HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) Supplemental Data All Versions of this Article: 2007-0264v1 25/10/2628    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Reprints/Permissions Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Luo, P. Articles by Wu, L. Search for Related Content PubMed PubMed Citation Articles by Luo, P. Articles by Wu, L.

THE STEM CELL NICHE

Intrinsic Retinoic Acid Receptor -Cyclin-Dependent Kinase-Activating Kinase Signaling Involves Coordination of the Restricted Proliferation and Granulocytic Differentiation of Human Hematopoietic Stem Cells

^aDepartment of Pathology,
^bDivision of Research Immunology/Bone Marrow Transplant, Childrens Hospital Los Angeles Saban Research Institute, Los Angeles, California, USA;
^cInstitute of Pharmacology and Toxicology, School of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China;
^dUniversity of Southern California Keck School of Medicine, Los Angeles, California, USA

Key Words. Retinoid-dependent signaling • Cell cycle G₁ exit • Proliferation/differentiation transition • Normal granulopoiesis

Correspondence: Lingtao Wu, M.D., Department of Pathology, MS# 103, Childrens Hospital Los Angeles, University of Southern California Keck School of Medicine, 4650 Sunset Boulevard, Los Angeles, California 90027, USA. Telephone: 323-644-6318; Fax: 323-671-3669; e-mail: lingtaow{at}usc.edu

Received on April 9, 2007; accepted for publication on July 1, 2007.

First published online in STEM CELLS EXPRESS  July 12, 2007.


Little is known about the mechanisms by which retinoic acid receptor (RAR) 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 is determined by its targeting subunit ménage à trois 1 (MAT1), regulates G₁ 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-CAK dissociation and MAT1 degradation suppresses cell differentiation by inhibiting CAK-dependent G₁ exit and sustaining CAK hyperphosphorylation of RAR. 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 phosphorylation by CAK induces RA-target gene expression and granulocytic differentiation. These studies suggest that the subversion of RAR-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.