TY - JOUR
T1 - The osterix transcription factor down-regulates interleukin-1α expression in mouse osteosarcoma cells
AU - Cao, Ying
AU - Jia, Shu Fang
AU - Chakravarty, Geetika
AU - De Crombrugghe, Benoit
AU - Kleinerman, Eugenie S.
PY - 2008/1/1
Y1 - 2008/1/1
N2 - K7M2 mouse osteosarcoma cells form lytic tumors and are deficient in osterix (Osx), a zinc finger-containing transcription factor required for osteoblast differentiation and bone formation. Our previous studies showed that replacement of Osx suppresses lytic bone destruction. Cytokines, including interleukin (IL)-1α, IL-6, IL-11, and prostaglandin E2, have been shown to stimulate osteoclast activity. We showed that IL-1α production by K7M2 cells was significantly suppressed following Osx transfection through a transcription-mediated mechanism. Osx had no effect on IL-6, IL-11, or prostaglandin E2. Site-directed mutagenesis and chromatin immunoprecipitation indicated that Osx down-regulated IL-1α through an Sp1-binding site on the IL-1α promoter. Inhibiting Osx by small interfering RNA in two cell lines (Dunn and DLM8) that expressed high levels of Osx led to enhanced IL-1α promoter activity and protein production and altered the phenotype from blastic to lytic. These data suggest that Osx down-regulates IL-1α expression in mouse osteosarcoma cells via transcriptional repression of IL-1α and this may in turn affect the lytic activity of the tumor cells.
AB - K7M2 mouse osteosarcoma cells form lytic tumors and are deficient in osterix (Osx), a zinc finger-containing transcription factor required for osteoblast differentiation and bone formation. Our previous studies showed that replacement of Osx suppresses lytic bone destruction. Cytokines, including interleukin (IL)-1α, IL-6, IL-11, and prostaglandin E2, have been shown to stimulate osteoclast activity. We showed that IL-1α production by K7M2 cells was significantly suppressed following Osx transfection through a transcription-mediated mechanism. Osx had no effect on IL-6, IL-11, or prostaglandin E2. Site-directed mutagenesis and chromatin immunoprecipitation indicated that Osx down-regulated IL-1α through an Sp1-binding site on the IL-1α promoter. Inhibiting Osx by small interfering RNA in two cell lines (Dunn and DLM8) that expressed high levels of Osx led to enhanced IL-1α promoter activity and protein production and altered the phenotype from blastic to lytic. These data suggest that Osx down-regulates IL-1α expression in mouse osteosarcoma cells via transcriptional repression of IL-1α and this may in turn affect the lytic activity of the tumor cells.
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U2 - 10.1158/1541-7786.MCR-07-0090
DO - 10.1158/1541-7786.MCR-07-0090
M3 - Article
C2 - 18234967
AN - SCOPUS:40749157096
SN - 1541-7786
VL - 6
SP - 119
EP - 126
JO - Molecular Cancer Research
JF - Molecular Cancer Research
IS - 1
ER -