Roussel M F, Ashmun R A, Sherr C J, Eisenman R N, Ayer D E
Department of Tumor Cell Biology, St. Jude Children's Research Hospital, Memphis, Tennessee 38105, USA.
Mol Cell Biol. 1996 Jun;16(6):2796-801. doi: 10.1128/MCB.16.6.2796.
Mad1 is a basic helix-loop-helix-leucine zipper protein that is induced upon differentiation of a number of distinct cell types. Mad1 dimerizes with Max and recognizes the same DNA sequences as do Myc:Max dimers. However, Mad1 and Myc appear to have opposing functions. Myc:Max heterodimers activate transcription while Mad:Max heterodimers repress transcription from the same promoter. In addition Mad1 has been shown to block the oncogenic activity of Myc. Here we show that ectopic expression of Mad1 inhibits the proliferative response of 3T3 cells to signaling through the colony-stimulating factor-1 (CSF-1) receptor. The ability of over-expressed Myc and cyclin D1 to complement the mutant CSF-1 receptor Y809F (containing a Y-to-F mutation at position 809) is also inhibited by Mad1. Cell cycle analysis of proliferating 3T3 cells transfected with Mad1 demonstrates a significant decrease in the fraction of cells in the S and G2/M phases and a concomitant increase in the fraction of G1 phase cells, indicating that Mad1 negatively influences cell cycle progression from the G1 to the S phase. Mutations in Mad1 which inhibit its activity as a transcription repressor also result in loss of Mad1 cell cycle inhibitory activity. Thus, the ability of Mad1 to inhibit cell cycle progression is tightly coupled to its function as a transcriptional repressor.
Mad1是一种碱性螺旋-环-螺旋-亮氨酸拉链蛋白，在多种不同细胞类型分化时被诱导产生。Mad1与Max二聚化，并识别与Myc:Max二聚体相同的DNA序列。然而，Mad1和Myc似乎具有相反的功能。Myc:Max异二聚体激活转录，而Mad:Max异二聚体则抑制来自同一启动子的转录。此外，Mad1已被证明可阻断Myc的致癌活性。在此我们表明，Mad1的异位表达抑制了3T3细胞通过集落刺激因子-1（CSF-1）受体进行信号传导的增殖反应。Mad1也抑制了过表达的Myc和细胞周期蛋白D1对突变型CSF-1受体Y809F（在第809位含有Y到F突变）的互补能力。对转染了Mad1的增殖3T3细胞进行细胞周期分析表明，处于S期和G2/M期的细胞比例显著降低，而G1期细胞比例相应增加，这表明Mad1对从G1期到S期的细胞周期进程产生负面影响。Mad1中抑制其作为转录抑制因子活性的突变也导致Mad1细胞周期抑制活性丧失。因此，Mad1抑制细胞周期进程的能力与其作为转录抑制因子的功能紧密相关。
