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Fli1 is a negative regulator of estrogen receptor ? in dermal fibroblasts.

ABSTRACT: Estrogen is an important regulator of dermal fibroblast functions, including extracellular matrix (ECM) synthesis. Estrogen mediates its effects through estrogen receptors (ERs), ER? and ER?; however, regulation of ERs in dermal fibroblasts remains poorly understood. Friend leukemia integration factor 1 (Fli1), a member of the Ets transcription factor family, has been shown to play a pivotal role in regulation of the ECM genes in dermal fibroblasts. The aim of this study was to examine a possible interaction between Fli1 and estrogen pathways, focusing on ER?. We show that treatment of human dermal fibroblasts with transforming growth factor-? (TGF-?) increases ER? protein and mRNA levels. Similarly, ER? expression was increased in response to small interfering RNA (siRNA)-mediated depletion of Fli1, suggesting that Fli1 is a mediator of the TGF-? effects on ER? expression. Accordingly, we showed that Fli1 binds to the most proximal region of the ER? promoter, and dissociates from the promoter upon TGF-? treatment. An inverse correlation between Fli1 and ER? expression levels was confirmed in cultured skin fibroblasts obtained from Fli1(+/-) mice and in the skin of Fli1(+/-) mice in vivo. This study supports a role of Fli1 as a negative regulator of the ER? gene in dermal fibroblasts.

SUBMITTER: Hattori T

PROVIDER: S-EPMC3825457 | biostudies-literature | 2011 Jul

REPOSITORIES: biostudies-literature

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Fli1 is a negative regulator of estrogen receptor α in dermal fibroblasts.

Hattori Tomoyasu T Stawski Lukasz L Nakerakanti Sashidhar S SS Trojanowska Maria M

The Journal of investigative dermatology 20110331 7

Estrogen is an important regulator of dermal fibroblast functions, including extracellular matrix (ECM) synthesis. Estrogen mediates its effects through estrogen receptors (ERs), ERα and ERβ; however, regulation of ERs in dermal fibroblasts remains poorly understood. Friend leukemia integration factor 1 (Fli1), a member of the Ets transcription factor family, has been shown to play a pivotal role in regulation of the ECM genes in dermal fibroblasts. The aim of this study was to examine a possibl ...[more]

PMID: 21451544

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Project description:Alternative splicing of precursor mRNA is a fundamental mechanism to generate multiple proteins from a single gene. Although constitutive and alternative mRNA splicing is temporally and spatially regulated, deregulation of mRNA splicing could cause development, progression, and metastasis of tumors. Through yeast two-hybrid screening of a human breast cDNA library using estrogen receptor-alpha (ERalpha) as bait, we identified a novel nuclear receptor box containing full-length protein, nuclear protein E3-3 (NPE3-3). Our results revealed that NPE3-3 associates with not only ERalpha but also with splicing factors, serine/arginine-rich protein (SRp)-30c, SRp40, and splicing factor SC-35, suggesting that NPE3-3 is likely to be involved in regulation of mRNA splicing. Accordingly, transient expression of NPE3-3 in cells resulted in expected splicing of the CD44 control minigene. We also discovered that NPE3-3-overexpressing clones produced a novel, previously unrecognized, alternatively spliced variant of ERalpha (termed ERalphaV), which had a molecular size of 37 kDa composed of only exons 1, 2, 7, and 8. ERalphaV was expressed and sequestered in the cytoplasm in MCF-7 cells stably overexpressing NPE3-3, suggesting its involvement in nongenomic hormone signaling. NPE3-3 clones exhibited up-regulation of ERK1/2 signaling, cyclin D1, and cathepsin D and enhanced tumor cell proliferation, migration, and tumorigenicity. Moreover, direct expression of the ERalphaV in breast cancer cells stimulated ERK1/2 up-regulation and cyclin D1 expression. We found that ERalphaV physically interacted with MAPK kinase (MEK)-1/2, and thus, an ERalphaV and MEK1/2 complex could lead to the activation of the ERK1/2 pathway. Interestingly, NPE3-3 was up-regulated in human breast tumors. These findings revealed a role for NPE3-3 in alternative splicing and suggest that ERalpha is a physiological target of NPE3-3, leading to a constitutive nongenomic signaling pathway in breast cancer cells.

Dataset Information

Fli1 is a negative regulator of estrogen receptor ? in dermal fibroblasts.

Publications

Fli1 is a negative regulator of estrogen receptor α in dermal fibroblasts.

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