Estrogen synthesis in adipose tissue is associated with the development of breast cancer. Tumors are preferentially found in breast quadrants with strongest expression of the cytochrome P450 aromatase (encoded by the gene CYP19A1). Several promoters regulated by various hormonal factors drive aromatase expression in human breast adipose fibroblasts (BAFs). As adipose tissue is a major source of retinoids, in this study, we investigated their role in the regulation of aromatase expression. The retinoids all-trans-retinoic acid (at-RA) and 9-cis-RA induce aromatase activity in human BAFs. In BAFs, at-RA induces aromatase gene expression via promoter I.4. In 3T3-L1 cells, both retinoids specifically drive luciferase reporter gene expression under the control of aromatase promoter I.4, whereas other promoters active in human adipose tissue are insensitive. Activation by retinoids depends on a 467 bp fragment (−256/+211) of promoter I.4 containing four putative retinoic acid response elements (RAREs). Site-directed mutagenesis revealed that only RARE2 (+91/+105) mediates the retinoid-dependent induction of reporter gene activity. In 3T3-L1 preadipocytes and human BAFs, RA receptor α (RARα (RARA)) expression is predominant, whereas RARβ (RARB) or RARγ (RARG) expression is low. Electrophoretic mobility shift assays with nuclear extracts obtained from human BAFs and 3T3-L1 cells identified a specific RARE2-binding complex. Retinoids enhanced complex formation, whereas pre-incubation with anti-RARα antibodies prohibited the binding of RARα to RARE2. Chromatin immunoprecipitation showed RA-dependent binding of RARα to the RARE2-containing promoter region in vivo. Furthermore, we provide evidence that RARE2 is also necessary for the basal activation of promoter I.4 in these cells. Taken together, these findings indicate a novel retinoid-dependent mechanism of aromatase activity induction in adipose tissue.
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Jan Wilde, Maria Erdmann, Michael Mertens, Gabriele Eiselt, and Martin Schmidt
Shaheen Khan, Fei Wu, Shengxi Liu, Qian Wu, and Stephen Safe
-responsive genes contain GC-rich motifs that bind Sp proteins ( Safe & Kim 2004 ). Some of the genes that fall into this category are important for cell proliferation, angiogenesis, and nucleotide metabolism and include E 2 F1, retinoic acid receptor α (RARα
Xiaodong Li, Stephanie L Nott, Yanfang Huang, Russell Hilf, Robert A Bambara, Xing Qiu, Andrei Yakovlev, Stephen Welle, and Mesut Muyan
expression of the trefoil factor 1 ( TFF1 ), complement factor 3 ( C3 ), matrix metallopeptidase 1 ( MMP1 ), and retinoic acid receptor α ( RARA ) genes. The cells were also infected with recombinant adenoviruses in the absence of E 2 and maintained for 48 h
Victoria Korsos and Wilson H Miller Jr
colony-stimulating factor-induced extracellular signal-regulated kinase 1/2 in histone modification and retinoic acid receptor α recruitment to gene promoters: relevance to acute promyelocytic leukemia cell differentiation’ . Molecular and Cellular
Stephen Safe and Kyoungkim Kim
, cathepsin D, c-fos , retinoic acid receptor α1 ( Rara1 ), adenosine deaminase, IGF-binding protein 4, Bcl2 , E2f1 , thymidylate synthase, vascular endothelial growth factor ( Vegf ), cyclin D1, creatine kinase B, DNA polymerase α, carbamoylphosphate
Mesut Muyan, Linda M Callahan, Yanfang Huang, and Andrew J Lee
retinoic acid receptor α, RARA , gene that contains two GC-boxes ( Sun et al . 1998 , Huang et al . 2004 , Li et al . 2004 ). In all reporter vectors, promoters drive the expression of the firefly luciferase cDNA as the reporter enzyme. A reporter
Kyle T Helzer, Christopher Hooper, Shigeki Miyamoto, and Elaine T Alarid
J Gianni M Kopf E Honoré N Chelbi-Alix M Koken M Quignon F Rochette-Egly C de The H 1999 Retinoic acid induces proteasome-dependent degradation of retinoic acid receptor α (RARα) and oncogenic RARα fusion proteins . PNAS 96
Fei Wu, Ivan Ivanov, Rui Xu, and Stephen Safe
examine both proximal and distal cis -elements. For example, based on proximal promoter analysis, we previously identified retinoic acid receptor α1 (RARA) as an E 2 -responsive gene regulated by ESR1/SP ( Sun et al . 1998 ); however, Laganiere et al
Yumiko Kashiwabara, Shigekazu Sasaki, Akio Matsushita, Koji Nagayama, Kenji Ohba, Hiroyuki Iwaki, Hideyuki Matsunaga, Shingo Suzuki, Hiroko Misawa, Keiko Ishizuka, Yutaka Oki, and Hirotoshi Nakamura
promyelocytic leukemia protein (PML) and the t(15;17)-generated PML-retinoic acid receptor α oncoprotein . Molecular and Cellular Biology 20 6276 – 6286 . Viger RS Guittot SM Anttonen M Wilson DB Heikinheimo M 2008 Role of the GATA family of
Christopher C Valley, Natalia M Solodin, Ginny L Powers, Stephanie J Ellison, and Elaine T Alarid
protein stability. This is also the case for other nuclear receptors, including progesterone receptor, retinoic acid receptor-α, and peroxisome proliferator-activated receptor-α ( Kopf et al . 2000 , Lange et al . 2000 , Blanquart et al . 2002