Abstract
Nur77 (NR4A1) and Nor-1 (NR4A3) are highly homologous orphan nuclear receptors that regulate the transcription of overlapping target genes. The transcriptional activity of both proteins is regulated in a ligand-independent manner by cell- and stimulus-specific gene induction and protein phosphorylation. Nor-1 and Nur77 have been implicated in a variety of cellular processes, including the transduction of hormonal, inflammatory, mitogenic, apoptotic and differentiative signals. Cellular responses to these proteins suggest that they may function as homeostatic regulators of proliferation, apoptosis and differentiation, and thus may regulate cellular susceptibility to tumorigenesis. Their physiological functions, however, remain poorly understood. Here we describe a previously unsuspected function of Nor-1 and Nur77-as critical tumor suppressors of myeloid leukemogenesis. The abrogation of these proteins in mice led to rapidly lethal acute myeloid leukemia (AML), involving abnormal expansion of hematopoietic stem cells (HSCs) and myeloid progenitors, decreased expression of the AP-1 transcription factors JunB and c-Jun and defective extrinsic apoptotic (Fas-L and TRAIL) signaling. We found that downregulation of NR4A3 ( NOR-1 ) and NR4A1 ( NUR77 ) was a common feature in leukemic blasts from human AML patients, irrespective of karyotype. Thus Nor-1 and Nur77 may provide potential targets for therapeutic intervention in AML.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Acute Disease
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Animals
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Blast Crisis / genetics
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Blast Crisis / pathology
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DNA-Binding Proteins / antagonists & inhibitors
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DNA-Binding Proteins / biosynthesis
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DNA-Binding Proteins / deficiency*
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DNA-Binding Proteins / genetics
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DNA-Binding Proteins / physiology*
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Down-Regulation / genetics
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Humans
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Leukemia, Myeloid / genetics*
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Leukemia, Myeloid / metabolism*
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Leukemia, Myeloid / pathology
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Mice
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Mice, Inbred C57BL
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Mice, Knockout
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Nerve Tissue Proteins / deficiency*
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Nerve Tissue Proteins / genetics
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Nerve Tissue Proteins / physiology*
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Nuclear Receptor Subfamily 4, Group A, Member 1
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Receptors, Cytoplasmic and Nuclear / antagonists & inhibitors
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Receptors, Cytoplasmic and Nuclear / biosynthesis
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Receptors, Cytoplasmic and Nuclear / deficiency*
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Receptors, Cytoplasmic and Nuclear / genetics
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Receptors, Cytoplasmic and Nuclear / physiology*
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Receptors, Steroid / antagonists & inhibitors
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Receptors, Steroid / biosynthesis
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Receptors, Steroid / deficiency*
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Receptors, Steroid / genetics
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Receptors, Steroid / physiology*
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Receptors, Thyroid Hormone / antagonists & inhibitors
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Receptors, Thyroid Hormone / biosynthesis
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Receptors, Thyroid Hormone / deficiency*
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Receptors, Thyroid Hormone / genetics
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Receptors, Thyroid Hormone / physiology*
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Transcription Factors / antagonists & inhibitors
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Transcription Factors / biosynthesis
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Transcription Factors / deficiency*
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Transcription Factors / genetics
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Transcription Factors / physiology*
Substances
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DNA-Binding Proteins
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NR4A1 protein, human
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NR4A3 protein, human
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Nerve Tissue Proteins
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Nr4a1 protein, mouse
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Nr4a3 protein, mouse
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Nuclear Receptor Subfamily 4, Group A, Member 1
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Receptors, Cytoplasmic and Nuclear
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Receptors, Steroid
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Receptors, Thyroid Hormone
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Transcription Factors