The Lkb1 metabolic sensor maintains haematopoietic stem cell survival

被引：314

作者：

Gurumurthy, Sushma ^{[1
,2
,3
]}

Xie, Stephanie Z. ^{[1
,2
,3
,4
,5
]}

Alagesan, Brinda ^{[1
,2
,3
]}

Kim, Judith ^{[1
,2
,3
]}

Yusuf, Rushdia Z. ^{[1
,2
,3
,4
,5
]}

Saez, Borja ^{[1
,2
,3
,4
,5
]}

Tzatsos, Alexandros ^{[1
,2
,3
]}

Ozsolak, Fatih ^{[6
]}

Milos, Patrice ^{[6
]}

Ferrari, Francesco ^{[7
,8
,9
]}

Park, Peter J. ^{[7
,8
,9
]}

Shirihai, Orian S. ^{[10
]}

Scadden, David T. ^{[1
,2
,3
,4
,5
]}

Bardeesy, Nabeel ^{[1
,2
,3
]}

机构：

[1] Massachusetts Gen Hosp, Ctr Canc, Boston, MA 02114 USA

[2] Massachusetts Gen Hosp, Ctr Regenerat Med, Boston, MA 02114 USA

[3] Harvard Univ, Sch Med, Boston, MA 02114 USA

[4] Harvard Univ, Harvard Stem Cell Inst, Boston, MA 02115 USA

[5] Harvard Univ, Dept Stem Cell & Regenerat Biol, Boston, MA 02115 USA

[6] Hel BioSci Corp, Cambridge, MA 02139 USA

[7] Childrens Hosp, Ctr Biomed Informat, Boston, MA 02115 USA

[8] Childrens Hosp, Informat Program, Boston, MA 02115 USA

[9] Harvard Univ, Sch Med, Boston, MA 02115 USA

[10] Boston Univ, Med Ctr, Mitochondria ARC, Evans Res Ctr,Dept Med, Boston, MA 02118 USA

来源：

NATURE | 2010年 / 468卷 / 7324期

关键词：

PEUTZ-JEGHERS-SYNDROME; GLUCOSE-HOMEOSTASIS; TUMOR SUPPRESSION; IN-VIVO; PATHWAY; KINASE; MICE; APOPTOSIS; SYSTEM; ENERGY;

D O I：

10.1038/nature09572

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

Haematopoietic stem cells (HSCs) can convert between growth states that have marked differences in bioenergetic needs. Although often quiescent in adults, these cells become proliferative upon physiological demand. Balancing HSC energetics in response to nutrient availability and growth state is poorly understood, yet essential for the dynamism of the haematopoietic system. Here we show that the Lkb1 tumour suppressor is critical for the maintenance of energy homeostasis in haematopoietic cells. Lkb1 inactivation in adult mice causes loss of HSC quiescence followed by rapid depletion of all haematopoietic subpopulations. Lkb1-deficient bone marrow cells exhibit mitochondrial defects, alterations in lipid and nucleotide metabolism, and depletion of cellular ATP. The haematopoietic effects are largely independent of Lkb1 regulation of AMP-activated protein kinase (AMPK) and mammalian target of rapamycin (mTOR) signalling. Instead, these data define a central role for Lkb1 in restricting HSC entry into cell cycle and in broadly maintaining energy homeostasis in haematopoietic cells through a novel metabolic checkpoint.

引用

页码：659 / U75

页数：6

共 35 条

[1] Loss of the Lkb1 tumour suppressor provokes intestinal polyposis but resistance to transformation [J].