Ladendorff N E, Wu S, Lipsick J S
Department of Pathology, Stanford University School of Medicine, 300 Pasteur Drive, Stanford, California, CA 94305-5324, USA.
Oncogene. 2001 Jan 4;20(1):125-32. doi: 10.1038/sj.onc.1204048.
The carboxyl terminus of c-Myb contains a negative regulatory domain that is absent in the v-Myb oncoprotein, but conserved among all the known Myb proteins of animals. This domain inhibits transcriptional activation by c-Myb in animal cells, but not in budding yeast, suggesting that additional protein(s) present in animal cells but not yeast are required for this negative regulatory function. A yeast two-hybrid screen identified BS69, an adenovirus E1A-associated protein, as interacting with the carboxy-terminal region of c-Myb. BS69 contains regions of similarity to the PHD finger, the bromodomain, and the MYND domain, all of which are found in other proteins present in high molecular weight complexes that regulate transcription and/or modify chromatin structure. Further study showed that BS69 inhibited the transcriptional activity of c-Myb, that this inhibition was specific, that it mapped to the carboxyl termini of the two proteins and that it was dose-dependent. A direct interaction between these two proteins was observed in vitro. Furthermore, the 289R E1A protein could inhibit the BS69-mediated decrease in transcriptional activation by c-Myb. By analogy with the inhibition of the Rb/E2F regulatory axis by E1A, we propose that a BS69/Myb regulatory circuit may also be a target of disruption during oncogenesis. Oncogene (2001) 20, 125 - 132.
c-Myb的羧基末端包含一个负调控结构域，该结构域在v-Myb癌蛋白中不存在，但在所有已知的动物Myb蛋白中保守。该结构域在动物细胞中抑制c-Myb的转录激活，但在芽殖酵母中则不然，这表明动物细胞中存在而酵母中不存在的其他蛋白质是这种负调控功能所必需的。酵母双杂交筛选鉴定出与c-Myb羧基末端区域相互作用的腺病毒E1A相关蛋白BS69。BS69包含与PHD指结构域、溴结构域和MYND结构域相似的区域，所有这些结构域都存在于调节转录和/或修饰染色质结构的高分子量复合物中的其他蛋白质中。进一步研究表明，BS69抑制c-Myb的转录活性，这种抑制是特异性的，定位于这两种蛋白质的羧基末端，并且是剂量依赖性的。在体外观察到这两种蛋白质之间的直接相互作用。此外，289R E1A蛋白可以抑制BS69介导的c-Myb转录激活的降低。通过与E1A对Rb/E2F调节轴的抑制作用进行类比，我们提出BS69/Myb调节回路也可能是肿瘤发生过程中破坏的靶点。《癌基因》（2001年）20卷，第125 - 132页。
