Orian A, Grewal S S, Knoepfler P S, Edgar B A, Parkhurst S M, Eisenman R N
Division of Basic Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington 98109-1024, USA.
Cold Spring Harb Symp Quant Biol. 2005;70:299-307. doi: 10.1101/sqb.2005.70.019.
Deregulated expression of members of the myc oncogene family has been linked to the genesis of a wide range of cancers, whereas their normal expression is associated with growth, proliferation, differentiation, and apoptosis. Myc proteins are transcription factors that function within a network of transcriptional activators (Myc) and repressors (Mxd/Mad and Mnt), all of which heterodimerize with the bHLHZ protein Mad and bind E-box sequences in DNA. These transcription factors recruit coactivator or corepressor complexes that in turn modify histones. Myc, Mxd/Max, and Mnt proteins have been thought to act on a specific subset of genes. However, expression array studies and, most recently, genomic binding studies suggest that these proteins exhibit widespread binding across the genome. Here we demonstrate by immunostaining of Drosophila polytene chromosome that Drosophila Myc (dMyc) is associated with multiple euchromatic chromosomal regions. Furthermore, many dMyc-binding regions overlap with regions containing active RNA polymerase II, although dMyc can also be found in regions lacking active polymerase. We also demonstrate that the pattern of dMyc expression in nuclei overlaps with histone markers of active chromatin but not pericentric heterochromatin. dMyc binding is not detected on the X chromosome rDNA cluster (bobbed locus). This is consistent with recent evidence that in Drosophila cells dMyc regulates rRNA transcription indirectly, in contrast to mammalian cells where direct binding of c-Myc to rDNA has been observed. We further show that the dMyc antagonist dMnt inhibits rRNA transcription in the wing disc. Our results support the view that the Myc/Max/Mad network influences transcription on a global scale.
myc癌基因家族成员的表达失调与多种癌症的发生有关，而它们的正常表达与生长、增殖、分化和细胞凋亡相关。Myc蛋白是转录因子，在转录激活因子（Myc）和转录抑制因子（Mxd/Mad和Mnt）网络中发挥作用，所有这些因子都与bHLHZ蛋白Mad异源二聚化，并结合DNA中的E-box序列。这些转录因子招募共激活因子或共抑制因子复合物，进而修饰组蛋白。Myc、Mxd/Max和Mnt蛋白一直被认为作用于特定的基因子集。然而，表达阵列研究以及最近的基因组结合研究表明，这些蛋白在全基因组范围内广泛结合。在这里，我们通过对果蝇多线染色体进行免疫染色证明，果蝇Myc（dMyc）与多个常染色质染色体区域相关。此外，许多dMyc结合区域与含有活性RNA聚合酶II的区域重叠，尽管dMyc也可以在缺乏活性聚合酶的区域中发现。我们还证明，dMyc在细胞核中的表达模式与活性染色质的组蛋白标记重叠，但与着丝粒周围异染色质不重叠。在X染色体rDNA簇（截毛位点）上未检测到dMyc结合。这与最近的证据一致，即在果蝇细胞中，dMyc间接调节rRNA转录，这与在哺乳动物细胞中观察到的c-Myc直接结合rDNA形成对比。我们进一步表明，dMyc拮抗剂dMnt抑制翅芽中的rRNA转录。我们的结果支持这样一种观点，即Myc/Max/Mad网络在全球范围内影响转录。
