Rao G, Rekhtman N, Cheng G, Krasikov T, Skoultchi A I
Department of Cell Biology, Albert Einstein College of Medicine, Bronx, New York 10461, USA.
Oncogene. 1997 Jan 9;14(1):123-31. doi: 10.1038/sj.onc.1200807.
Murine erythroleukemia (MEL) cells are transformed erythroid precursors that are blocked from completing the late stages of erythroid differentiation. A frequent event in the generation of these malignant cells is deregulation of the hematopoietic-specific transcription factor PU.1 (Spi-1) by retroviral insertion of the spleen-focus-forming virus component of Friend virus. During chemically induced reinitiation of MEL cell terminal differentiation, expression of PU.1 is rapidly down-regulated, suggesting that PU.1 might interfere with processes required for terminal differentiation of erythroid precursors. To investigate the role of PU.1 in erythroid differentiation we transfected MEL cells with a PU.1 cDNA controlled by the eucaryotic translation elongation factor EF1 alpha promoter. Deregulated expression of PU.1 blocked chemically induced differentiation and terminal cell division. Deregulated expression of two other protooncogenes, c-myc and c-myb, also has been shown to block MEL differentiation. We present evidence that PU.1 inhibits terminal differentiation at an earlier step than c-Myc and c-Myb. Thus reinitiation of MEL cell terminal differentiation appears to be controlled by an ordered program of turning off several protooncogenes. Down-regulation of PU.1 may be a very early step in this program.
小鼠红白血病(MEL)细胞是转化的红系前体细胞,它们在红系分化的晚期阶段受阻。这些恶性细胞生成过程中的一个常见事件是,Friend病毒的脾集落形成病毒成分通过逆转录病毒插入,导致造血特异性转录因子PU.1(Spi-1)失调。在化学诱导的MEL细胞终末分化重新启动过程中,PU.1的表达迅速下调,这表明PU.1可能会干扰红系前体细胞终末分化所需的过程。为了研究PU.1在红系分化中的作用,我们用一个由真核翻译延伸因子EF1α启动子控制的PU.1 cDNA转染了MEL细胞。PU.1的失调表达阻断了化学诱导的分化和终末细胞分裂。另外两个原癌基因c-myc和c-myb的失调表达也已被证明会阻断MEL分化。我们提供的证据表明,PU.1在比c-Myc和c-Myb更早的步骤抑制终末分化。因此,MEL细胞终末分化的重新启动似乎受关闭几个原癌基因的有序程序控制。PU.1的下调可能是该程序中非常早期的一个步骤。