ENFORCED EXPRESSION OF THE C-MYC ONCOGENE INHIBITS CELL-DIFFERENTIATION BY PRECLUDING ENTRY INTO A DISTINCT PREDIFFERENTIATION STATE IN G0/G1
ENFORCED EXPRESSION OF THE C-MYC ONCOGENE INHIBITS CELL-DIFFERENTIATION BY PRECLUDING ENTRY INTO A DISTINCT PREDIFFERENTIATION STATE IN G0/G1
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DOI：
10.1128/mcb.8.4.1614
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发表时间：
1988-04-01
影响因子：
5.3
通讯作者：
FREYTAG, SO
中科院分区：
文献类型：
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作者：
FREYTAG, SO
广泛的数据基础表明，c-myc原癌基因在控制细胞周期和细胞分化中起着重要作用。为了进一步确定myc在这些过程中的作用，我研究了强制myc表达对几个被认为是导致终末分化状态的重要步骤的事件的影响：(I)阻止G0/G1期生长的能力，(Ii)启动分化程序时复制基因组的能力，以及(Iii)失去对有丝分裂原的反应性并退出细胞周期的能力。在Rous肉瘤病毒(RSV)启动子的转录调控下，通过导入重组myc基因，建立了表达不同水平myc基因的3T3-L1前脂肪细胞系。高表达pRSVmyc mRNA的细胞在G0/G1期的密度与融合时正常细胞的密度相似。在分化程序启动后，这些细胞以与正常细胞相似的动力学方式穿过细胞周期，随后停滞在G0/G1期。因此，强制表达myc对细胞在G0/G1期停止生长或在分化程序开始时复制基因组的能力没有影响。然后对细胞在接触高浓度血清后重新进入细胞周期的能力和分化能力进行测试。与正常细胞相比，表达高组成水平myc RNA的细胞在30%的血清刺激下重新进入细胞周期，并未能终末分化。Myc反义RNA的高表达可逆转诱导分化的抑制作用，说明诱导分化的抑制是由于pRSVmyc表达增强所致。这些结果表明，3T3-L1前脂肪细胞在分化诱导剂处理后，在G0-G1进入特定的状态，高组成水平的myc RNA表达的细胞不能进入该状态。我认为myc起着分子开关的作用，将细胞引导到可导致持续增殖或终末分化的途径。
A broad base of data has implicated a role for the c-myc proto-oncogene in the control of the cell cycle and cell differentiation. To further define the role of myc in these processes, I examined the effect of enforced myc expression on several events that are thought to be important steps leading to the terminally differentiated state: (i) the ability to arrest growth in G0/G1, (ii) the ability to replicate the genome upon initiation of the differentiation program, and (iii) the ability to lose responsiveness to mitogens and withdraw from the cell cycle. 3T3-L1 preadipocyte cell lines expressing various levels fo myc mRNA were established by transfection with a recombinant myc gene under the transcriptional control of the Rous sarcoma virus (RSV) promoter. Cells that expressed high constitutive levels of pRSVmyc mRNA arested in G0/G1 at densities similar to those of normal cells at confluence. Upon initiation of the differentiation program, such cells traversed the cell cycle with kinetics similar to those of normal cells and subsequently arrested in G0/G1. Thus, enforced expression of myc had no effect on the ability of cells to arrest growth in G0/G1 or to replicate the genome upon initiation of the differentiation program. Cells were then tested for their ability to reenter the cell cycle upon exposure to high concentrations of serum and for their capacity to differentiate. In contrast to normal cells, cells expressing high constitutive levels of myc RNA reentered the cell cycle when challenged with 30% serum and failed to terminally differentiate. The block to differentiation could be reversed by high expression of myc antisense RNA, showing that the induced block was specifically due to enforced expression of pRSVmyc. These findings indicate that 3T3-L1 preadipocytes enter a specific state in G0-G1 after treatment with differentiation inducers, into which cells expressing high constitutive levels of myc RNA are precluded from entering. I propose that myc acts as a molecular switch and directs cells to pathway that can lead to continued proliferation or to terminal differentiation.