Tamoxifen increases nuclear respiratory factor 1 transcription by activating estrogen receptor β and AP‐1 recruitment to adjacent promoter binding sites

Ivanova, Margarita; Luken, Kristen H.; Zimmer, Amber S.; Lenzo, Felicia L.; Smith, Ryan J.; Arteel, Maia W.; Kollenberg, Tara J.; Mattingly, Kathleen A.; Klinge, Carolyn M.

doi:10.1096/fj.10-169029

Cited by 27 publications

(33 citation statements)

References 73 publications

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“…E2F is better associated with transcriptional activation and, more recently, with histone H3K56 acetylation (57). NRF1 is well known for its role in mitochondrial function, but recently has been associated with the mediation of estrogen effects on ER␣ gene transcription (58), something that may be relevant to the current finding for specific effects of EB on DNA methylation at that site in intron 1. Finally, the intron 1 sequence also contained five STAT sites in our region of analysis, a finding that highlights the potential importance of this transcription factor in Esr1 regulation.…”

Section: Lifelong Epigenetic Changes In Esr1 Induced By Perinatal Edcmentioning

confidence: 77%

Early Life Exposure to Endocrine-Disrupting Chemicals Causes Lifelong Molecular Reprogramming of the Hypothalamus and Premature Reproductive Aging

Gore

Walker

Zama

et al. 2011

Molecular Endocrinology

136

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Gestational exposure to the estrogenic endocrine disruptor methoxychlor (MXC) disrupts the female reproductive system at the molecular, physiological, and behavioral levels in adulthood. The current study addressed whether perinatal exposure to endocrine disruptors re-programs expression of a suite of genes expressed in the hypothalamus that control reproductive function and related these molecular changes to premature reproductive aging. Fischer rats were exposed daily for 12 consecutive days to vehicle (dimethylsulfoxide), estradiol benzoate (EB) (1 mg/kg), and MXC (low dose, 20 μg/kg or high dose, 100 mg/kg), beginning on embryonic d 19 through postnatal d 7. The perinatally exposed females were aged to 16-17 months and monitored for reproductive senescence. After euthanasia, hypothalamic regions [preoptic area (POA) and medial basal hypothalamus] were dissected for real-time PCR of gene expression or pyrosequencing to assess DNA methylation of the Esr1 gene. Using a 48-gene PCR platform, two genes (Kiss1 and Esr1) were significantly different in the POA of endocrine-disrupting chemical-exposed rats compared with vehicle-exposed rats after Bonferroni correction. Fifteen POA genes were up-regulated by at least 50% in EB or high-dose MXC compared with vehicle. To understand the epigenetic basis of the increased Esr1 gene expression, we performed bisulfite conversion and pyrosequencing of the Esr1 promoter. EB-treated rats had significantly higher percentage of methylation at three CpG sites in the Esr1 promoter compared with control rats. Together with these molecular effects, perinatal MXC and EB altered estrous cyclicity and advanced reproductive senescence. Thus, early life exposure to endocrine disruptors has lifelong effects on neuroendocrine gene expression and DNA methylation, together with causing the advancement of reproductive senescence.

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Section: Lifelong Epigenetic Changes In Esr1 Induced By Perinatal Edcmentioning

confidence: 77%

Early Life Exposure to Endocrine-Disrupting Chemicals Causes Lifelong Molecular Reprogramming of the Hypothalamus and Premature Reproductive Aging

Gore

Walker

Zama

et al. 2011

Molecular Endocrinology

136

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“…We previously reported that E 2 and 4-OHT increased NRF-1 gene expression in MCF-7 breast cancer cells by activating ERα (Mattingly et al 2008) and ERβ (Ivanova et al 2011), respectively. Here we examined if E 2 or the selective estrogen receptor modulators (SERMs) 4-OHT and RAL regulate NRF-1 transcription in HUVECs.…”

Section: Resultsmentioning

confidence: 99%

Diesel exhaust particulate extracts inhibit transcription of nuclear respiratory factor-1 and cell viability in human umbilical vein endothelial cells

Mattingly

Klinge

2011

Arch Toxicol

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Endothelial dysfunction precedes cardiovascular disease and is accompanied by mitochondrial dysfunction. Here we tested the hypothesis that diesel exhaust particulate extracts (DEPEs), prepared from a truck run at different speeds and engine loads, would inhibit genomic estrogen receptor activation of nuclear respiratory factor-1 (NRF-1) transcription in human umbilical vein endothelial cells (HUVECs). Additionally, we examined how DEPEs affect NRF-1 regulated TFAM expression and, in turn, Tfam-regulated mtDNA-encoded cytochrome c oxidase subunit I (COI, MTCO1) and NADH dehydrogenase subunit I (NDI) expression as well as cell proliferation and viability. We report that 17β-estradiol (E2), 4-hydroxytamoxifen (4-OHT), and raloxifene increased NRF-1 transcription in HUVECs in an ER-dependent manner. DEPEs inhibited NRF-1 transcription and this suppression was not ablated by concomitant treatment with E2, 4-OHT, or raloxifene, indicating that the effect was not due to inhibition of ER activity. While E2 increased HUVEC proliferation and viability, DEPEs inhibited viability but not proliferation. Resveratrol increased NRF-1 transcription in an ER-dependent manner in HUVECs, and ablated DEPE inhibition of basal NRF-1 expression. Given that NRF-1 is a key nuclear transcription factor regulating genes involved in mitochondrial activity and biogenesis, these data suggest that DEPEs may adversely affect mitochondrial function leading to endothelial dysfunction and resveratrol may block these effects.

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“…Western blotting followed standard procedures (Ivanova et al 2011; Mattingly et al 2008). In brief, 30-40 μg of protein lysates (see individual Figures) were separated on 10 or 14 % SDS PAGE gels and electroblotted to PVDF membranes.…”

Section: Methodsmentioning

confidence: 99%

“…After aspiration of the PBS, the tissues were frozen at −80°C. The tissues were mechanical homogenized in ChIP buffer (Ivanova et al 2011) and genomic DNA was shared by sonication on ice. 300 μg of lysed extracts were incubated with anti-ERα (HC-20) antibody or normal rabbit IgG (both from Santa Cruz).…”

Section: Methodsmentioning

confidence: 99%

“…We reported that E 2 and 4-hydroxytamoxifen (4-OHT), an active tamoxifen (TAM) metabolite, stimulate transcription of nuclear-encoded nuclear respiratory factor 1 (NRF-1) by binding ERα and ERβ, respectively, and increasing ERα, ERβ, and RNA polymerase II recruitment to the promoter of NRF1 in MCF-7 breast cancer cells (Ivanova, et al 2011; Mattingly, et al 2008). NRF-1 regulates the transcription of nuclear-encoded, mitochondrial genes, e.g ., mitochondrial transcription factors TFAM, TFB1M , and TFB2M , and nuclear encoded components of OXPHOS, e.g ., cytochrome c ( CYCS ) (Cam, et al 2004; Richard C 2011; Scarpulla 2006; Scarpulla 2008a).…”

Section: Introductionmentioning

confidence: 99%

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Estradiol and tamoxifen regulate NRF-1 and mitochondrial function in mouse mammary gland and uterus

Ivanova

Radde

Son

et al. 2013

Journal of Molecular Endocrinology

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Nuclear respiratory factor-1 (NRF-1) stimulates the transcription of nuclear-encoded genes that regulate mitochondrial genome transcription and biogenesis. We reported that estradiol (E2) and 4-hydroxytamoxifen (4-OHT) stimulate NRF-1 transcription in an estrogen receptor α- and β- (ERα, ERβ) dependent manner in human breast cancer cells. The aim of this study was to determine if E2 and 4-OHT increase NRF-1 in vivo. Here we report that E2 and 4-OHT increase NRF-1 expression in mammary gland and uterus of ovariectomized C57BL/6 mice in a time-dependent manner. E2 increased NRF-1 protein in the uterus and mammary gland; however, in mammary gland, 4-OHT increased Nrf1 mRNA but not protein. Chromatin immunoprecipitation (ChIP) assays revealed increased in vivo recruitment of ERα to the Nrf1 promoter and intron 3 in mammary gland and uterus 6 h after E2 and 4-OHT treatment, commensurate with increased NRF-1 expression. E2 and 4-OHT- induced increases in NRF-1 and its target genes Tfam, Tfb1m, and Tfb2m were coordinated in mammary gland but not uterus, due to uterine-selective inhibition of the expression of the NRF-1 coactivators Ppargc1a and Ppargc1b by E2 and 4-OHT. E2 transiently increased NRF-1 and PGC-1α nuclear staining while reducing PGC-1α in uterus. E2, not 4-OHT, activates mitochondrial biogenesis in mammary gland and uterus in a time-dependent manner. E2 increased mitochondrial outer membrane Tom40 protein levels in mammary gland and uterus whereas 4-OHT increased Tom40 only in uterus. These data support the hypothesis of tissue-selective regulation of NRF-1 and its downstream targets by E2 and 4-OHT in vivo.

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Tamoxifen increases nuclear respiratory factor 1 transcription by activating estrogen receptor β and AP‐1 recruitment to adjacent promoter binding sites

Cited by 27 publications

References 73 publications

Early Life Exposure to Endocrine-Disrupting Chemicals Causes Lifelong Molecular Reprogramming of the Hypothalamus and Premature Reproductive Aging

Early Life Exposure to Endocrine-Disrupting Chemicals Causes Lifelong Molecular Reprogramming of the Hypothalamus and Premature Reproductive Aging

Diesel exhaust particulate extracts inhibit transcription of nuclear respiratory factor-1 and cell viability in human umbilical vein endothelial cells

Estradiol and tamoxifen regulate NRF-1 and mitochondrial function in mouse mammary gland and uterus

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