgehog (HH) signaling activity. Androgens are produced by the testes to facilitate masculinization of the fetus. Recent evidence shows that intricate interactions between the HH and androgen signaling pathways are...
Article
Full-text available
STARD1 moves cholesterol (CHOL) from the outer mitochondrial membrane (OMM) to the inner membrane (IMM) in steroidogenic cells. This activity is integrated into CHOL trafficking and synthesis homeostasis, involving uptake through SR-B1 and LDL receptors and distribution through endosomes, ER, and lipid droplets. In adrenal cells, STARD1 is imported...
Article
Polycyclic aromatic hydrocarbons (PAHs) are ubiquitous pollutants that are metabolized to carcinogenic dihydrodiol epoxides (PAHDE) by cytochrome P450 1B1 (CYP1B1). This metabolism occurs in bone marrow (BM) mesenchymal stem cells (MSC), which sustain hematopoietic stem and progenitor cells (HSPC). In BM, CYP1B1-mediated metabolism of 7, 12-dimethy...
Article
Full-text available
Background Cytochrome P450 1b1 (Cyp1b1) deletion and dietary retinol deficiency during pregnancy (GVAD) affect perinatal liver functions regulated by Srebp. Cyp1b1 is not expressed in perinatal liver but appears in the E9.5 embryo, close to sites of retinoic acid (RA) signaling. Hypothesis Parallel effects of Cyp1b1 and retinol on postnatal Srebp...
Article
Open microfluidic cell culture systems are powerful tools for interrogating biological mechanisms. We have previously presented a microscale cell culture system, based on spontaneous capillary flow of biocompatible hydrogels, that is integrated into a standard cell culture well plate, with flexible cell compartment geometries and easy pipet access....
Article
Cholesterol trafficking from serum lipoproteins converges on steroidogenic acute regulator (StAR/STARD1) at the outer mitochondrial membrane (OMM). ¹⁹⁵S-Phospho-StAR directs cholesterol released by lipid droplets or endosomes to the inner mitochondrial membrane (IMM) for metabolism at CYP11A1. A helical N-terminal domain slows StAR import, providin...
Preprint
Open microfluidic cell culture systems are powerful tools for interrogating biological mechanisms. We have previously presented a microscale cell culture system, based on spontaneous capillary flow of biocompatible hydrogels, that is integrated into a standard cell culture well plate, with flexible cell compartment geometries and easy pipet access....
Article
Full-text available
We are increasingly exposed to environmental pollutants, including the carcinogen benzo[a]pyrene (BaP), which has prompted extensive research into human metabolism of toxicants. However, little is known about metabolic mechanisms employed by fungi that are able to use some toxic pollutants as the substrates for growth, leaving innocuous by-products...
Article
Mutations in cytochrome P450 1B1 (CYP1B1) gene are reported in patients with primary congenital glaucoma. Cyp1b1-deficient (Cyp1b1-/-) mice show dysgenesis of the trabecular meshwork (TM) tissue and attenuation of retinal neovascularization during oxygen-induced ischemic retinopathy (OIR). Although retinal vascular cells, including endothelial cell...
Article
Supplemental oxygen is a life-saving intervention administered to individuals suffering from respiratory distress, including adults with acute lung injury (ALI) and acute respiratory distress syndrome (ARDS). Despite the clinical benefit, supplemental oxygen can create a hyperoxic environment that increases reactive oxygen species (ROS), oxidative...
Article
Cholesterol is an important regulator of cell signaling, both through direct impacts on cell membranes and through oxy-metabolites that activate specific receptors (steroids, hydroxy-cholesterols, bile acids). Cholesterol moves slowly through and between cell membranes with the assistance of specific binding proteins and transfer processes. The pro...
Article
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Cellular metabolites act as important signaling cues, but are subject to complex unknown chemistry. Kynurenine is a tryptophan metabolite that plays a crucial role in cancer and the immune system. Despite its atypical, non-ligand-like, highly polar structure, kynurenine activates the aryl hydrocarbon receptor (AHR), a PAS family transcription facto...
Article
Full-text available
Recent advances in fluorescence microscopy, coupled with CRISPR/Cas9 gene editing technology, provide opportunities for understanding gene regulation at the single-cell level. The application of direct imaging shown here provides an in situ side-by-side comparison of CRISPR/Cas9-edited cells and adjacent unedited cells. We apply this methodology to...
Article
Full-text available
Cyp1b1 deletion and gestational vitamin A deficiency (GVAD) redirect adult liver gene expression. A matched sufficient pre- and post-natal diet, which has high carbohydrate and normal iron content (LF12), increased inflammatory gene expression markers in adult livers that were suppressed by GVAD and Cyp1b1 deletion. At birth on the LF12 diet, Cyp1b...
Article
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For mice, a maternal vitamin A (VA) deficient diet initiated from mid-gestation (GVAD) produces serum retinol deficiency in mature offspring. We hypothesize that the effects of GVAD arise from pre-weaning developmental changes. We compare the effect of this GVAD protocol in combination with a post-weaning high fat diet (HFD) or high carbohydrate di...
Conference Paper
Cyp1b1 has minimal expression in hepatocytes but is robustly expressed in endothelia, pericytes and mesenchymal progenitors of bone marrow (BM). Cyp1b1 mediates suppression of BM lymphoid ,myeloid and erythroid progenitors by DMBA within 6h . This effect of PAH reactive metabolites is measured by loss of colony forming activity for each lineage. Th...
Article
The Steroidogenic acute regulatory protein (StAR) directs mitochondrial cholesterol uptake through a C-terminal cholesterol binding domain (CBD) and a 62 amino acid N-terminal regulatory domain (NTD) that contains an import sequence and conserved sites for inner membrane metalloproteases. Deletion of the NTD prevents mitochondrial import while main...
Article
Full-text available
The cholesterol transfer function of steroidogenic acute regulatory protein (StAR) is uniquely integrated into adrenal cells, with mRNA translation and protein kinase A (PKA) phosphorylation occurring at the mitochondrial outer membrane (OMM). The StAR C-terminal cholesterol-binding domain (CBD) initiates mitochondrial intermembrane contacts to rap...
Article
Full-text available
cAMP response element binding protein (CREB) is a key regulator of glucose metabolism and synaptic plasticity that is canonically regulated through recruitment of transcriptional coactivators. Here we show that phosphorylation of CREB on a conserved cluster of Ser residues (the ATM/CK cluster) by the DNA damage-activated protein kinase ataxia-telan...
Article
Supplemental oxygen, which is routinely administered to preterm infants with pulmonary insufficiency, contributes to bronchopulmonary dysplasia (BPD) in these infants. Hyperoxia also contributes to the development of acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) in adults. The mechanisms of oxygen-mediated pulmonary toxicit...
Article
Full-text available
The steroidogenic acute regulatory protein (StAR) has been proposed to serve as the switch that can turn on/off steroidogenesis. We investigated the events that facilitate dynamic StAR transcription in response to cAMP stimulation in MA-10 Leydig cells, focusing on splicing anomalies at StAR gene loci. We used 3' reverse primers in a single reactio...
Conference Paper
Benzo[a]pyrene (BP) but not 7,12 dimethylbenz[a]anthracene (DMBA) extensively stimulates many cytokines, including Tnfα, Il6, Cxcl10 and Ifn- in bone marrow (BM) within 6h. This process is attenuated in Cyp1a1-ko mice. Intermediate increases in these cytokines are produced by depletion of the Cyps in absence of PAH (Cyp1b1-ko > Cyp1a1-ko). These c...
Article
Full-text available
Cytochrome P450 1b1 (Cyp1b1) is expressed in endothelia, stellate cells and pre-adipocytes, but not hepatocytes. Deletion alters liver fatty acid metabolism and prevents obesity and hepatic steatosis. This suggests a novel extra-hepatocyte regulation directed from cells that express Cyp1b1. To characterize these mechanisms, microarray gene expressi...
Article
Full-text available
7,12-Dimethylbenz(a)anthracene (DMBA) rapidly suppresses hematopoietic progenitors, measured as colony forming units (CFU), in mouse bone marrow (BM) leading to mature cell losses as replenishment fails. These losses are mediated by Cyp1b1, independent of the AhR, despite induction of Cyp1b1. BM mesenchymal progenitor cells (MPC) may mediate these...
Article
In mouse steroidogenic cells the activation of cholesterol metabolism is mediated by steroidogenic acute regulatory protein (StAR). Here, we visualized a coordinated regulation of StAR transcription, splicing and post-transcriptional processing, which are synchronized by salt inducible kinase (SIK1) and CREB-regulated transcription coactivator (CRT...
Article
Full-text available
Cytochrome P450 monooxygenase (CYP) superfamily contributes a broad array of biological functions in living organisms. In fungi, CYPs play diverse and pivotal roles in versatile metabolism and fungal adaptation to specific ecological niches. In this report, CYPomes in the 47 genomes of fungi belong to the phyla Ascomycota, Basidiomycota, Chytridiom...
Article
Cytochrome P450 1B1 (CYP1B1) is involved in the metabolism of xenobiotic compounds and endogenous metabolites. Disruption of Cyp1b1 in mice results in suppression of high-fat diet (HFD)-induced obesity and an extensive change in hepatic energy regulation despite minimal constitutive expression of CYP1B1 in hepatocytes. Lack of CYP1B1 is correlated...
Article
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Female sex steroid hormones, estradiol-17β (E2-17β) and progesterone (P4) regulate reproductive function and gene expression in a broad range of tissues. Given the central role of the liver in regulating homeostasis including steroid hormone metabolism, we sought to understand how E2-17β and P4 interact to affect global gene expression in liver. Ov...
Article
Full-text available
Mutation in CYP1B1 has been reported for patients with congenital glaucoma. However, the underlying mechanisms remain unknown. Here we show increased diurnal intraocular pressure (IOP) in Cyp1b1-deficient (Cyp1b1−/−) mice. Cyp1b1−/− mice presented ultrastructural irregular collagen distribution in their trabecular meshwork (TM) tissue along with in...
Article
Full-text available
Perivascular supporting cells, including pericytes and smooth muscle cells (PC/SMC), have an integral role during angiogenesis and control vascular remodeling, maturation, and stabilization of neoteric vessels. We recently showed that a Cyp1B1 deficiency in mice results in the attenuation of angiogenesis in vivo and the pro-angiogenic activity of e...
Article
Cytochrome P4501B1 (Cyp1b1) is expressed specifically in certain neural crest (NC) cells during embryogenesis. Mesenchymal progenitor cells that develop from NC cells are modeled here by mouse C3H10T1/2 and 3T3-L1 cells. Dexamethasone in combination with methylisobutylxanthine (DM) induces Cyp1b1 and a 6.7 kb mouse Cyp1b1 promoter-luciferase report...
Article
Full-text available
Bone marrow (BM) hematopoietic cells are selectively sensitive to polycyclic aromatic hydrocarbons (PAH) in vivo. 7,12-Dimethylbenz(a)anthracene (DMBA), but not benzo(a)pyrene (BP), depletes BM hematopoietic cells in C57BL/6 mice. This difference is due to a BP-selective aryl hydrocarbon receptor (AhR)-mediated recovery. Colony-forming unit assays...
Article
The steroidogenic acute regulatory (StAR) protein is generated in rodents from 1.6 kb and 3.5 kb mRNA formed by alternative polyadenylation. The zinc finger protein, TIS11B (also Znf36L1), is elevated by cAMP in adrenal cells in parallel with StAR mRNA. TIS11b selectively destabilizes the 3.5 kb mRNA through AU-rich sequences at the end of the 3'UT...
Conference Paper
Acute disruption of bone marrow hematopoietic progenitor cells by benzo(a)pyrene (BP) is reversed by processes dependent on Ah Receptor activation Alhaji U. N’jai1,2, M. Larsen3, C.J.Czuprynski1,2,4and C.R. Jefcoate2,3, 1Dept. of Pathobiological Sc, 2Mol. and Environ. Tox., 3Dept. of Pharmacology, 4Food Research Institute, UW Madison. We use...
Article
Full-text available
We have recently shown that deletion of constitutively expressed CYP1B1 is associated with attenuation of retinal endothelial cell (EC) capillary morphogenesis (CM) in vitro and angiogenesis in vivo. This was largely caused by increased intracellular oxidative stress and increased production of thrombospondin-2, an endogenous inhibitor of angiogene...
Article
In this study we used colony forming unit (CFU) assays to demonstrate rapid suppression (within 6h) of lymphoid (CFU-preB) and myeloid (CFU-GM) progenitor cells in DMBA-treated mice. The duration of these changes were consistent with the blood levels of DMBA and its metabolites that were achieved by either IP or oral DMBA administration. CFU-GM and...
Article
Full-text available
Star is expressed in steroidogenic cells as 3.5- and 1.6-kb transcripts that differ only in their 3'-untranslated regions (3'-UTR). In mouse MA10 testis and Y-1 adrenal lines, Br-cAMP preferentially stimulates 3.5-kb mRNA. ACTH is similarly selective in primary bovine adrenocortical cells. The 3.5-kb form harbors AU-rich elements (AURE) in the exte...
Article
Full-text available
Reactive species derived from cell oxygenation processes play an important role in vascular homeostasis and the pathogenesis of many diseases including retinopathy of prematurity. We show that CYP1B1-deficient (CYP1B1(-/-)) mice fail to elicit a neovascular response during oxygen-induced ischemic retinopathy. In addition, the retinal endothelial ce...
Article
Full-text available
Cytochrome P450 1B1 (Cyp1b1) metabolism contributes to physiologic functions during embryogenesis but also to carcinogenic activation of polycyclic aromatic hydrocarbons (PAH). We generated Cyp1b1-deficient mice carrying the Min allele of the adenomatous polyposis coli gene. These Cyp1b1-deficient Min mice developed twice as many tumors as Min cont...
Article
The mouse embryo fibroblast cell lines 3T3-L1 and C3H10T1/2 differentiate to adipocytes that exhibit similar insulin regulation of lipogenesis. These cell lines, however, differ appreciably in the processes that produce the major regulator PPAR gamma. Each line is stimulated by a mixture of insulin, dexamethasone, and methylisobutylxanthine (IDM)....
Article
Obesity enhances prostate cancer (PC) metastasis to bone. Factors secreted from adipocytes enhance PC growth. We hypothesized that feeding a high fat diet to C57BL/6 mice would enhance bone marrow (BM) fibroblastic progenitor differentiation to adipocytes. Mice were fed isocaloric low (LFD) and high (HFD) fat diets for up to 11 weeks postweaning. B...
Article
Full-text available
cAMP stimulation of rodent steroidogenic cells produces two StAR transcripts, a major 3.5 kb and a minor 1.6 kb mRNA, differing only in their 3' untranslated regions (3' UTR). They exhibit very different responses to stimulation and removal of 8-Br-cAMP, with the 3.5 kb form increasing and declining much more rapidly than the 1.6 kb form. The 3' en...
Article
Stimulation of PPARgamma1 and adipogenesis in multipotential C3H10T1/2 cells by the combination of dexamethasone and 3-isobutyl-1-methylxanthine (DM) is suppressed by 2,3,7,8 tetrachlorodibenzodioxin (TCDD) (10 nM). This suppression requires sustained activation of extracellular signal-regulated kinase (Erk)1/2. We show that it arises from an effec...
Article
Steroidogenic acute regulatory (StAR) protein is an important regulatory protein in steroidogenesis and rapidly undergoes proteolysis after import into the mitochondria. In this study, we determined the proteolytic cleavage sites and investigated the effects on the stimulation of steroidogenic activity of the blockage of these sites by mutation. Th...
Article
Liver X receptors (LXRs) broadly limit cholesterol accumulation by regulating expression of genes involved in cholesterol efflux and storage. In this issue of the JCI, Cummins et al. report that LXRalpha is involved in similar regulation in the adrenal cortex, but it also substantially modulates glucocorticoid synthesis (see the related article beg...
Article
Polycyclic aromatic hydrocarbons (PAHs) are common environmental contaminants that are carcinogenic and immunosuppressive. Benzo(a)pyrene (BP) and 7,12-dimethylbenz(a)anthracene (DMBA) are two prototypic PAHs known to impair the cell-mediated and humoral immune responses. We have previously shown that, in C57BL/6J mice, total bone marrow (BM) cellu...
Article
Full-text available
Cytochrome P450 (CYP) 1B1, which catalyzes 17β-estradiol 4-hydroxylation, is expressed in steroid-related tissues including ovary, testis, and adrenal gland. Generally, the expressions of steroidogenic CYPs are transcriptionally regulated by steroidogenic factor-1 (SF-1) and cAMP response element (CRE) binding protein (CREB). In the present study,...
Article
C3H10T1/2 mouse embryo fibroblasts differentiate into adipocytes when stimulated by a standard hormonal mixture (IDMB). 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD), via the aryl hydrocarbon receptor (AhR), inhibits induction of the key adipogenic gene peroxisome proliferator-activated receptor gamma (PPARgamma) and subsequent adipogenesis. This TCDD...
Article
Stimulation of C3H10T1/2 cells by an adipogenic hormonal mixture (IDM) consisting of insulin (I), dexamethasone (D), and methylisobutylxanthine (M) substantially induces cytochrome P450 (CYP) 1B1 expression. This stimulation represents up to 40% of the level produced by maximum activation of the arylhydrocarbon receptor (AhR) with 2,3,7,8-tetrachlo...
Article
The steroidogenic acute regulator (StAR) gene is transcribed to 1.6 kb and 3.5 kb mRNAs that differ only through the length of the 3'-untranslated region (3'-UTR). These forms result from alternative polyadenylation sites in exon 7. These sites are utilized similarly in unstimulated adrenal cells whereas Br-cAMP selectively stimulates 3.5 kb mRNA....
Article
We have previously reported that 7,12-dimethylbenz[a]anthracene (DMBA) induced apoptosis in precursor B lymphocytes (pre-B cells) only when they were co-cultured with bone marrow stromal (BMS) cells. The goal of this research was to determine whether this process was dependent on the adherence of the pre-B cells and stromal cells. Conditioned media...
Article
We have previously reported that 7,12-dimethylbenz[a]anthracene (DMBA) induced apoptosis in precursor B lymphocytes (pre-B cells) only when they were co-cultured with bone marrow stromal (BMS) cells. The goal of this research was to determine whether this process was dependent on the adherence of the pre-B cells and stromal cells. Conditioned media...
Article
Antibodies raised in rabbits against highly purified preparations of two cytochromes (cytochrome P‐450 CAM from Pseudomonas putida and cytochrome P‐450 scc from bovine adrenocortical mitochondria) were found to be specific for their respective antigens in Ouchterlony doublediffusion assays. In each case a single sharp curve was observed and no resp...
Article
CYP1B1 activates polycyclic aromatic hydrocarbon carcinogens in cAMP-regulated tissues such as the adrenal, ovary, and testis. A 27-fold cAMP stimulation of the CYP1B1-luciferase reporter in Y-1 adrenal cells depends entirely on a far upstream enhancer region (FUER; -5298 to -5110). Cooperative participation of multiple steroidogenic factor 1 (SF-1...
Article
Polycyclic aromatic hydrocarbons (PAHs) (50 mg/kg, i.p.) selectively deplete mouse bone marrow (BM) hematopoietic cells through a process that is dependent on CYP1B1. 7,12-dimethylbenz(a)anthracene (DMBA), which forms greater amounts of dihydrodiol-epoxide-DNA adducts in BM, is much more effective in depleting BM cells than benzo(a)pyrene (BP). BM...
Article
Cholesterol metabolism to pregnenolone is dependent on the steroidogenic acute regulatory protein (StAR), which activates mitochondrial transfer of cholesterol to cytochrome CYP450scc. In mouse Y-1 adrenal cells and testis MA10 cells stimulation by 8-Bromo-cAMP (Br-cAMP) is augmented by a novel signaling initiated by low concentrations of arsenite...
Article
TCDD exposure of multipotential C3H10T1/2 fibroblasts for 72 h altered the expression of over 1000 genes, including coordinated changes across large functionally similar gene clusters. TCDD coordinately induced 23 cell cycle-related genes similar to epidermal growth factor (EGF)-induced levels but without any affect on the major mitogenic signaling...
Article
Full-text available
Polycyclic aromatic hydrocarbons (PAHs) are known to be activated by the cytochrome P450 (P450) 1 family. However, the precise role of individual P4501 family members in PAH bioactivation remains to be fully elucidated. We therefore investigated the formation of PAH-DNA adducts in the epidermis of Cyp1a2(-/-), Cyp1b1(-/-), and Ahr(-/-) knockout mic...
Article
Acute steroidogenesis in either Y-1 or MA-10 cells is sensitive to different effects of fatty acids compare to a chronic stimulation. A 3-h stimulation of StAR expression in both cell types was completely blocked by NDGA and AA861, each functioning as lipoxygenase inhibitors. However, the acute 15-min stimulation in Y-1 cells was inhibited by these...
Chapter
Mitochondria in steroidogenic cells (in adrenal cortex, ovaries, and testis) convert cholesterol to pregnenolone via cytochrome P450scc under hormonal control. It is now recognized that an equivalent process also occurs in other tissues, including specialized cells in the brain. Steroidogenic cells have specialized mechanisms for uptake and transfe...
Article
The aryl hydrocarbon receptor (AhR) is activated by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), but activation without an exogenous ligand also occurs when normal cell-cell contact is prevented. Suspension of several C3H10T1/2 fibroblast clonal sub-lines that contain an integrated AhR-responsive reporter produced a time course and level of reporter...
Article
In addition to being carcinogenic, polycyclic aromatic hydrocarbons (PAHs) are known to cause deleterious effects on the immune system, including a marked reduction in bone marrow granulocytes and B lymphocytes. The molecular mechanisms underlying bone marrow hypocellularity are incompletely understood. Hematopoiesis is governed by the production o...
Article
Hormone (IDMB)-induced adipogenesis in C3H10T1/2 cells is suppressed by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) via the aryl hydrocarbon receptor (AhR). We have previously reported that TCDD addition 48 h before the hormonal stimulation of IDMB suppresses a key mediator of adipogenesis, the peroxisome proliferator-activated receptor (PPARgamma),...
Article
Adipogenesis is typically stimulated in mouse embryo fibroblast (MEF) lines by a standard hormonal combination of insulin (I), dexamethasone (D), and methylisobutylxanthine (M), administered with a fresh serum renewal. In C3H10T1/2 (10T1/2) cells, peroxisome proliferator-activated receptor gamma1 (PPARgamma1) expression, an early phase key adipogen...
Article
Acute steroidogenesis in either Y-1 or MA-10 cells is sensitive to different effects of fatty acids compare to a chronic stimulation. A 3-h stimulation of StAR expression in both cell types was completely blocked by NDGA and AA861, each functioning as lipoxygenase inhibitors. However, the acute 15-min stimulation in Y-1 cells was inhibited by these...
Article
Cyp1B1 is expressed constitutively in many extrahepatic cells and is induced by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). An enhancer region (AhER-810 to -1075 of the mouse Cyp1B1 promoter), which mediates aryl hydrocarbon receptor (AhR) regulation of transcription, contains three consensus XRE sequences (designated XRE1, XRE4, and XRE5) and a ce...
Article
We have previously used CYP1B1-null mice to demonstrate that dimethylbenz(a)anthracene (DMBA) requires CYP1B1 for bone marrow (BM) toxicity. Benzo(a)pyrene (BP), a much more potent Ah receptor ligand, shows very different responses that nevertheless depend on CYP1B1. Wild-type (AhR(b)) mice treated with DMBA for 48 h exhibit a large loss in BM cell...
Article
CYP1B1 is unique among P450 cytochromes in exhibiting inductive responses mediated by both the Ah receptor (AhR) and cAMP. cAMP induction was mediated either by a 189bp far upstream enhancer region (FUER, -5110 to -5298) or by a 230bp AhR-responsive enhancer region (AhER) (-797 to -1026). CYP1B1 luciferase reporters respond selectively to cAMP and...
Article
Polycyclic aromatic hydrocarbons (PAHs) are known immunotoxins and carcinogens. Our laboratory and others have demonstrated that metabolism of these compounds by CYP1B1 is required for carcinogenicity and immunotoxicity to occur. Previously, our laboratory reported significantly decreased bone marrow cellularity in mice following 7,12-dimethlybenz[...
Article
Activation of the aryl-hydrocarbon receptor (AhR) by pretreatment with 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) blocks hormone (IDM/BRL)-induced adipocyte differentiation of C3H10T1/2 cells in proportion to the suppression of the elevation of the key mediator, peroxisome proliferator-activated receptor (PPARgamma1). Inhibition of MEK-induced ERK...
Article
The adrenal cortex is a tissue of excess in terms of both cholesterol metabolism and cholesterol exchange with the circulation. Exceptionally high levels of lipoprotein receptors in this highly vascularized tissue provide ready access to dietary cholesterol, allowing the adrenocortical cells to maintain impressive stores of cytoplasmic cholesterol...
Article
Polycyclic aromatic hydrocarbons (PAHs) have been demonstrated to cause a variety of tumors and immunosuppressive effects. Our laboratory, and others, have demonstrated that coculture of progenitor B lymphocytes (pre-B cells) with bone marrow stromal cells and the model PAH 7,12-dimethylbenz[a]anthracene (DMBA) results in pre-B cell apoptosis. In t...
Article
Full-text available
The metabolism of cholesterol by cytochrome P450 side chain cleavage enzyme is hormonally regulated in steroidogenic tissues via intramitochondrial cholesterol transport. The mediating steroidogenic acute regulatory protein (StAR) is synthesized as a 37-kDa (p37) precursor that is phosphorylated by protein kinase A and cleaved within the mitochondr...
Article
2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) induced erbB2 and erbB3 in estrogen receptor (ER) positive T47D (T47D+) cells, but substantially slower than the direct induction of CYP1A1 or CYP1B1. Similar maximum erbB levels were observed in ER- T47D cells or in T47D+ cells cultured in estrogen (E2)-free, defined media (SFM) or serum media with anti-e...
Article
Experiments in Y-1 and primary adrenal cells have established that basal StAR mRNA is sufficient for maximum cAMP-stimulated cholesterol metabolism providing that newly synthesized p37 StAR precursor is phosphorylated, transferred to the matrix and proteolytically cleaved to pp30. This form is active at the inner membrane. The majority of mitochond...
Article
Humans are exposed to polycyclic aromatic hydrocarbons (PAHs) through many environmental pollutants, especially cigarette smoke. These chemicals cause a variety of tumors and immunotoxic effects, as a consequence of bioactivation by P-450 cytochromes to dihydrodiol epoxides. The recently identified cytochrome P4501B1 (CYP1B1) bioactivates PAHs but...
Article
Full-text available
Estrogen exposure represents the major known risk factor for development of breast cancer in women and is implicated in the development of prostate cancer in men. Human breast tissue has been shown to be a site of oxidative metabolism of estrogen due to the presence of specific cytochrome P450 enzymes. The oxidative metabolism of 17 &bgr;-estradiol...
Article
Full-text available
Estrogen exposure represents the major known risk factor for development of breast cancer in women and is implicated in the development of prostate cancer in men. Human breast tissue has been shown to be a site of oxidative metabolism of estrogen due to the presence of specific cytochrome P450 enzymes. The oxidative metabolism of 17beta-estradiol (...
Article
We previously demonstrated that murine bone marrow stromal cells express high levels of cytochrome P4501B1 (CYP1B1) that metabolizes 7,12-dimethylbenza[a]anthracene (DMBA), and that DMBA activates the Ah receptor (AhR) in these cells in vitro. More recently, we reported that CYP1B1 is required for DMBA-induced lymphoblastoma formation in vivo. In t...
Article
We have used polycyclic aromatic hydrocarbon (PAH) alkyne metabolism-based inhibitors to test whether CYP1B1 metabolism is linked to aryl hydrocarbon receptor (AhR) activation in mouse embryo fibroblasts (MEF). 1-ethynylpyrene (1EP) selectively inactivated CYP1B1 dimethylbenzanthracene (DMBA) metabolism in C3H10T1/2 MEFs; whereas 1-(1-propynyl)pyre...
Article
We measured concentrations of polychlorinated biphenyls (PCBs), polychlorinated dibenzo-p-dioxins (PCDDs), and polychlorinated dibenzofurans (PCDFs) in northern leopard frogs collected from the Green Bay ecosystem and explored the catalytic activity of hepatic cytochrome P450-associated monooxygenase (P450 enzyme) as a biomarker for exposure to ary...
Article
Treatment of intact C3H10T1/2 cells or microsomes therefrom with 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and benzanthracene (BA) enhanced CYP1B1 activity and CYP1B1 expression as revealed by elevations of CYP1B1-catalyzed DMBA metabolism, CYP1B1 apoprotein level and CYP1B1 gene expression. One hundred microM DHEA caused an 80-90% inhibition of c...
Article
The impact of estrogen receptor (ER) was examined for expression and activity of cytochrome P4501B1 (CYP1B1) and cytochrome P4501A1 (CYP1A1) in two pairs of ER+/ER- human breast epithelial cell lines derived from single lineages, and representing earlier (T47D) or later (MDA-MB-231) stages of tumorigenesis. Acute loss of ER was evaluated using the...
Article
Full-text available
A 57-kDa protein whose expression in rat adrenocortical microsomes is increased after weaning has been identified as cytochrome P4501B1 (CYP1B1). Levels of CYP1B1 protein were moderately expressed in late gestation fetuses and on postnatal day 1 (pdl), but were nearly undetectable on pd6 and pd1O. CYP1B1 expression initially increased in the late p...
Article
The effects of co-treatment of C3H10T1/2 (10T1/2) cells with 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and 12-O-tetradecanoylphorbol-13-acetate (TPA) on the expression of the novel cytochrome P4501B1 (CYP1B1) were investigated. As monitored by CYP1B1-catalyzed 7,12-dimethylbenzanthracene (DMBA) metabolism, TPA suppressed basal and TCDD-induced DMB...
Article
Cytochrome P-450 (CYP) 1B1 expression in mouse hepatoma (Hepa-1) wild-type (WT) cells was compared with responses in Hepa-1 variants LA1 and LA2, which, respectively, exhibit low aryl hydrocarbon receptor (AhR) level and defective AhR nuclear translocator (ARNT) protein. 10T1/2 mouse embryo fibroblasts express predominantly CYP1B1 and at a 100 time...
Article
CYP1B1-null mice, created by targeted gene disruption in embryonic stem cells, were born at the expected frequency from heterozygous matings with no observable phenotype, thus establishing that CYP1B1 is not required for mouse development. CYP1B1 was not detectable in cultured embryonic fibroblast (EF) or in different tissues, such as lung, of the...

Citations

... These enzymes affect multiple biochemical pathways, including those related to hormone synthesis and regulation [18][19][20]; estrogen and iron metabolism in particular are closely related [141,142]. For instance, the Cytochrome-P450 enzymes, which process steroid hormones like estrogen and progesterone, significantly depend on iron [143]. Similarly, iron is indispensable for the enzymes Prolyl Hydroxylase [144] and Lysyl Hydroxylase [145] involved in collagen synthesis [146], thereby influencing the health of the connective tissue in reproductive organs [147]. ...
... Our data are consistent with studies performed in experimental rodent and human liver disease (57)(58)(59), showing that injuryinduced release of Hedgehog ligands from epithelia leads to hepatic myofibroblast activation. Studies in other organs in humans, mice, zebrafish, and fruit flies also support the ability of Hedgehog signaling to drive local and remote tissue development, cancer, and post-injury fibrosis (60)(61)(62)(63)(64)(65). The literature on cardiac Hedgehog signaling has focused mainly on the beneficial impact of Hedgehog signaling in cardiac development and on successful scar formation in the first 7 days after myocardial infarction (66). ...
... This complex is required for the transport of precursor proteins into the mitochondria to maintain mitochondrial function 1 . Furthermore, TOMM40 has been shown to interact with key regulators of mitochondrial function such as BAP31 2 , affect calcium signalling via its interaction with VDAC channels (voltage dependent anion channels) [3][4][5] , and have effects at mitochondria-ER contact sites (MERCs) that impact mitochondrial cholesterol transport via steroidogenic acute regulatory protein (STAR aka STARD1) 6,7 . In mouse Leydig cells, the absence of TOMM40 causes STAR to lose its ability as a cholesterol transporter, depleting mitochondrial cholesterol content 8 . ...
... Гемопоэтические стволовые и прогениторные клетки имеют минимальный набор цитохромов P450. В двух исследованиях было показано присутствие мРНК и белков только цитохромов P450 1B1и 2E1 в CD34+ гемопоэтических стволовых и клетках-предшественниках и отсутствие P4503A4/7 и P450 2C9 [28,29]. На более поздних стадиях дифференцировки и в клетках периферической крови количество экспрессируемых цитохромов Р450 возрастает. ...
... Cyp1a1 deletion has much less of an effect. These Cyp1b1-AhR changes show non-canonical features that could arise from ROS participation, mediated by NF-κB [38][39][40][41] or Nrf2 partnership with AhR [42][43][44][45]. The relationship between Cyp1b1 and AhR in these adherent BM assemblies has been systematically addressed by examining the gene expression effects of in vivo Cyp1 deletions (1a1 -/-, 1b1 -/-, and dual deletions 1a1 -/-;1b1 -/-(DKO)). ...
... This OLFR's presence in both DKO(+) and DKO(-) clusters, as well as in BMS2 cells, suggested expression in lineage-related BM-MSC cells. These GPCRs sense volatile organic molecules generated by microbiome bacteria [13,23,62]. This ectopic expression has been documented in pancreatic islet cells, with appreciable overlap with the present OLFR set (Table S8) [25]. ...
... But the depth of the cavity is non-uniform with this technique [91] . Injection molding has good reproducibility, while the process of the mold is complex [92] . Hot embossing can produce high-aspect-ratio structures, but the process is expensive [93] . ...
... In addition, AKAP1 may control cholesterol transport by regulating the activity of steroid acute regulatory factors through a post-transcriptional mechanism [23,24] and possibly affecting the structure of mitochondrial-associated endoplasmic reticulum membrane [23,25]. However, no evidence in our study and others showed the relationship between AKAP1 and cholesterol. ...
... In the degradation process of BaP, P266 was recognized through GC/MS analysis. The fungal community in the soil could produce certain intracellular enzymes, such as cytochrome P450 monooxygenase and epoxide hydrolase, which play a role in the degradation of 2-5-ring PAHs, resulting in the formation of epoxy products [60,61]. Moreover, bacteria could use BaP as a carbon source or synthesize enzymes that could transform the five-ring PAHs [10,62] Afterwards, P266 could be further transformed into the mono-hydroxylation product P268 or the di-hydroxylation product P284. ...
... In isolated EC and pericytes, Cyp1b1 -/additionally increased Cyp1a1 expression ( Figure 5B). Similar oxygen-mediated stimulation of Cyp1a1 in lung epithelia is mediated by AhR [30]. ...