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

Takashi Asai, Yan Liu, Silvana Di Giandomenico, Narae Bae, Delphine Ndiaye-Lobry, Anthony Deblasio, Silvia Menendez, Yevgeniy Antipin, Boris Reva, Rachel Wevrick, Stephen D. Nimer

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33 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)1601-1612
Number of pages12
JournalBlood
Volume120
Issue number8
DOIs
StatePublished - Aug 23 2012

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ASJC Scopus subject areas

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

Cite this

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. (2012). Necdin, a p53 target gene, regulates the quiescence and response to genotoxic stress of hematopoietic stem/progenitor cells. Blood, 120(8), 1601-1612. https://doi.org/10.1182/blood-2011-11-393983