TY - JOUR
T1 - Estrogen receptor α and β heterodimers exert unique effects on estrogen- and tamoxifen-dependent gene expression in human U2Os osteosarcoma cells
AU - Monroe, David G.
AU - Secreto, Frank J.
AU - Subramaniam, Malayannan
AU - Getz, Barbara J.
AU - Khosla, Sundeep
AU - Spelsberg, Thomas C.
PY - 2005/6
Y1 - 2005/6
N2 - The 17β-estradiol (E2) receptor isoforms [estrogen receptor (ER) α and ERβ] bind E2 and selective ER modulators (SERMs) as homodimers (α/α or β/β) or heterodimers (α/β) to regulate gene expression. Although recent studies have shown that ER homodimers regulate unique sets of E2-responsive genes, little information exists regarding the transcriptional actions of the ERα/β heterodimer. This paper describes the development of a U2OS human osteosarcoma (osteoblast) cell line stably expressing both ERα and ERβ isoforms at a ratio of 1:4, a ratio reported to exist in normal, mature osteoblast cells derived from cancellous bone. The regulation of endogenous genes by E2 and 4-hydroxy-tamoxifen were measured in these cells using gene microarrays and real-time RT-PCR. Both E2 and 4-hydroxy-tamoxifen were shown to regulate unique sets of endogenous genes in the U2OS-ERα/β heterodimer cell line (20% and 27% of total, respectively), compared with all the genes regulated in U2OS-ER homodimer cell lines. Furthermore, two novel E2-regulated genes, retino-blastoma binding protein 1 and 7-dehydrocholesterol reductase, were found to contain estrogen response element-like sequences that directly bind the ERα/β heterodimer. These results suggest that the expression of both ER isoforms, forming functional ERα/β heterodimers, result in unique patterns of gene regulation, many of which are distinct from the genes regulated by the ER homodimers.
AB - The 17β-estradiol (E2) receptor isoforms [estrogen receptor (ER) α and ERβ] bind E2 and selective ER modulators (SERMs) as homodimers (α/α or β/β) or heterodimers (α/β) to regulate gene expression. Although recent studies have shown that ER homodimers regulate unique sets of E2-responsive genes, little information exists regarding the transcriptional actions of the ERα/β heterodimer. This paper describes the development of a U2OS human osteosarcoma (osteoblast) cell line stably expressing both ERα and ERβ isoforms at a ratio of 1:4, a ratio reported to exist in normal, mature osteoblast cells derived from cancellous bone. The regulation of endogenous genes by E2 and 4-hydroxy-tamoxifen were measured in these cells using gene microarrays and real-time RT-PCR. Both E2 and 4-hydroxy-tamoxifen were shown to regulate unique sets of endogenous genes in the U2OS-ERα/β heterodimer cell line (20% and 27% of total, respectively), compared with all the genes regulated in U2OS-ER homodimer cell lines. Furthermore, two novel E2-regulated genes, retino-blastoma binding protein 1 and 7-dehydrocholesterol reductase, were found to contain estrogen response element-like sequences that directly bind the ERα/β heterodimer. These results suggest that the expression of both ER isoforms, forming functional ERα/β heterodimers, result in unique patterns of gene regulation, many of which are distinct from the genes regulated by the ER homodimers.
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U2 - 10.1210/me.2004-0381
DO - 10.1210/me.2004-0381
M3 - Article
C2 - 15802376
AN - SCOPUS:22344449235
SN - 0888-8809
VL - 19
SP - 1555
EP - 1568
JO - Molecular Endocrinology
JF - Molecular Endocrinology
IS - 6
ER -