Division of Gastroenterology, Department of Medicine, Washington University School of Medicine, St. Louis, MO, USA.
Department of Surgical Oncology and General Surgery, Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors, First Hospital of China Medical University, Shenyang, Liaoning Province, China.
Autophagy. 2021 Feb;17(2):588-589. doi: 10.1080/15548627.2020.1857080. Epub 2020 Dec 7.
Differentiated cells have evolved paligenosis, a conserved program to return to a stem or progenitor state and reenter the cell cycle to fuel tissue repair. Paligenosis comprises three sequential stages: 1) quenching of MTORC1 activity with induction of massive macroautophagy/autophagy that remodels differentiated cell architecture; 2) induced expression of progenitor/repair-associated genes; 3) MTORC1 reactivation with cell cycle reentry. Here, we summarize work showing that evolutionarily conserved genes - and - are critical regulators of paligenosis. DDIT4 suppresses MTORC1 function to induce lysosomes and autophagosomes in paligenosis stage 1. As DDIT4 decreases during paligenosis, TRP53 continues MTORC1 suppression until cells are licensed to reenter the cell cycle by IFRD1 suppression of TRP53. Cells with DNA damage maintain TRP53 until either the damage is repaired, or they undergo apoptosis. The concept of paligenosis and identification of paligenosis-dedicated genes may provide new angles to harness tissue regeneration and specifically target tumor cells.
分化细胞已经进化出返老还童（paligenosis），这是一种保守的程序，可以使其回到干细胞或祖细胞状态，并重新进入细胞周期，为组织修复提供燃料。返老还童包括三个连续的阶段：1）抑制 MTORC1 活性，诱导大量巨自噬/自噬，重塑分化细胞的结构；2）诱导祖细胞/修复相关基因的表达；3）MTORC1 重新激活，细胞周期重新进入。在这里，我们总结了工作表明，进化保守基因 - 和 - 是返老还童的关键调节因子。DDIT4 抑制 MTORC1 功能，在返老还童阶段 1 中诱导溶酶体和自噬体。随着返老还童的进行，DDIT4 的减少，TRP53 继续抑制 MTORC1，直到细胞通过 IFRD1 抑制 TRP53 获得重新进入细胞周期的许可。具有 DNA 损伤的细胞会一直保持 TRP53 的活性，直到损伤得到修复，或者它们发生细胞凋亡。返老还童的概念和返老还童专用基因的鉴定可能为组织再生提供新的角度，并专门针对肿瘤细胞。
