Ubiquitination of HEXIM1 by HDM2

Hexamethylene bis‐acetamide inducible protein 1 (HEXIM1) is an inhibitor of 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 HDM2, another important regulator of p53, ubiquitylates HEXIM1 specifically. We also identify the lysine residues, which are located with the basic region of HEXIM1, required for ubiquityl modification. Interestingly, the HDM2‐induced HEXIM1 ubiquitination does not lead to proteasome‐mediated protein degradation. Our results demonstrate that HDM2 functions as a specific E3 ubiquitin ligase for HEXIM1, suggesting a possible role for HEXIM1 in the regulation of p53 signaling pathway.

[1]  T. Lim,et al.  Nucleophosmin interacts with HEXIM1 and regulates RNA polymerase II transcription. , 2008, Journal of molecular biology.

[2]  D. Lane,et al.  Updates on p53: modulation of p53 degradation as a therapeutic approach , 2008, British Journal of Cancer.

[3]  D. Lane,et al.  HEXIM1 and the Control of Transcription Elongation: From Cancer and Inflammation to AIDS and Cardiac Hypertrophy , 2007, Cell cycle.

[4]  L. Lania,et al.  Activation of P-TEFb Induces p21 Leading to Cell Cycle Arrest , 2007, Cell cycle.

[5]  A. Giordano,et al.  Cdk9 phosphorylates p53 on serine 392 independently of CKII , 2006, Journal of cellular physiology.

[6]  B. Peterlin,et al.  Controlling the elongation phase of transcription with P-TEFb. , 2006, Molecular cell.

[7]  Pier Paolo Pandolfi,et al.  Nucleophosmin and cancer , 2006, Nature Reviews Cancer.

[8]  R. Berro,et al.  Potential use of pharmacological cyclin-dependent kinase inhibitors as anti-HIV therapeutics. , 2006, Current pharmaceutical design.

[9]  A. Gartel,et al.  CDK9 Phosphorylates p53 on Serine Residues 33, 315 and 392 , 2006, Cell cycle.

[10]  M. Montano,et al.  The breast cell growth inhibitor, estrogen down regulated gene 1, modulates a novel functional interaction between estrogen receptor alpha and transcriptional elongation factor cyclin T1 , 2005, Oncogene.

[11]  O. Bensaude,et al.  Inhibition of Tat activity by the HEXIM1 protein , 2005, Retrovirology.

[12]  C. Korgaonkar,et al.  Nucleophosmin (B23) Targets ARF to Nucleoli and Inhibits Its Function , 2005, Molecular and Cellular Biology.

[13]  K. Jeang,et al.  Ubiquitination of Human T-Cell Leukemia Virus Type 1 Tax Modulates Its Activity , 2004, Journal of Virology.

[14]  D. Lane,et al.  Mdm2-Mediated NEDD8 Conjugation of p53 Inhibits Its Transcriptional Activity , 2004, Cell.

[15]  Leena Latonen,et al.  Nucleolar protein NPM interacts with HDM2 and protects tumor suppressor protein p53 from HDM2-mediated degradation. , 2004, Cancer cell.

[16]  David Hawke,et al.  Tumor suppressor ARF degrades B23, a nucleolar protein involved in ribosome biogenesis and cell proliferation. , 2003, Molecular cell.

[17]  A. Link,et al.  Inhibition of P-TEFb (CDK9/Cyclin T) kinase and RNA polymerase II transcription by the coordinated actions of HEXIM1 and 7SK snRNA. , 2003, Molecular cell.

[18]  K. Jeang,et al.  A non-proteolytic role for ubiquitin in Tat-mediated transactivation of the HIV-1 promoter , 2003, Nature Cell Biology.

[19]  O. Bensaude,et al.  MAQ1 and 7SK RNA Interact with CDK9/Cyclin T Complexes in a Transcription-Dependent Manner , 2003, Molecular and Cellular Biology.

[20]  Guillermina Lozano,et al.  Pirh2, a p53-Induced Ubiquitin-Protein Ligase, Promotes p53 Degradation , 2003, Cell.

[21]  A. Giordano,et al.  Activation and function of cyclin T–Cdk9 (positive transcription elongation factor-b) in cardiac muscle-cell hypertrophy , 2002, Nature Medicine.

[22]  Pier Giuseppe Pelicci,et al.  Nucleophosmin regulates the stability and transcriptional activity of p53 , 2002, Nature Cell Biology.

[23]  J. Labbé,et al.  Interaction between Cyclin T1 and SCFSKP2 Targets CDK9 for Ubiquitination and Degradation by the Proteasome , 2001, Molecular and Cellular Biology.

[24]  Tamás Kiss,et al.  7SK small nuclear RNA binds to and inhibits the activity of CDK9/cyclin T complexes , 2001, Nature.

[25]  Qiang Zhou,et al.  The 7SK small nuclear RNA inhibits the CDK9/cyclin T1 kinase to control transcription , 2001, Nature.

[26]  D. Price,et al.  Flavopiridol Inactivates P-TEFb and Blocks Most RNA Polymerase II Transcription in Vivo * , 2001, The Journal of Biological Chemistry.

[27]  D. Lane,et al.  Different effects of p14ARF on the levels of ubiquitinated p53 and Mdm2 in vivo , 2001, Oncogene.

[28]  A. Caudy,et al.  Regulation of Transcriptional Activation Domain Function by Ubiquitin , 2001, Science.

[29]  E. Sausville,et al.  Flavopiridol Inhibits P-TEFb and Blocks HIV-1 Replication* , 2000, The Journal of Biological Chemistry.

[30]  Junmin Peng,et al.  Cyclin K Functions as a CDK9 Regulatory Subunit and Participates in RNA Polymerase II Transcription* , 1999, The Journal of Biological Chemistry.

[31]  R. Hay,et al.  SUMO‐1 modification activates the transcriptional response of p53 , 1999, The EMBO journal.

[32]  J. Milton,et al.  Identification of multiple cyclin subunits of human P-TEFb. , 1998, Genes & development.

[33]  M. Mathews,et al.  Transcription elongation factor P-TEFb is required for HIV-1 tat transactivation in vitro. , 1997, Genes & development.

[34]  H. Sakamoto,et al.  Phosphorylation of serine 392 stabilizes the tetramer formation of tumor suppressor protein p53. , 1997, Biochemistry.

[35]  A. Giordano,et al.  PITALRE, a nuclear CDC2-related protein kinase that phosphorylates the retinoblastoma protein in vitro. , 1994, Proceedings of the National Academy of Sciences of the United States of America.