Gfer is a critical regulator of HSC proliferation

Uma Sankar, Anthony R. Means

Research output: Contribution to journalReview article

9 Scopus citations

Abstract

Hematopoietic stem cells (HSC) are a relatively quiescent pool of cells that perform the arduous task of replacing the short-lived mature cells of the peripheral blood. While a rapid expansion of HSCs under periods of hematological stress is warranted, their enhanced proliferation during homeostasis leads to loss of function. We recently reported that in HSCs, the evolutionarily conserved growth factor erv1-like (Gfer) acts to counter jun activation-domain binding protein 1 (Jab1)-mediated nuclear export and destabilization of the cell cycle inhibitor, p27kip1, by directly binding to and sequestering the COP9 signalosome (CSN) subunit. Through this mechanism, Gfer promotes quiescence and maintains the functional integrity of HSCs. Here we extend our study to demonstrate an association between Gfer and Ca2+/calmodulin- dependent protein kinase IV (CaMKIV) in the regulation of HSC proliferation. Highly proliferative and functionally deficient Camk4-/- HSCs possess significantly lower levels of Gfer and p27kip1. Ectopic expression of Gfer restores quiescence and elevates p27kip1 expression in Camk4-/- HSCs. These results further substantiate a critical role for Gfer in the restriction of unwarranted proliferation in HSCs through the inhibition of Jab1 and subsequent stabilization and nuclear retention of p27kip1. This Gfermediated pro-quiescence mechanism could be therapeutically exploited in the treatment of hematological malignancies associated with elevated Jab1 and reduced p27kip1.

Original languageEnglish (US)
Pages (from-to)2263-2268
Number of pages6
JournalCell Cycle
Volume10
Issue number14
DOIs
StatePublished - Jul 15 2011
Externally publishedYes

Keywords

  • Bcl-2
  • CaMKIV
  • Gfer
  • Hematopoietic stem cells
  • Jab1
  • Proliferation
  • Quiescence

ASJC Scopus subject areas

  • Molecular Biology
  • Developmental Biology
  • Cell Biology

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