Laboratory of Molecular Pharmacology, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD 20890, USA.
Nucleic Acids Res. 2011 Aug;39(15):6620-32. doi: 10.1093/nar/gkr208. Epub 2011 Apr 29.
Mitochondrial DNA (mtDNA) is entirely dependent on nuclear genes for its transcription and replication. One of these genes is TOP1MT, which encodes the mitochondrial DNA topoisomerase IB, involved in mtDNA relaxation. To elucidate TOP1MT regulation, we performed genome-wide profiling across the 60-cell line panel (the NCI-60) of the National Cancer Institute Developmental Therapeutics Program. We show that TOP1MT mRNA expression varies widely across these cell lines with the highest levels in leukemia (HL-60, K-562) and melanoma (SK-MEL-28), intermediate levels in breast (MDA-MB-231), ovarian (OVCAR) and colon (HCT-116, HCT-15, KM-12), and lowest levels in renal (ACHN, A498), prostate (PC-3, DU-145) and central nervous system cell lines (SF-539, SF-268, SF-295). Genome-wide analyses show that TOP1MT expression is significantly correlated with the other mitochondrial nuclear-encoded genes including the mitochondrial nucleoid genes, and demonstrate an overall co-regulation of the mitochondrial nuclear-encoded genes. We also find very high correlation between the expression of TOP1MT and the proto-oncogene MYC (c-myc). TOP1MT contains E-boxes (c-myc binding sites) and TOP1MT transcription follows MYC up- and down-regulation by MYC promoter activation and siRNA against MYC. Our finding implicates MYC as a novel regulator of TOP1MT and confirms its role as a master regulator of MNEGs and mitochondrial nucleoids.
线粒体 DNA（mtDNA）的转录和复制完全依赖于核基因。这些基因中的一个是 TOP1MT，它编码线粒体 DNA 拓扑异构酶 IB，参与 mtDNA 的松弛。为了阐明 TOP1MT 的调控机制，我们在国立癌症研究所发展治疗学计划的 60 细胞系面板（NCI-60）上进行了全基因组分析。我们表明，TOP1MT mRNA 表达在这些细胞系中差异很大，白血病（HL-60、K-562）和黑色素瘤（SK-MEL-28）中的表达水平最高，乳腺癌（MDA-MB-231）、卵巢癌（OVCAR）和结肠癌（HCT-116、HCT-15、KM-12）中的表达水平中等，而在肾癌（ACHN、A498）、前列腺癌（PC-3、DU-145）和中枢神经系统细胞系（SF-539、SF-268、SF-295）中的表达水平最低。全基因组分析表明，TOP1MT 的表达与其他线粒体核编码基因，包括线粒体核区基因显著相关，并证明了线粒体核编码基因的整体协同调控。我们还发现 TOP1MT 表达与原癌基因 MYC（c-myc）之间存在非常高的相关性。TOP1MT 含有 E-Boxes（c-myc 结合位点），TOP1MT 的转录遵循 MYC 的上调和下调，由 MYC 启动子的激活和针对 MYC 的 siRNA 调节。我们的发现表明 MYC 是 TOP1MT 的一个新的调控因子，并证实了它作为 MNEGs 和线粒体核区的主要调控因子的作用。
