LIM-domain-binding 1 (LDB1) is a cofactor that participates in formation of regulatory complexes involving transcription factors containing LIM domains as well as other factors. We have examined the ability of transcriptional intermediary factor 1 gamma (TIF1 gamma) to decrease LDB1 expression. An expression vector for T1F1 gamma was found to decrease expression of LDB1. A mutation which disrupts the ubiquitin ligase activity of TIF1 gamma was found to block the ability of TIF1 gamma to decrease LDB1 expression. Proteasome inhibitors were also able to block TIF1 gamma effects on LDB1. Immunoprecipitation studies provided evidence that LDB1 interacts with TIF1 gamma in intact cells. Knockdown of TIF1 gamma in zebrafish embryos led to increased expression of LDB1 providing evidence for a physiological role of TIF1 gamma in regulating LDB1 expression. Reporter gene assays demonstrated that TIF1 gamma can alter the activity of LIM-homeodomain transcription factor-responsive promoters. These studies are consistent with a model in which TIF1 gamma acts to ubiquitinate LDB1 leading to degradation of LDB1 and changes in transcription of LDB1-dependent promoters. (C) 2010 Elsevier Inc. All rights reserved.