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Molecular and Cellular Biology, August 2005, p. 6509-6520, Vol. 25, No. 15
0270-7306/05/$08.00+0     doi:10.1128/MCB.25.15.6509-6520.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Regulation of p53-MDMX Interaction by Casein Kinase 1 Alpha

Lihong Chen, Changgong Li, Yu Pan, and Jiandong Chen*

Molecular Oncology Program, H. Lee Moffitt Comprehensive Cancer Center and Research Institute, 12902 Magnolia Drive, Tampa, Florida 33612

Received 5 April 2005/ Accepted 4 May 2005

MDMX is a homolog of MDM2 that is critical for regulating p53 function during mouse development. MDMX degradation is regulated by MDM2-mediated ubiquitination. Whether there are other mechanisms of MDMX regulation is largely unknown. We found that MDMX binds to the casein kinase 1 alpha isoform (CK1{alpha}) and is phosphorylated by CK1{alpha}. Expression of CK1{alpha} stimulates the ability of MDMX to bind to p53 and inhibit p53 transcriptional function. Regulation of MDMX-p53 interaction requires CK1{alpha} binding to the central region of MDMX and phosphorylation of MDMX on serine 289. Inhibition of CK1{alpha} expression by isoform-specific small interfering RNA (siRNA) activates p53 and further enhances p53 activity after ionizing irradiation. CK1{alpha} siRNA also cooperates with DNA damage to induce apoptosis. These results suggest that CK1{alpha} is a functionally relevant MDMX-binding protein and plays an important role in regulating p53 activity in the absence or presence of stress.

* Corresponding author. Mailing address: H. Lee Moffitt Cancer Center, MRC3057A, 12902 Magnolia Drive, Tampa, FL 33612. Phone: (813) 903-6822. Fax: (813) 903-6817. E-mail: jchen{at}moffitt.usf.edu.

Molecular and Cellular Biology, August 2005, p. 6509-6520, Vol. 25, No. 15
0022-538X/05/$08.00+0     doi:10.1128/MCB.25.15.6509-6520.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



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