Role of USP4 in the regulation of gene expression

Abstract

USP4 is a deubiquitinating enzyme whose levels have been shown to be elevated in certain human lung tumors. USP4 is thought to possess oncogenic properties due to its ability to promote tumors in nude mice assays. The lack of an overall effect on ubiquitin levels in overexpression studies has led to the hypothesis that USP4 may act on a few select substrates to edit their ubiquitination status. Although the structure/function relationship is more documented, the physiological substrates and role in vivo are not. In order to elucidate the mechanism by which USP4 could potentially exert its tumorigenic effect, an RNA knockdown approach was undertaken. The effect of changes in USP4 levels was investigated to determine if USP4 plays a role in transcription or mRNA stability. The data suggest that USP4 does not affect levels of mRNAs containing an ARE sequence in NIH-3T3 or Cos-7 cells. Although USP4 was not shown to have an mRNA stabilizing effect, USP4 was found to bind CBP in vivo using an immunoprecipitation experiment and to exert an effect on basal transcription levels. This data suggests that USP4 levels may affect global transcription, perhaps through binding with the transcriptional co-activator CBP.