Role for the mortality factors MORF4, MRGX, and MRG15 in transcriptional repression via associations with Pf1, mSin3A, and Transducin-Like Enhancer of Split.
mSin3A and Transducin-Like Enhancer of Split (TLE) are two histone deacetylase (HDAC)-containing corepressors that function to repress transcription at targeted genes. Pf1 is a plant homeodomain zinc finger protein that interacts with both mSin3A and TLE, suggesting that it coordinates their function. Here we show that mSin3A and TLE interact with members of the mortality factor (MORF) family of putative transcriptional regulators. This family comprises MORF on chromosome 4 (MORF4) and MORF-related genes on chromosomes X and 15 (MRGX and MRG15, respectively) and is proposed to contribute to cellular senescence. Consistent with a role in transcription, we demonstrate that Gal4 fusions to each MORF family member repress transcription from a Gal4-dependent luciferase reporter. By using both mapping experiments and a dominant negative form of TLE, we show that repression by MORFs requires associations with mSin3A and TLE. Therefore, common functions of the MORFs are likely elicited through the action of a MORF/mSin3A/TLE complex. While the MORFs may have common functions, MRG15, but not MRGX or MORF4, interacted with Pf1. Therefore, MRG15 may have functions that are distinct from those of MRGX and MORF4. Consistent with this hypothesis, Pf1 reduced transcriptional repression by Gal4-MRG15 but it had no effect on repression by MRGX and MORF4. Pf1 has independent binding sites for MRG15 and mSin3A. In addition, Pf1 and MRG15 bind different domains on mSin3A. Together, these data suggest that the unique functions of MRG15 are elicited through the action of an MRG15/Pf1/mSin3A complex.
Yochum
Gregory S
GS
Department of Oncological Sciences, Huntsman Cancer Institute, University of Utah, Salt Lake City, Utah 84112-5550, USA.
Ayer
Donald E
DE
D000818:Animals; D002460:Cell Line; D016922:Cellular Senescence / Q000502:physiology; D002884:Chromosomes, Human, Pair 15 / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D017930:Genes, Reporter; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D046911:Macromolecular Substances; D051379:Mice; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D011485:Protein Binding; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic; D020798:Two-Hybrid System Techniques; D014960:X Chromosome / Q000235:genetics; D016335:Zinc Fingers
D004268:DNA-Binding Proteins; D018398:Homeodomain Proteins; C109882:MORF4 protein, human; D046911:Macromolecular Substances; D009687:Nuclear Proteins; C430869:PHF12 protein, human; D016271:Proto-Oncogene Proteins c-myc; D011993:Recombinant Fusion Proteins; D012097:Repressor Proteins; D014157:Transcription Factors