Retinoids in myelopoiesis.
The vitamin A derivative retinoic acid plays a critical role during the differentiation of myeloid progenitors towards the neutrophil lineage. This role is primarily mediated by binding of retinoic acid to retinoic acid receptor alpha (RARalpha), a nuclear receptor that modulates the expression of multiple downstream targets via retinoic acid response elements. The importance of this signalling pathway in myelopoiesis is evidenced by the recurrent disruption of the RARalpha gene by chromosomal rearrangements in all cases of acute promyelocytic leukemia (APL). Biochemical evidence suggests RARalpha performs two opposing functions, one as a repressor of gene expression in the absence of ligand, the second as a transcriptional activator in the presence of ligand, each controlled by multimeric complexes of transcription corepressors and coactivators, respectively. Here the molecular mechanisms activated by retinoic acid during myelopoiesis in the context of neutrophil development will be reviewed, together with some of the more recently identified targets of the retinoic signalling pathway.
Gaines
P
P
Section of Hematology, Department of Internal Medicine, Yale University School of Medicine, New Haven, CT 06510, USA. peter.gaines@yale.edu
Berliner
N
N
D036541:ADP-ribosyl Cyclase / Q000378:metabolism; D051997:ADP-ribosyl Cyclase 1; D000818:Animals; D015703:Antigens, CD / Q000378:metabolism; D002454:Cell Differentiation; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D051741:Kruppel-Like Transcription Factors; D015473:Leukemia, Promyelocytic, Acute / Q000378:metabolism / Q000473:pathology; D008562:Membrane Glycoproteins; D038042:Myelopoiesis; D011494:Protein Kinases / Q000378:metabolism; D018168:Receptors, Retinoic Acid / Q000235:genetics / Q000378:metabolism*; D012176:Retinoids / Q000096:biosynthesis / Q000378:metabolism*; D015398:Signal Transduction; D014157:Transcription Factors / Q000378:metabolism
D015703:Antigens, CD; C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D004268:DNA-Binding Proteins; D051741:Kruppel-Like Transcription Factors; C085969:MZF1 protein, human; D008562:Membrane Glycoproteins; D018168:Receptors, Retinoic Acid; D012176:Retinoids; D014157:Transcription Factors; D011494:Protein Kinases; C106686:(CaM)-dependent protein kinase Ia kinase; D036541:ADP-ribosyl Cyclase; C498154:CD38 protein, human; D051997:ADP-ribosyl Cyclase 1