期刊
JOURNAL OF BIOLOGICAL CHEMISTRY
卷 278, 期 47, 页码 47275-47280出版社
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.M304652200
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资金
- NIAMS NIH HHS [AR 47628, AR 45378] Funding Source: Medline
- NIA NIH HHS [AG 22021] Funding Source: Medline
- NIBIB NIH HHS [EB 01019] Funding Source: Medline
CITED2 (CBP/p300-interacting transactivator with ED-rich tail 2) is a member of the Cited family of nuclear regulators, previously known as mrg1 (melanocyte-specific gene-related gene 1). CITED2 is inducible by varying stimuli including lipopolysaccharide, hypoxia, and cytokines such as interleukin 9 and interferon gamma. Using the immortalized human chondrocyte cell line, C-28/I2, we investigated whether CITED2 could be responsive to mechanical stimuli, and if so, whether CITED2 could mediate shear-driven regulation of matrix metalloproteinase (MMP) genes. The C-28/I2 cells were cultured under flow shear at 1 - 20 dyn/cm(2), and the role of CIT-ED2 in regulation of MMPs was examined using the plasmids encoding sense and antisense CITED2 DNA sequences. The results showed that flow shear at 5 dyn/ cm(2) increased CITED2 mRNA and protein levels and down-regulated MMP-1 and MMP-13 mRNA and protein levels as well as enzyme activities. Consistent with the coordinated expression patterns of CITED2 and MMPs, overexpression of CITED2 repressed MMP-1 and MMP-13 mRNA levels and activities, whereas antisense CITED2 plasmids prevented the shear-induced downregulation of MMP expression. Interleukin-1beta induced the formation of p300-Ets-1 complexes without affecting expression of CITED2. Transforming growth factor-beta as well as flow shear at 5 dyn/ cm2 stimulated not only the expression of CITED2 but also the association of CITED2 with p300 by dissociating Ets-1 from p300. These results indicate that CITED2 plays a major role in shear-induced down-regulation of MMP-1 and MMP-13 via a transforming growth factor-beta-dependent pathway.
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