The orphan nuclear receptor Nurr1 restricts the proliferation of haematopoietic stem cells

Abstract

Successful hematopoiesis requires long-term retention of the quiescent state of hematopoietic stem cells (HSCs). The transcriptional regulation of stem cell quiescence, especially by factors with specific functions in HSCs, is only beginning to be understood. Here we demonstrate that Nurr1, a nuclear receptor transcription factor, has such a regulatory role. Enforced expression of Nurr1 drives early hematopoietic progenitors into quiescence. When stem cells overexpressing Nurr1 are transplanted into lethally irradiated mice, they home to the bone marrow but do not contribute to regeneration of the blood system. Furthermore, the loss of only one allele of Nurr1 is sufficient to induce HSCs to enter the cell cycle and proliferate. Molecular analysis revealed an association between Nurr1 overexpression and upregulation of the cell cycle inhibitor p18, INK4C, suggesting a mechanism by which Nurr1 could regulate HSC quiescence. Our findings provide critical insight into the transcriptional control mechanisms that determine whether HSCs remain dormant or enter the cell cycle and begin to proliferate.

Orphan Nuclear Receptor Nurr1 as a Potential Novel Marker for Progression in Human Prostate Cancer

“…Jian Wang 1 , Jing Yang 2 , Ying Zou 1 , Guo-Liang Huang 1 , Zhi-Wei He 1 * Sirin et al, 2010), apoptosis (Ke et al, 2004), migration (Maijenburg et al, 2012) and differentiation in a cell type-specific manner. Recently, the oncogenic activities of Nurr1 are emerging.…”

Essential role for DNA-PK-mediated phosphorylation of NR4A nuclear orphan receptors in DNA double-strand break repair

“…Received May 10, 2011;revised version accepted August 31, 2011. Nur77 (NR4A1), Nurr1 (NR4A2), and Nor1 (NR4A3) are orphan members of the nuclear receptor family that have been suggested to function as ligand-independent transcription factors (Baker et al 2003;Wang et al 2003). A distinguishing feature of the NR4A family of nuclear receptors is that they are rapidly induced by various acute stimuli and are functioning in adaptive and stress-responsive physiological functions, in addition to important roles in cellular differentiation into midbrain dopamine neurons and cells of the hematopoietic lineage (Zetterströ m et al 1997;Castillo et al 1998;Saucedo-Cardenas et al 1998;Ponnio et al 2002;Mullican et al 2007;Pearen and Muscat 2010;Sirin et al 2010;Zhao and Bruemmer 2010). Moreover, NR4A proteins have recently been identified as tumor suppressors in myeloid cells, and NR4A loss of function results in acute myeloid leukemia (Mullican et al 2007;Ramirez-Herrick et al 2011).…”

Regulation of Hematopoietic Stem Cell Fate: Self-Renewal, Quiescence and Survival

“…On the other hand, loss of one Nurr1 allele resulted in enhanced cycling and sensitivity to the chemotherapeutic agent 5-fluorouracil (5-FU). Molecular analysis showed that Nurr1 overexpression is positively correlated with the upregulation of the cell-cycle inhibitor p18 INK4C , suggesting a mechanism by which Nurr1 may regulate HSC quiescence (Sirin et al, 2010).…”

“…The results of in vitro overexpression and knockdown experiments identified a role for necdin in the maintenance of HSC quiescence and self-renewal. However, necdin appears to have a modest functional role in HSCs in vivo (Kubota et al, 2009), and necdin overexpression does not result in enhanced HSC quiescence (Sirin et al, 2010).…”