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      Lkb1 regulates cell cycle and energy metabolism in haematopoietic stem cells

      1 , 2 , 2 , 3 , 1 , 2 , 4


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          Little is known about metabolic regulation in stem cells and how this modulates tissue regeneration or tumour suppression. We studied the Lkb1 tumour suppressor, and its substrate AMPK, kinases that coordinate metabolism with cell growth. Lkb1 deletion caused increased haematopoietic stem cell (HSC) division, rapid HSC depletion, and pancytopenia. HSCs depended more acutely on Lkb1 for cell cycle regulation and survival than many other haematopoietic cells. HSC depletion did not depend on mTOR activation or oxidative stress. Lkb1-deficient HSCs, but not myeloid progenitors, had reduced mitochondrial membrane potential and ATP. AMPK-deficient HSCs showed similar changes in mitochondrial function but remained able to reconstitute irradiated mice. Lkb1-deficient HSCs, but not AMPK-deficient HSCs, exhibited defects in centrosomes and mitotic spindles in culture, and became aneuploid. Lkb1 is therefore required for HSC maintenance through AMPK-dependent and AMPK-independent mechanisms, revealing differences in metabolic and cell cycle regulation between HSCs and some other haematopoietic progenitors.

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          Most cited references 32

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          AMP-activated/SNF1 protein kinases: conserved guardians of cellular energy.

          The SNF1/AMP-activated protein kinase (AMPK) family maintains the balance between ATP production and consumption in all eukaryotic cells. The kinases are heterotrimers that comprise a catalytic subunit and regulatory subunits that sense cellular energy levels. When energy status is compromised, the system activates catabolic pathways and switches off protein, carbohydrate and lipid biosynthesis, as well as cell growth and proliferation. Surprisingly, recent results indicate that the AMPK system is also important in functions that go beyond the regulation of energy homeostasis, such as the maintenance of cell polarity in epithelial cells.
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            A highly efficient recombineering-based method for generating conditional knockout mutations.

            Phage-based Escherichia coli homologous recombination systems have recently been developed that now make it possible to subclone or modify DNA cloned into plasmids, BACs, or PACs without the need for restriction enzymes or DNA ligases. This new form of chromosome engineering, termed recombineering, has many different uses for functional genomic studies. Here we describe a new recombineering-based method for generating conditional mouse knockout (cko) mutations. This method uses homologous recombination mediated by the lambda phage Red proteins, to subclone DNA from BACs into high-copy plasmids by gap repair, and together with Cre or Flpe recombinases, to introduce loxP or FRT sites into the subcloned DNA. Unlike other methods that use short 45-55-bp regions of homology for recombineering, our method uses much longer regions of homology. We also make use of several new E. coli strains, in which the proteins required for recombination are expressed from a defective temperature-sensitive lambda prophage, and the Cre or Flpe recombinases from an arabinose-inducible promoter. We also describe two new Neo selection cassettes that work well in both E. coli and mouse ES cells. Our method is fast, efficient, and reliable and makes it possible to generate cko-targeting vectors in less than 2 wk. This method should also facilitate the generation of knock-in mutations and transgene constructs, as well as expedite the analysis of regulatory elements and functional domains in or near genes.
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              Boveri revisited: chromosomal instability, aneuploidy and tumorigenesis.

              The mitotic checkpoint is a major cell cycle control mechanism that guards against chromosome missegregation and the subsequent production of aneuploid daughter cells. Most cancer cells are aneuploid and frequently missegregate chromosomes during mitosis. Indeed, aneuploidy is a common characteristic of tumours, and, for over 100 years, it has been proposed to drive tumour progression. However, recent evidence has revealed that although aneuploidy can increase the potential for cellular transformation, it also acts to antagonize tumorigenesis in certain genetic contexts. A clearer understanding of the tumour suppressive function of aneuploidy might reveal new avenues for anticancer therapy.

                Author and article information

                26 October 2010
                2 December 2010
                2 June 2011
                : 468
                : 7324
                : 653-658
                [1 ]Howard Hughes Medical Institute, Life Sciences Institute, Center for Stem Cell Biology, University of Michigan, Ann Arbor, Michigan, 48109-2216
                [2 ]Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, 48109-2216
                [3 ]Transgenic Animal Model Core, University of Michigan, Ann Arbor, Michigan, 48109-2216
                Author notes

                Author Contributions D.N. performed all experiments. T.S. helped to design and make the Lkb1 fl mice. D.N. and S.J.M. designed and interpreted all experiments and wrote the paper.

                [4 ] Author for correspondence: 5435 Life Sciences Institute, 210 Washtenaw Ave., Ann Arbor, Michigan, 48109-2216; phone 734-647-6261; fax 734-615-8133; seanjm@ 123456umich.edu

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                Funded by: Howard Hughes Medical Institute
                Award ID: ||HHMI_



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