University of Wuerzburg, Department of Physiological Chemistry I, Biocenter, Wuerzburg, Germany.
Mol Cell Biol. 2010 Jun;30(12):2896-908. doi: 10.1128/MCB.00028-10. Epub 2010 Apr 19.
The retinoblastoma tumor suppressor protein (pRB) and related p107 and p130 "pocket proteins" function together with the E2F transcription factors to repress gene expression during the cell cycle and development. Recent biochemical studies have identified the multisubunit DREAM pocket protein complexes in Drosophila melanogaster and Caenorhabditis elegans in regulating developmental gene repression. Although a conserved DREAM complex has also been identified in mammalian cells, its physiological function in vivo has not been determined. Here we addressed this question by targeting Lin9, a conserved core subunit of DREAM. We found that LIN9 is essential for early embryonic development and for viability of adult mice. Loss of Lin9 abolishes proliferation and leads to multiple defects in mitosis and cytokinesis because of its requirement for the expression of a large set of mitotic genes, such as Plk1, Aurora A, and Kif20a. While Lin9 heterozygous mice are healthy and normal, they are more susceptible to lung tumorigenesis induced by oncogenic c-Raf than wild-type mice. Together these experiments provide the first direct genetic evidence for the role of LIN9 in development and mitotic gene regulation and they suggest that it may function as a haploinsufficient tumor suppressor.
视网膜母细胞瘤肿瘤抑制蛋白 (pRB) 和相关的 p107 和 p130“口袋蛋白”与 E2F 转录因子一起在细胞周期和发育过程中抑制基因表达。最近的生化研究在果蝇和秀丽隐杆线虫中鉴定出多亚基 DREAM 口袋蛋白复合物在调节发育基因抑制中的作用。尽管在哺乳动物细胞中也鉴定出了保守的 DREAM 复合物，但它在体内的生理功能尚未确定。在这里，我们通过靶向 DREAM 的保守核心亚基 Lin9 来解决这个问题。我们发现 LIN9 对于早期胚胎发育和成年小鼠的存活是必需的。由于 Lin9 对于大量有丝分裂基因（如 Plk1、Aurora A 和 Kif20a）的表达是必需的，因此失去 Lin9 会导致增殖停止，并导致有丝分裂和胞质分裂中的多种缺陷。虽然 Lin9 杂合子小鼠健康且正常，但它们比野生型小鼠更容易受到致癌 c-Raf 诱导的肺癌形成的影响。这些实验共同提供了 LIN9 在发育和有丝分裂基因调控中的作用的第一个直接遗传证据，并表明它可能作为一个单倍不足的肿瘤抑制因子发挥作用。
