Trithorax, Hox, and TALE-class homeodomain proteins ensure cell survival through repression of the BH3-only gene egl-1.
Mutations that aberrantly activate trithorax-group proteins, Hox transcription factors and TALE-class Hox cofactors promote leukemogenesis, but their target genes critical for leukemogenesis remain largely unknown. Through genetic analyses in C. elegans, we find that the trithorax-group gene lin-59 and the TALE-class Hox cofactor unc-62 are required for survival of the VC motor neurons. With the goal of providing a model for how aberrantly active Hox complexes might promote leukemia, we elucidate the mechanism through which these new inhibitors of programmed cell death act: lin-59 maintains transcription of the Hox gene lin-39, while unc-62 promotes nuclear localization of the TALE-class Hox cofactor ceh-20. A LIN-39/CEH-20 complex binds the promoter of the pro-apoptotic BH3-only gene egl-1, repressing its transcription and ensuring survival of the VC neurons. In the absence of this regulatory mechanism, egl-1 is transcribed and the VC neurons die. Furthermore, ectopic expression of the Hox gene lin-39, as occurs for human Hox genes in leukemia, is sufficient to block death of some cells. This work identifies BH3-only pro-apoptotic genes as targets of Hox-mediated repression and suggests that aberrant activation of Hox networks may promote leukemia in part by inhibiting apoptosis.
Potts
Malia B
MB
Department of Pediatrics, Division of Pediatric Hematology-Oncology, University of Texas Southwestern Medical Center, Dallas, TX 75390-9148, USA.
Wang
David P
DP
Cameron
Scott
S
D017209:Apoptosis / Q000235:genetics; D029742:Caenorhabditis elegans Proteins / Q000235:genetics*; D002470:Cell Survival / Q000502:physiology*; D024202:Electrophoretic Mobility Shift Assay; D018398:Homeodomain Proteins / Q000235:genetics / Q000502:physiology*; D006801:Humans; D009046:Motor Neurons / Q000166:cytology; D016297:Mutagenesis, Site-Directed; D012097:Repressor Proteins / Q000235:genetics*; D014158:Transcription, Genetic
D029742:Caenorhabditis elegans Proteins; C112486:EGL-1 protein, C elegans; D018398:Homeodomain Proteins; D012097:Repressor Proteins