Pulverer B, Sommer A, McArthur G A, Eisenman R N, Lüscher B
Division of Basic Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA.
J Cell Physiol. 2000 Jun;183(3):399-410. doi: 10.1002/(SICI)1097-4652(200006)183:3<399::AID-JCP13>3.0.CO;2-7.
Transcription factors of the Myc/Max/Mad network affect multiple aspects of cellular behavior, including proliferation, differentiation, and apoptosis. Recent studies have shown that Mad proteins can inhibit cellular growth and transformation and thus antagonize the function of Myc proteins. To define further the contribution of these proteins to cellular growth control, we have studied the expression of the respective genes and proteins in 3T3-L1 cells, both upon serum stimulation of quiescent cells and during adipocytic differentiation in response to insulin, dexamethasone, and isobutylmethylxanthine. We found distinct expression patterns for the mad genes. Mad4 was induced when cells exit the cell cycle and, together with mad1, during the late phase of differentiation. In contrast, mad3 expression was associated with progression through S phase and the proliferative burst of differentiating preadipocytes, overlapping in part c-myc expression. DNA binding analyses revealed that the most prominent network complex both in cycling and in differentiating cells was Mnt/Max, whereas c-Myc/Max complexes were detectable only during peak c-Myc expression periods. Ectopic expression of Mad1 in preadipocytes resulted in the inhibition of S phase and the proliferation associated with the proliferative burst; as a consequence, adipocytic differentiation was significantly inhibited. Our findings suggest that the precise temporal regulation of Myc/Max/Mad network proteins is critical for determining cellular behavior.
Myc/Max/Mad网络的转录因子会影响细胞行为的多个方面，包括增殖、分化和凋亡。最近的研究表明，Mad蛋白可以抑制细胞生长和转化，从而拮抗Myc蛋白的功能。为了进一步确定这些蛋白在细胞生长控制中的作用，我们研究了静止细胞经血清刺激以及在胰岛素、地塞米松和异丁基甲基黄嘌呤作用下脂肪细胞分化过程中3T3-L1细胞中各基因和蛋白的表达情况。我们发现了mad基因的不同表达模式。Mad4在细胞退出细胞周期时以及与mad1一起在分化后期被诱导表达。相反，mad3的表达与S期进程以及分化前脂肪细胞的增殖爆发相关，部分与c-myc表达重叠。DNA结合分析表明，在循环细胞和分化细胞中最主要的网络复合物都是Mnt/Max，而c-Myc/Max复合物仅在c-Myc表达高峰期可检测到。前脂肪细胞中Mad1的异位表达导致S期和与增殖爆发相关的增殖受到抑制；因此，脂肪细胞分化受到显著抑制。我们的研究结果表明，Myc/Max/Mad网络蛋白的精确时间调控对于决定细胞行为至关重要。
