LKB1 作为肝再生过程中肝细胞增殖和基因组完整性的守门员。

LKB1 as a Gatekeeper of Hepatocyte Proliferation and Genomic Integrity during Liver Regeneration.

机构信息

INSERM, U1016, Institut Cochin, Paris, France; CNRS, UMR8104, Paris, France; Université Paris Descartes, Sorbonne Paris Cité, Paris, France.

INSERM, U1016, Institut Cochin, Paris, France; CNRS, UMR8104, Paris, France; Université Paris Descartes, Sorbonne Paris Cité, Paris, France; Université Paris Diderot, Sorbonne Paris Cité, Paris, France.

出版信息

Cell Rep. 2018 Feb 20;22(8):1994-2005. doi: 10.1016/j.celrep.2018.01.086.

DOI:10.1016/j.celrep.2018.01.086

PMID:29466728

Abstract

Liver kinase B1 (LKB1) is involved in several biological processes and is a key regulator of hepatic metabolism and polarity. Here, we demonstrate that the master kinase LKB1 plays a dual role in liver regeneration, independently of its major target, AMP-activated protein kinase (AMPK). We found that the loss of hepatic Lkb1 expression promoted hepatocyte proliferation acceleration independently of metabolic/energetic balance. LKB1 regulates G/G progression, specifically by controlling epidermal growth factor receptor (EGFR) signaling. Furthermore, later in regeneration, LKB1 controls mitotic fidelity. The deletion of Lkb1 results in major alterations to mitotic spindle formation along the polarity axis. Thus, LKB1 deficiency alters ploidy profile at late stages of regeneration. Our findings highlight the dual role of LKB1 in liver regeneration, as a guardian of hepatocyte proliferation and genomic integrity.

摘要

肝激酶 B1（LKB1）参与多种生物过程，是肝脏代谢和极性的关键调节因子。在这里，我们证明了主要激酶 LKB1 在肝脏再生中发挥双重作用，而不依赖其主要靶标，即 AMP 激活的蛋白激酶（AMPK）。我们发现，肝 Lkb1 表达的丧失促进了肝细胞增殖的加速，而不依赖于代谢/能量平衡。LKB1 调节 G1/S 期进展，具体是通过控制表皮生长因子受体（EGFR）信号。此外，在再生的后期，LKB1 控制有丝分裂保真度。Lkb1 的缺失导致沿着极性轴有丝分裂纺锤体形成的主要改变。因此，LKB1 缺乏会改变再生后期的倍性谱。我们的研究结果强调了 LKB1 在肝脏再生中的双重作用，作为肝细胞增殖和基因组完整性的守护者。