Potentiation of GATA-2 activity through interactions with the promyelocytic leukemia protein (PML) and the t(15;17)-generated PML-retinoic acid receptor alpha oncoprotein.
The hematopoietically expressed GATA family of transcription factors function as key regulators of blood cell fate. Among these, GATA-2 is implicated in the survival and growth of multipotential progenitors. Here we report that the promyelocytic leukemia protein (PML) can complex with GATA-2 and potentiate its transactivation capacity. The binding is mediated through interaction of the zinc finger region of GATA-2 and the B-box domain of PML. The B-box region of PML is retained in the PML-RARalpha (retinoic acid receptor alpha) fusion protein generated by the t(15;17) translocation characteristic of acute promyelocytic leukemia (APL). Consistent with this, we provide evidence that GATA-2 can physically associate with PML-RARalpha. Functional experiments further demonstrated that this interaction has the capacity to render GATA-dependent transcription inducible by retinoic acid, raising the possibility that GATA target genes may be involved in the molecular pathogenesis of APL.
Tsuzuki
S
S
Section of Gene Function and Regulation, Institute of Cancer Research, London SW3 6JB, United Kingdom.
Towatari
M
M
Saito
H
H
Enver
T
T
D000818:Animals; D019556:COS Cells; D002460:Cell Line; D002467:Cell Nucleus / Q000378:metabolism; D002884:Chromosomes, Human, Pair 15; D002886:Chromosomes, Human, Pair 17; D004247:DNA / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000737:chemistry / Q000378:metabolism*; D050989:GATA2 Transcription Factor; D006801:Humans; D015473:Leukemia, Promyelocytic, Acute / Q000378:metabolism; D051379:Mice; D009363:Neoplasm Proteins / Q000737:chemistry / Q000378:metabolism*; D009687:Nuclear Proteins; D015514:Oncogene Proteins, Fusion; D010957:Plasmids / Q000378:metabolism; D011233:Precipitin Tests; D000071156:Promyelocytic Leukemia Protein; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D018168:Receptors, Retinoic Acid / Q000378:metabolism*; D000072482:Retinoic Acid Receptor alpha; D014157:Transcription Factors / Q000737:chemistry / Q000378:metabolism*; D015533:Transcriptional Activation; D014178:Translocation, Genetic; D014212:Tretinoin / Q000494:pharmacology; D014407:Tumor Cells, Cultured; D025521:Tumor Suppressor Proteins; D020798:Two-Hybrid System Techniques
D004268:DNA-Binding Proteins; D050989:GATA2 Transcription Factor; C494711:GATA2 protein, human; C494712:Gata2 protein, mouse; D009363:Neoplasm Proteins; D009687:Nuclear Proteins; D015514:Oncogene Proteins, Fusion; C513293:Pml protein, mouse; D000071156:Promyelocytic Leukemia Protein; C000607071:RARA protein, human; C000607072:Rara protein, mouse; D018168:Receptors, Retinoic Acid; D000072482:Retinoic Acid Receptor alpha; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins; C070576:PML protein, human; D014212:Tretinoin; D004247:DNA