Ubiquitination of HEXIM1 by HDM2

Abstract

Hexamethylene bis-acetamide inducible protein 1 (HEXIM1) is an inhibitor of the  positive transcription elongation factor b (P-TEFb), which controls RNA polymerase II transcription and human immunodeficiency virus Tat transactivation.  In cells, more than half of P-TEFb is associated with HEXIM1 resulting in the inactivation of P-TEFb.  Recently, we found that nucleophosmin (NPM), a key factor involved in p53 signaling pathway, interacts with HEXIM1 and activates P-TEFb-dependent transcription.  Here we report that human double minute-2 protein (HDM2), a p53-specific E3 ubiquitin ligase, specifically ubiquitinates HEXIM1 through the lysine residues located within the basic region of HEXIM1.  However, the HDM2-induced HEXIM1 ubiquitination does not lead to proteasome-mediated protein degradation.  Fusion of ubiquitin to HEXIM1 demonstrates stronger inhibition on P-TEFb-dependent transcription.  Our results demonstrate that HDM2 functions as a specific E3 ubiquitin ligase for HEXIM1, suggesting a possible role for HEXIM1 ubiquitination in the regulation of P-TEFb activity.