Key Laboratory of Saline‑Alkali Vegetation Ecology Restoration, Ministry of Education, College of Life Science, Northeast Forestry University, Harbin, Heilongjiang 150040, P.R. China.
Department of Pathology and Comprehensive Cancer Center, Wake Forest University School of Medicine, Winston‑Salem, NC 27157, USA.
Int J Oncol. 2021 Jan;58(1):20-32. doi: 10.3892/ijo.2020.5146. Epub 2020 Nov 10.
The cyclin D binding myb‑like transcription factor 1 (DMTF1), a haplo‑insufficient tumor suppressor gene, has 3 alternatively spliced mRNA isoforms encoding DMTF1α, β and γ proteins. Previous studies have indicated a tumor suppressive role of DMTF1α and the oncogenic activity of DMTF1β, while the function of DMTF1γ remains largely undetermined. In the present study, the mechanisms regulating DMTF1 isoform expression were investigated and the functional interplay of DMTF1β and γ with DMTF1α was characterized. It was found that specific regions of DMTF1β and γ transcripts can impair their mRNA integrity or stability, and thus reduce protein expression levels. Additionally, DMTF1β and γ proteins exhibited a reduced stability compared to DMTF1α and all 3 DMTF1 isoforms were localized in the nuclei. Two basic residues, K52 and R53, in the DMTF1 isoforms determined their nuclear localization. Importantly, both DMTF1β and γ could associate with DMTF1α and antagonize its transactivation of the ARF promoter. Consistently, the ratios of both DMTF1β/α and γ/α were significantly associated with a poor prognoses of breast cancer patients, suggesting oncogenic roles of DMTF1β and γ isoforms in breast cancer development.
细胞周期蛋白 D 结合的 Myb 样转录因子 1（DMTF1）是一种单倍体不足的肿瘤抑制基因，有 3 种选择性剪接的 mRNA 异构体，编码 DMTF1α、β 和 γ 蛋白。先前的研究表明 DMTF1α 具有肿瘤抑制作用，DMTF1β 具有致癌活性，而 DMTF1γ 的功能则在很大程度上尚未确定。在本研究中，研究了调节 DMTF1 异构体表达的机制，并表征了 DMTF1β 和 γ 与 DMTF1α 的功能相互作用。研究发现，DMTF1β 和 γ 转录本的特定区域可损害其 mRNA 的完整性或稳定性，从而降低蛋白质表达水平。此外，DMTF1β 和 γ 蛋白的稳定性低于 DMTF1α，并且所有 3 种 DMTF1 异构体均定位于细胞核中。DMTF1 异构体中的两个碱性残基 K52 和 R53 决定了它们的核定位。重要的是，DMTF1β 和 γ 均可与 DMTF1α 结合并拮抗其对 ARF 启动子的转录激活。一致地，DMTF1β/α 和 γ/α 的比值与乳腺癌患者的不良预后显著相关，提示 DMTF1β 和 γ 异构体在乳腺癌发展中具有致癌作用。
