SMRT COREPRESSOR INTERACTS WITH PLZF AND WITH THE PML-RETINOIC ACID RECEPTOR-ALPHA (RAR-ALPHA) AND PLZF-RAR-ALPHA ONCOPROTEINS ASSOCIATED WITH ACUTE PROMYELOCYTIC LEUKEMIA

Retinoic acid receptors (RARs) are hormone-regulated transcription fac tors that control ky aspects of normal differentiation. Aberrant RAR a ctivity may be a causal factor in neoplasia. Human acute promyelocytic leukemia, for example, is tightly linked to chromosomal translocation s that fuse novel amino acid sequences (denoted PML, PLZF, and NPM) to the DNA-binding and hormone-binding domains of RAR alpha. The resulti ng chimeric receptors have unique transcriptional properties that mag contribute to leukemogenesis. Normal RARs repress gene transcription b y associating with ancillary factors denoted corepressors (also referr ed to as SMRT, N-CoR, TRAC, or RIP13), We report here that the PML-RAR alpha and PLZF-RAR alpha oncoproteins retain the ability of RAR alpha to associate with corepressors, and that this corepressor association correlates with certain aspects of the leukemic phenotype. Unexpected ly, the PLZF moiety itself can interact with SMRT corepressor, This in teraction with corepressor is mediated, in part, by a POZ motif within PLZF, Given the presence of POZ motifs in a number of known transcrip tional repressors, similar interactions with SMRT may play a role in t ranscriptional silencing by a variety of both receptor and nonreceptor transcription factors.