The proto-oncogene c-myc in hematopoietic development and leukemogenesis
The proto-oncogene c-myc in hematopoietic development and leukemogenesis
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DOI：
10.1038/sj.onc.1205400
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发表时间：
2002-05-13
期刊：
影响因子：
8
通讯作者：
Liebermann, DA
中科院分区：
文献类型：
--
作者：
Hoffman, B;Amanullah, A;Liebermann, DA
原癌基因c-myc在细胞周期调节、代谢、凋亡、分化、细胞粘附和肿瘤发生中起关键作用，并参与调节造血稳态。它是一种转录调节因子，是广泛的相互作用因子网络的一部分。最有可能的是，不同的生物反应引起的不同重叠的亚组c-Myc靶基因，诱导和抑制。从采用小鼠模型的研究中获得的结果是一致的，需要至少一个，可能是两个，除了失调的c-myc突变的恶性肿瘤的形成。c-myc的抑制是许多细胞类型（包括造血细胞）终末分化所必需的。研究表明，c-myc在小鼠骨髓来源的M1髓性白血病细胞和正常髓性细胞中的表达失调，不仅阻断了终末分化及其相关的生长停滞，而且诱导了依赖于Fas/CD 95途径的细胞凋亡。有证据表明，CD 95/Fas死亡受体途径是与正常终末髓样分化程序结束相关的凋亡反应的组成部分，并且失调的c-myc表达可以过早地激活该信号传导途径。当与c-myc共表达时，c-fos-1促进终末髓样分化的能力，以及c-fos部分消除由去调节的c-myc对髓样分化的阻断的能力，使这两个基因成为候选肿瘤抑制基因。几种不同的转录因子参与了分化过程中c-myc表达的下调，包括C/EBPalpha、CTCF、BLIMP-1和RFX 1。这些转录因子或c-Myc和Max相互作用蛋白（如MM-1和Mxil）的表达和/或功能的改变可影响肿瘤过程。了解c-Myc如何控制细胞表型，包括白血病表型，应提供新的工具，设计药物，以促进白血病细胞的分化和/或凋亡。
The proto-oncogene c-myc has been shown to play a pivotal role in cell cycle regulation, metabolism, apoptosis, differentiation, cell adhesion, and tumorigenesis, and participates in regulating hematopoietic homeostasis. It is a transcription regulator that is part of an extensive network of interacting factors. Most probably, different biological responses are elicited by different overlapping subsets of c-Myc target genes, both induced and suppressed. Results obtained from studies employing mouse models are consistent with the need for at least one, and possibly two, mutations in addition to deregulated c-myc for malignant tumor formation. Repression of c-myc is required for terminal differentiation of many cell types, including hematopoietic cells. It has been shown that deregulated expression of c-myc in both M1 myeloid leukemic cells and normal myeloid cells derived from murine bone marrow, not only blocked terminal differentiation and its associated growth arrest, but also induced apoptosis, which is dependent on the Fas/CD95 pathway. There is evidence to suggest that the CD95/Fas death receptor pathway is an integral part of the apoptotic response associated with the end of the normal terminal myeloid differentiation program, and that deregulated c-myc expression can activate this signaling pathway prematurely. The ability of egr-1 to promote terminal myeloid differentiation when co-expressed with c-myc, and of c-fos to partially abrogate the block imparted by deregulated c-myc on myeloid differentiation, make these two genes candidate tumor suppressors. Several different transcription factors have been implicated in the down-regulation of c-myc expression during differentiation, including C/EBPalpha, CTCF, BLIMP-1, and RFX1. Alterations in the expression and/or function of these transcription factors, or of the c-Myc and Max interacting proteins, such as MM-1 and Mxil, can influence the neoplastic process. Understanding how c-Myc controls cellular phenotypes, including the leukemic phenotype, should provide novel tools for designing drugs to promote differentiation and/ or apoptosis of leukemic cells.