DNA recognition by the aberrant retinoic acid receptors implicated in human acute promyelocytic leukemia.
Human acute promyelocytic leukemias (APLs) are associated with chromosomal translocations that replace the NH2 terminus of wild-type retinoic acid receptor (RAR) alpha with portions of the promyelocytic leukemia protein (PML) or promyelocytic leukemia zinc-finger protein (PLZF). The wild-type RARalpha readily forms heterodimers with the retinoid X receptors (RXRs), and these RAR/RXR heterodimers appear to be the principal mediators of retinoid signaling in normal cells. In contrast, PML-RARalpha and PLZF-RARa display an enhanced ability to form homodimers, and this enhanced homodimer formation is believed to contribute to the neoplastic properties of these chimeric oncoproteins. We report here that the DNA recognition specificity of the RXRalpha/RARa heterodimer, which is presumed to be the dominant receptor species in normal cells, differs from that of the PML-RARalpha and PLZF-RARalpha homodimers, which are thought to prevail in the oncogenic cell. We suggest that differences in target gene recognition by the normal and oncogenic RARalpha proteins may contribute to the leukemogenic phenotype.
Section of Microbiology, Division of Biological Sciences, University of California at Davis, 95616, USA.
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Privalsky
D000595:Amino Acid Sequence / Q000235:genetics; D019943:Amino Acid Substitution; D004268:DNA-Binding Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D051741:Kruppel-Like Transcription Factors; D015473:Leukemia, Promyelocytic, Acute / Q000235:genetics*; D009363:Neoplasm Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D009687:Nuclear Proteins; D000071156:Promyelocytic Leukemia Protein; D000075722:Promyelocytic Leukemia Zinc Finger Protein; D011485:Protein Binding; D018168:Receptors, Retinoic Acid / Q000737:chemistry* / Q000235:genetics* / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000737:chemistry / Q000235:genetics; D047488:Retinoid X Receptors; D014157:Transcription Factors / Q000737:chemistry* / Q000235:genetics* / Q000378:metabolism; D014178:Translocation, Genetic; D025521:Tumor Suppressor Proteins
D004268:DNA-Binding Proteins; D051741:Kruppel-Like Transcription Factors; D009363:Neoplasm Proteins; D009687:Nuclear Proteins; D000071156:Promyelocytic Leukemia Protein; D000075722:Promyelocytic Leukemia Zinc Finger Protein; D018168:Receptors, Retinoic Acid; D011993:Recombinant Fusion Proteins; D047488:Retinoid X Receptors; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins; C070576:PML protein, human; C092037:ZBTB16 protein, human