Intrinsic retinoic acid receptor alpha-cyclin-dependent kinase-activating kinase signaling involves coordination of the restricted proliferation and granulocytic differentiation of human hematopoietic stem cells

Stem Cells. 2007 Oct;25(10):2628-37. doi: 10.1634/stemcells.2007-0264. Epub 2007 Jul 12.

Abstract

Little is known about the mechanisms by which retinoic acid receptor alpha (RAR alpha) mediates the effects of retinoic acid (RA) to coordinate granulocytic proliferation/differentiation (P/D) transition. Cyclin-dependent kinase-activating kinase (CAK) complex, whose activity in phosphorylation of RAR alpha is determined by its targeting subunit ménage à trois 1 (MAT1), regulates G(1) exit, a cell cycle stage when cells commonly commit to proliferation or to differentiation. We previously found that in myeloid leukemia cells, the lack of RA-induced RAR alpha-CAK dissociation and MAT1 degradation suppresses cell differentiation by inhibiting CAK-dependent G(1) exit and sustaining CAK hyperphosphorylation of RAR alpha. This contrasts with our recent findings about the P/D transition in normal primitive hematopoietic cells, where MAT1 degradation proceeds intrinsically together with granulocytic development, in accord with dynamic expression of aldehyde dehydrogenases (ALDHs) 1A1 and 1B1, which catalyze RA synthesis. Blocking ALDH activity inhibits MAT1 degradation and granulocytic differentiation, whereas loss of RAR alpha phosphorylation by CAK induces RA-target gene expression and granulocytic differentiation. These studies suggest that the subversion of RAR alpha-CAK signaling during normal granulopoiesis is crucial to myeloid leukemogenesis and challenges the current paradigm that RA induces cell differentiation solely by transactivating target genes. Disclosure of potential conflicts of interest is found at the end of this article.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Aldehyde Dehydrogenase / physiology
  • Aldehyde Dehydrogenase 1
  • Aldehyde Dehydrogenase, Mitochondrial
  • Aldehyde Oxidoreductases / physiology
  • Carrier Proteins / physiology*
  • Cell Differentiation
  • Cells, Cultured / cytology
  • Cells, Cultured / metabolism
  • Colony-Forming Units Assay
  • Cyclin H
  • Cyclin-Dependent Kinase Inhibitor p21 / biosynthesis
  • Cyclin-Dependent Kinase Inhibitor p21 / genetics
  • Cyclin-Dependent Kinases / physiology*
  • Cyclins / physiology*
  • G1 Phase / physiology
  • Gene Expression Regulation, Developmental
  • Granulocytes / cytology*
  • Hematopoietic Stem Cells / cytology
  • Hematopoietic Stem Cells / metabolism*
  • Humans
  • Multienzyme Complexes
  • Myeloid Cells / cytology
  • Myeloid Cells / metabolism
  • Phosphorylation
  • Protein Processing, Post-Translational / physiology
  • Receptors, Retinoic Acid / physiology*
  • Retinal Dehydrogenase
  • Retinoblastoma Protein / metabolism
  • Retinoic Acid Receptor alpha
  • Signal Transduction / physiology*
  • Tretinoin / metabolism
  • Tretinoin / pharmacology

Substances

  • Aldehyde Dehydrogenase 1
  • CCNH protein, human
  • CDKN1A protein, human
  • Carrier Proteins
  • Cyclin H
  • Cyclin-Dependent Kinase Inhibitor p21
  • Cyclins
  • MNAT1 protein, human
  • Multienzyme Complexes
  • RARA protein, human
  • Receptors, Retinoic Acid
  • Retinoblastoma Protein
  • Retinoic Acid Receptor alpha
  • Tretinoin
  • Aldehyde Oxidoreductases
  • ALDH1B1 protein, human
  • Aldehyde Dehydrogenase
  • Aldehyde Dehydrogenase, Mitochondrial
  • ALDH1A1 protein, human
  • Retinal Dehydrogenase
  • Cyclin-Dependent Kinases
  • cyclin-dependent kinase-activating kinase