PML4 induces differentiation by Myc destabilization
PML4 induces differentiation by Myc destabilization
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DOI：
10.1038/sj.onc.1210128
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发表时间：
2007-05-17
期刊：
影响因子：
8
通讯作者：
Di Croce, L.
中科院分区：
文献类型：
--
作者：
Buschbeck, M.;Uribesalgo, I.;Di Croce, L.
c-Myc和早幼粒细胞白血病（PML）蛋白分别具有癌基因和肿瘤抑制等相反的功能。已知Myc可抑制造血前体细胞的分化，而PML可促进细胞分化。我们进一步证明PML和Myc在体内形成复合物。这两种蛋白的相互作用导致Myc的不稳定，其方式依赖于PML真正有趣的新基因（RING）结构域。尽管几种PML同工异构体能够与Myc相互作用，但破坏Myc稳定的能力是PML4所特有的。重要的是，pml诱导的不稳定导致Myc抑制基因上启动子结合Myc的减少。因此，PML诱导myc抑制的靶基因重新激活，包括肿瘤、细胞周期抑制剂cdkn1a/p21和cdkn2b/ p15的抑制基因。总之，这些结果表明pml介导的Myc不稳定和细胞周期抑制基因的抑制是一个重要的调节机制，允许细胞分化并防止由不受控制的Myc活性驱动的异常增殖。
Opposing functions like oncogene and tumor suppressions have been established for c-Myc and promyelocytic leukemia (PML) protein, respectively. Myc is known to inhibit differentiation of hematopoietic precursor cells, and here we report that PML promotes cell differentiation. We further demonstrate that PML and Myc form a complex in vivo. The interaction of the two proteins leads to the destabilization of Myc in a manner dependent on the really interesting new gene (RING) domain of PML. Although several PML isoforms are able to interact with Myc, the ability to destabilize Myc is specific for PML4. Importantly, the PML-induced destabilization resulted in a reduction of promoter-bound Myc on Myc-repressed genes. Thereby, PML induced the re-activation of Myc-repressed target genes including the tumor, suppressive genes of the cell cycle inhibitors cdkn1a/p21 and cdkn2b/ p15. Together, these results establish PML-mediated destabilization of Myc and the derepression of cell cycle inhibitor genes as an important regulatory mechanism that allows cell differentiation and prevents aberrant proliferation driven by uncontrolled Myc activity.