Department of Clinical Proteomics, National Cancer Center Research Institute, Tokyo, Japan.
Department of Pathology, Beckman Research Institute, City of Hope, Duarte, CA, United States of America.
PLoS One. 2018 Jul 18;13(7):e0200714. doi: 10.1371/journal.pone.0200714. eCollection 2018.
Over 400 million years ago, the evolution of vertebrates gave rise to a life cycle in which the organism began to live longer particularly as an adult. To accommodate such a longer lifespan, the organism underwent adaptation, developing a mechanism for long-lived cellular homeostasis. This adaptation required a population of long-lived relatively quiescent somatic stem cells (SSCs) along with a more proliferative differentiated daughter cell population, and was necessary to safeguard the genetic attributes with which SSCs were endowed. Intriguingly, cAMP response element binding protein (CREB)-binding protein (CBP) and E1A-binding protein, 300 kDa (p300), the highly homologous Kat3 coactivators had diverged, through duplication of ancestral Kat3, immediately preceding the evolution of vertebrates, given that both CBP and p300 have been detected in nearly all vertebrates versus non-vertebrates. We now demonstrate that a relatively small, highly evolutionarily conserved, amino terminal 9 amino acid deletion in CBP versus p300, plays a critical role in allowing for both robust maintenance of genomic integrity in stem cells and the initiation of a feed-forward differentiation mechanism by tightly controlling the interaction of the nuclear receptor family with the Wnt signaling cascade in either an antagonistic or synergistic manner.
4 亿多年前，脊椎动物的进化产生了一种生命周期，其中生物体开始活得更长，特别是作为成年人。为了适应这种更长的寿命，生物体经历了适应，发展出一种维持长期细胞内稳态的机制。这种适应需要一群寿命长、相对静止的体干细胞（SSCs），以及一个更具增殖性的分化子细胞群体，这对于保护 SSCs 所具有的遗传属性是必要的。有趣的是，cAMP 反应元件结合蛋白（CREB）结合蛋白（CBP）和 E1A 结合蛋白，300kDa（p300），高度同源的 Kat3 共激活因子已经分化，通过祖先 Kat3 的复制，就在脊椎动物进化之前，因为 CBP 和 p300 都在几乎所有的脊椎动物中被检测到，而在非脊椎动物中没有。我们现在证明，CBP 相对于 p300 存在一个相对较小但高度进化保守的氨基末端 9 个氨基酸缺失，在允许干细胞中基因组完整性的稳健维持和通过紧密控制核受体家族与 Wnt 信号级联的相互作用，以拮抗或协同的方式启动正向分化机制方面发挥着关键作用。
