Sharma Sudarshana M, Bronisz Agnieszka, Hu Rong, Patel Krupen, Mansky Kim C, Sif Said, Ostrowski Michael C
Department of Molecular and Cellular Biochemistry and the Comprehensive Cancer Center, Ohio State University, Columbus, Ohio 43210, USA.
J Biol Chem. 2007 May 25;282(21):15921-9. doi: 10.1074/jbc.M609723200. Epub 2007 Apr 2.
Transcription factors NFATc1, PU.1, and MITF collaborate to regulate specific genes in response to colony-stimulating factor-1 (CSF-1) and receptor activator of NF-kappaB ligand (RANKL) signaling during osteoclast differentiation. However, molecular details concerning timing and mechanism of specific events remain ill-defined. In bone marrow-derived precursors, CSF-1 alone promoted assembly of MITF-PU.1 complexes at osteoclast target gene promoters like cathepsin K and acid 5 phosphatase without increasing gene expression. The combination of RANKL and CSF-1 concurrently increased the levels of MAPK-phosphorylated forms of MITF, p38 MAPK, and SWI/SNF chromatin-remodeling complexes bound to these target promoters and markedly increased expression of the genes. NFATc1 was subsequently recruited to complexes at the promoters during terminal stages of osteoclast differentiation. Genetic analysis of Mitf and Pu.1 in mouse models supported the critical interaction of these genes in osteoclast differentiation. The results define MITF and PU.1 as nuclear effectors that integrate CSF-1/RANKL signals during osteoclast differentiation to initiate expression of target genes, whereas a complex that includes NFATc1 may act to maintain target gene expression in differentiated cells.
在破骨细胞分化过程中，转录因子NFATc1、PU.1和MITF协同作用，以响应集落刺激因子-1（CSF-1）和核因子κB受体激活剂配体（RANKL）信号来调节特定基因。然而，关于特定事件的时间和机制的分子细节仍不明确。在骨髓来源的前体细胞中，单独的CSF-1促进了MITF-PU.1复合物在破骨细胞靶基因启动子（如组织蛋白酶K和酸性磷酸酶5）处的组装，但并未增加基因表达。RANKL和CSF-1的联合作用同时增加了与这些靶启动子结合的MITF、p38丝裂原活化蛋白激酶（MAPK）的MAPK磷酸化形式以及SWI/SNF染色质重塑复合物的水平，并显著增加了这些基因的表达。在破骨细胞分化的终末阶段，NFATc1随后被招募到启动子处的复合物中。对小鼠模型中Mitf和Pu.1的基因分析支持了这些基因在破骨细胞分化中的关键相互作用。这些结果将MITF和PU.1定义为在破骨细胞分化过程中整合CSF-1/RANKL信号以启动靶基因表达的核效应器，而包含NFATc1的复合物可能在分化细胞中维持靶基因的表达。
