Ubiquitination of HEXIM1 by HDM2

Cell Cycle. 2009 Jul 15;8(14):2247-54. doi: 10.4161/cc.8.14.9015.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Line
  • Cysteine Proteinase Inhibitors / pharmacology
  • Humans
  • Leupeptins / pharmacology
  • Nuclear Proteins / metabolism
  • Nucleophosmin
  • Positive Transcriptional Elongation Factor B / genetics
  • Positive Transcriptional Elongation Factor B / metabolism*
  • Proto-Oncogene Proteins c-mdm2 / metabolism*
  • RNA-Binding Proteins / metabolism*
  • Signal Transduction
  • Transcription Factors
  • Tumor Suppressor Protein p53 / metabolism
  • Ubiquitin-Protein Ligases / metabolism
  • Ubiquitination*

Substances

  • Cysteine Proteinase Inhibitors
  • HEXIM1 protein, human
  • Leupeptins
  • NPM1 protein, human
  • Nuclear Proteins
  • RNA-Binding Proteins
  • Transcription Factors
  • Tumor Suppressor Protein p53
  • Nucleophosmin
  • MDM2 protein, human
  • Proto-Oncogene Proteins c-mdm2
  • Ubiquitin-Protein Ligases
  • Positive Transcriptional Elongation Factor B
  • benzyloxycarbonylleucyl-leucyl-leucine aldehyde