Winship Cancer Institute, Department of Hematology and Medical Oncology, Emory University School of Medicine, Atlanta, Georgia, United States of America.
PLoS One. 2014 Mar 20;9(3):e92746. doi: 10.1371/journal.pone.0092746. eCollection 2014.
ATBF1/ZFHX3 is a large transcription factor that functions in development, tumorigenesis and other biological processes. ATBF1 is normally localized in the nucleus, but is often mislocalized in the cytoplasm in cancer cells. The mechanism underlying the mislocalization of ATBF1 is unknown. In this study, we analyzed the nuclear localization of ATBF1, and found that ectopically expressed ATBF1 formed nuclear body (NB)-like dots in the nucleus, some of which indeed physically associated with promyelocytic leukemia (PML) NBs. We also defined a 3-amino acid motif, KRK2615-2617, as the nuclear localization signal (NLS) for ATBF1. Interestingly, diffusely distributed nuclear SUMO1 proteins were sequestered into ATBF1 dots, which could be related to ATBF1's physical association with PML NBs, known SUMOylation hotspots. Furthermore, ATBF1 itself was SUMOylated. ATBF1 SUMOylation occurred at more than 3 lysine residues including K2349, K2806 and K3258 and was nuclear specific. Finally, the PIAS3 SUMO1 E3 ligase, which interacts with ATBF1 directly, diminished rather than enhanced ATBF1 SUMOylation, preventing the co-localization of ATBF1 with SUMO1 in the nucleus. These findings suggest that nuclear localization and SUMOylation are important for the transcription factor function of ATBF1, and that ATBF1 could cooperate with PML NBs to regulate protein SUMOylation in different biological processes.
ATBF1/ZFHX3 是一种大型转录因子，在发育、肿瘤发生和其他生物过程中发挥作用。ATBF1 通常位于细胞核内，但在癌细胞中常发生核质异位。ATBF1 异位的机制尚不清楚。在本研究中，我们分析了 ATBF1 的核定位，发现过表达的 ATBF1 在核内形成核体（NB）样斑点，其中一些确实与早幼粒细胞白血病（PML）NB 物理相关。我们还定义了一个 3 个氨基酸基序 KRK2615-2617，作为 ATBF1 的核定位信号（NLS）。有趣的是，弥散分布的核 SUMO1 蛋白被募集到 ATBF1 斑点中，这可能与 ATBF1 与 PML NB 的物理相互作用有关，PML NB 是 SUMOylation 的热点。此外，ATBF1 本身也被 SUMO 化。ATBF1 的 SUMO 化发生在 3 个以上赖氨酸残基上，包括 K2349、K2806 和 K3258，并且具有核特异性。最后，与 ATBF1 直接相互作用的 PIAS3 SUMO1 E3 连接酶减少而不是增强 ATBF1 的 SUMO 化，防止 ATBF1 与 SUMO1 在核内共定位。这些发现表明，核定位和 SUMO 化对 ATBF1 的转录因子功能很重要，ATBF1 可能与 PML NB 合作，在不同的生物过程中调节蛋白质 SUMO 化。
