Necdin, a p53 target gene, regulates the quiescence and response to genotoxic stress of hematopoietic stem/progenitor cells Journal Article

   

Authors:	Asai, T.; Liu, Y.; Di Giandomenico, S.; Bae, N.; Ndiaye-Lobry, D.; Deblasio, A.; Menendez, S.; Antipin, Y.; Reva, B.; Wevrick, R.; Nimer, S. D.
Article Title:	Necdin, a p53 target gene, regulates the quiescence and response to genotoxic stress of hematopoietic stem/progenitor cells
Abstract:	We recently defined a critical role for p53 in regulating the quiescence of adult hematopoietic stem cells (HSCs) and identified necdin as a candidate p53 target gene. Necdin is a growth-suppressing protein and the gene encoding it is one of several that are deleted in patients with Prader-Willi syndrome. To define the intrinsic role of necdin in adult hematopoiesis, in the present study, we transplanted necdin-null fetal liver cells into lethally irradiated recipients. We show that necdin-null adult HSCs are less quiescent and more proliferative than normal HSCs, demonstrating the similar role of necdin and p53 in promoting HSC quiescence during steady-state conditions. However, wild-type recipients repopulated with necdin-null hematopoietic stem/progenitor cells show enhanced sensitivity to irradiation and chemotherapy, with increased p53-dependent apoptosis, myelosuppression, and mortality. Necdin controls the HSC response to genotoxic stress via both cell-cycle-dependent and cell-cycle-independent mechanisms, with the latter occurring in a Gas2L3-dependent manner.We conclude that necdin functions as a molecular switch in adult hematopoiesis, acting in a p53-like manner to promote HSC quiescence in the steady state, but suppressing p53-dependent apoptosis in response to genotoxic stress. © 2012 by The American Society of Hematology.
Keywords:	controlled study; mortality; fluorouracil; nonhuman; cell proliferation; animal cell; mouse; cell cycle; apoptosis; bone marrow suppression; steady state; protein p53; hematopoietic stem cell; liver cell; necdin; genotoxicity
Journal Title:	Blood
Volume:	120
Issue:	8
ISSN:	0006-4971
Publisher:	American Society of Hematology
Date Published:	2012-08-23
Start Page:	1601
End Page:	1612
Language:	English
DOI:	10.1182/blood-2011-11-393983
PROVIDER:	scopus
PMCID:	PMC3429304
PUBMED:	22776820
DOI/URL:	http://www.scopus.com/inward/record.url?eid=2-s2.0-84865414435&partnerID=40&md5=36f128b3c478d04a18247af46362a271
Notes:	--- - "Export Date: 1 October 2012" - "CODEN: BLOOA" - "Source: Scopus"

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