The osterix transcription factor down-regulates interleukin-1 alpha expression in mouse osteosarcoma cells.
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)-1alpha, IL-6, IL-11, and prostaglandin E2, have been shown to stimulate osteoclast activity. We showed that IL-1alpha 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-1alpha through an Sp1-binding site on the IL-1alpha promoter. Inhibiting Osx by small interfering RNA in two cell lines (Dunn and DLM8) that expressed high levels of Osx led to enhanced IL-1alpha promoter activity and protein production and altered the phenotype from blastic to lytic. These data suggest that Osx down-regulates IL-1alpha expression in mouse osteosarcoma cells via transcriptional repression of IL-1alpha and this may in turn affect the lytic activity of the tumor cells.
Cao
Ying
Y
Division of Pediatrics, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
Jia
Shu-Fang
SF
Chakravarty
Geetika
G
de Crombrugghe
Benoit
B
Kleinerman
Eugenie S
ES
D000818:Animals; D001665:Binding Sites; D001859:Bone Neoplasms / Q000235:genetics*; D045744:Cell Line, Tumor; D015536:Down-Regulation; D015972:Gene Expression Regulation, Neoplastic; D053582:Interleukin-1alpha / Q000235:genetics*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D009154:Mutation / Q000235:genetics; D053244:Osteoprotegerin / Q000235:genetics; D012516:Osteosarcoma / Q000235:genetics* / Q000473:pathology; D010641:Phenotype; D011401:Promoter Regions, Genetic / Q000235:genetics; D034741:RNA, Small Interfering; D016329:Sp1 Transcription Factor / Q000378:metabolism; D000076182:Sp7 Transcription Factor; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic
D053582:Interleukin-1alpha; D053244:Osteoprotegerin; D034741:RNA, Small Interfering; D016329:Sp1 Transcription Factor; D000076182:Sp7 Transcription Factor; C479466:Sp7 protein, mouse; D014157:Transcription Factors