Journal
JOURNAL OF CELLULAR PHYSIOLOGY
Volume 227, Issue 3, Pages 1138-1147Publisher
WILEY-BLACKWELL
DOI: 10.1002/jcp.22834
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Funding
- Japan Society for the Promotion of Science [C22591047]
- MEXT
- Astra Zeneca
- Jichi Medical University
- Grants-in-Aid for Scientific Research [22591047, 23791089] Funding Source: KAKEN
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Latexin is the only known carboxypeptidase A inhibitor in mammals and shares structural similarity with cystatin C, suggesting that latexin regulates the abundance of as yet unidentified target proteins. A forward genetic approach revealed that latexin is involved in homeostasis of hematopoietic stem cells (HSCs) in mice; however, little is known about the mechanisms by which latexin negatively affects the numbers of HSCs. In this study, we found that latexin is preferentially expressed in hematopoietic stem/progenitor cells, and is co-localized with the molecules responsible for the interaction of HSCs with a bone marrow niche, such as N-cadherin, Tie2, and Roundabout 4. Latexin-knockout young female mice showed an increase in the numbers of KSL (c-Kit+/Sca-1+/linegae marker-negative) cells, which may be attributable to enhanced self-renewal because latexin-deficient KSL cells formed more colonies than their wild-type counterparts in methylcellulose culture. Proteomic analysis of Sca-1+ bone marrow cells demonstrated that latexin ablation reduced the abundance of multiple cellular proteins, including N-cadherin, Tie2, and Roundabout 4. Finally, we found that latexin expression was lost or greatly reduced in approximately 50% of human leukemia/lymphoma cell lines. These results imply that latexin inhibits the self-renewal of HSCs by facilitating the lodgment of HSCs within a bone marrow niche to maintain HSC homeostasis. J. Cell. Physiol. 227: 11381147, 2012. (C) 2011 Wiley Periodicals, Inc.
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