Positive and negative regulation of myogenic differentiation of C2C12 cells by isoforms of the multiple homeodomain zinc finger transcription factor ATBF1
Positive and negative regulation of myogenic differentiation of C2C12 cells by isoforms of the multiple homeodomain zinc finger transcription factor ATBF1
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DOI：
10.1074/jbc.m010378200
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发表时间：
2001-07-06
影响因子：
4.8
通讯作者：
Tamaoki, T
中科院分区：
文献类型：
--
作者：
Berry, FB;Miura, Y;Tamaoki, T
ATBF 1基因编码两种蛋白质亚型，404-kDa ATBF 1-A，具有4个同源结构域和23个锌指，和306-kDa ATBF 1-B B，缺乏ATBF 1-A的920个氨基酸的N-末端区域，其含有5个锌指。在体外，ATBF 1-A在增殖的C2 C12成肌细胞中表达，但在低血清培养基中诱导成肌分化后，其表达水平降低。ATBF 1-A在C2 C12细胞中的强制表达导致MyoD和myogenin表达的抑制以及Id 3和cyclin D1表达的升高，从而导致低血清中成肌分化的抑制。相比之下，用ATBF 1-B亚型转染C2 C12细胞导致肌原性分化加速，如肌球蛋白重链表达的较早开始和多核肌管的较高百分比的形成所示。ATBF 1-A的第四同源结构域结合到肌肉调节因子4启动子的E1 E盒附近的AT富集元件，介导转录抑制。ATBF 1-A特异性N-末端区域具有一般转录抑制活性。这些结果表明，ATBF 1-A在维持未分化成肌细胞状态中发挥作用，其下调是启动C2 C12细胞终末分化的先决条件。
The ATBF1 gene encodes two protein isoforms, the 404-kDa ATBF1-A, possessing four homeodomains and 23 zinc fingers, and the 306-kDa ATBF1-B, lacking a 920-amino acid N-terminal region of ATBF1-A which contains 5 zinc fingers. ln vitro, ATBF1-A was expressed in proliferating C2C12 myoblasts, but its expression levels decreased upon induction of myogenic differentiation in low serum medium. Forced expression of ATBF1-A in C2C12 cells resulted in repression of MyoD and myogenin expression and elevation of Id3 and cyclin D1 expression, leading to inhibition of myogenic differentiation in low serum. In contrast, transfection of C2C12 cells with the ATBF1-B isoform led to an acceleration of myogenic differentiation, as indicated by an earlier onset of myosin heavy chain expression and formation of a higher percentage of multinucleated myotubes. The fourth homeodomain of ATBF1-A bound to an AT-rich element adjacent to the El E-box of the muscle regulatory factor 4 promoter mediating transcriptional repression. The ATBF1-A-specific N-terminal region possesses general transcription repressor activity. These results suggest that ATBF1-A plays a role in the maintenance of the undifferentiated myoblast state, and its down-regulation is a prerequisite to initiate terminal differentiation of C2C12 cells.