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      Tightrope act: autophagy in stem cell renewal, differentiation, proliferation, and aging

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          Abstract

          Autophagy is a constitutive lysosomal catabolic pathway that degrades damaged organelles and protein aggregates. Stem cells are characterized by self-renewal, pluripotency, and quiescence; their long life span, limited capacity to dilute cellular waste and spent organelles due to quiescence, along with their requirement for remodeling in order to differentiate, all suggest that they require autophagy more than other cell types. Here, we review the current literature on the role of autophagy in embryonic and adult stem cells, including hematopoietic, mesenchymal, and neuronal stem cells, highlighting the diverse and contrasting roles autophagy plays in their biology. Furthermore, we review the few studies on stem cells, lysosomal activity, and autophagy. Novel techniques to detect autophagy in primary cells are required to study autophagy in different stem cell types. These will help to elucidate the importance of autophagy in stem cells during transplantation, a promising therapeutic approach for many diseases.

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          Most cited references82

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          Beclin 1, an autophagy gene essential for early embryonic development, is a haploinsufficient tumor suppressor.

          The biochemical properties of beclin 1 suggest a role in two fundamentally important cell biological pathways: autophagy and apoptosis. We show here that beclin 1-/- mutant mice die early in embryogenesis and beclin 1+/- mutant mice suffer from a high incidence of spontaneous tumors. These tumors continue to express wild-type beclin 1 mRNA and protein, establishing that beclin 1 is a haploinsufficient tumor suppressor gene. Beclin 1-/- embryonic stem cells have a severely altered autophagic response, whereas their apoptotic response to serum withdrawal or UV light is normal. These results demonstrate that beclin 1 is a critical component of mammalian autophagy and establish a role for autophagy in tumor suppression. They both provide a biological explanation for recent evidence implicating beclin 1 in human cancer and suggest that mutations in other genes operating in this pathway may contribute to tumor formation through deregulation of autophagy.
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            Nix is a selective autophagy receptor for mitochondrial clearance.

            Autophagy is the cellular homeostatic pathway that delivers large cytosolic materials for degradation in the lysosome. Recent evidence indicates that autophagy mediates selective removal of protein aggregates, organelles and microbes in cells. Yet, the specificity in targeting a particular substrate to the autophagy pathway remains poorly understood. Here, we show that the mitochondrial protein Nix is a selective autophagy receptor by binding to LC3/GABARAP proteins, ubiquitin-like modifiers that are required for the growth of autophagosomal membranes. In cultured cells, Nix recruits GABARAP-L1 to damaged mitochondria through its amino-terminal LC3-interacting region. Furthermore, ablation of the Nix:LC3/GABARAP interaction retards mitochondrial clearance in maturing murine reticulocytes. Thus, Nix functions as an autophagy receptor, which mediates mitochondrial clearance after mitochondrial damage and during erythrocyte differentiation.
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              p62 at the crossroads of autophagy, apoptosis, and cancer.

              The signaling adaptor p62 is a multidomain protein implicated in the activation of the transcription factor NF-kappaB. Recent findings link p62 activity to the extrinsic apoptosis pathway, and Mathew et al. (2009) now show that the modulation of p62 by autophagy is a key factor in tumorigenesis. These findings place p62 at critical decision points that control cell death and survival.
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                Author and article information

                Contributors
                kanchan.phadwal@ndm.ox.ac.uk
                alec.watson@balliol.ox.ac.uk
                +44-1865-222910 , +44-1865-222502 , katja.simon@ndm.ox.ac.uk
                Journal
                Cell Mol Life Sci
                Cell. Mol. Life Sci
                Cellular and Molecular Life Sciences
                SP Birkhäuser Verlag Basel (Basel )
                1420-682X
                1420-9071
                5 June 2012
                5 June 2012
                January 2013
                : 70
                : 1
                : 89-103
                Affiliations
                [ ]BRC Translational Immunology Lab, NIHR, Nuffield Department of Medicine, John Radcliffe Hospital, University of Oxford, Oxford, OX3 9DU UK
                [ ]MRC Human Immunology Unit, Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, University of Oxford, Oxford, OX3 9DS UK
                Article
                1032
                10.1007/s00018-012-1032-3
                3535400
                22669258
                aea5b834-bc0a-4a84-99b5-aa64f7807e64
                © The Author(s) 2012
                History
                : 2 December 2011
                : 9 May 2012
                : 10 May 2012
                Categories
                Review
                Custom metadata
                © Springer Basel 2013

                Molecular biology
                aging,autophagy,esc,hsc,lysosomes,msc,nsc,senescence,stem cells
                Molecular biology
                aging, autophagy, esc, hsc, lysosomes, msc, nsc, senescence, stem cells

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