Ubiquitination of HEXIM1 by HDM2.
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.
Lau
Joanne
J
Expression Engineering Group, Bioprocessing Technology Institute, Agency for Science, Technology and Research (A*STAR), Centros, Singapore.
Lew
Qiao Jing
QJ
Diribarne
Gaelle
G
Michels
Annemieke A
AA
Dey
Anwesha
A
Bensaude
Olivier
O
Lane
David P
DP
Chao
Sheng-Hao
SH
D002460:Cell Line; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D006801:Humans; D007976:Leupeptins / Q000494:pharmacology; D009687:Nuclear Proteins / Q000378:metabolism; D000090243:Nucleophosmin; D042925:Positive Transcriptional Elongation Factor B / Q000235:genetics / Q000378:metabolism*; D051736:Proto-Oncogene Proteins c-mdm2 / Q000378:metabolism*; D016601:RNA-Binding Proteins / Q000378:metabolism*; D015398:Signal Transduction; D014157:Transcription Factors; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism; D054875:Ubiquitination
D015853:Cysteine Proteinase Inhibitors; C476123:HEXIM1 protein, human; D007976:Leupeptins; C000716967:NPM1 protein, human; D009687:Nuclear Proteins; D016601:RNA-Binding Proteins; D014157:Transcription Factors; D016159:Tumor Suppressor Protein p53; D000090243:Nucleophosmin; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2; D044767:Ubiquitin-Protein Ligases; D042925:Positive Transcriptional Elongation Factor B; C072553:benzyloxycarbonylleucyl-leucyl-leucine aldehyde