Oncotarget

Research Papers:

Multifaceted interactions and regulation between antizyme and its interacting proteins cyclin D1, ornithine decarboxylase and antizyme inhibitor

Yen-Chin Liu _, Chien-Yun Lee, Chi-Li Lin, Hui-Yi Chen, Guang-Yaw Liu and Hui-Chih Hung

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Oncotarget. 2015; 6:23917-23929. https://doi.org/10.18632/oncotarget.4469

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Abstract

Yen-Chin Liu1,*, Chien-Yun Lee1,2,3,*, Chi-Li Lin4, Hui-Yi Chen5,6, Guang-Yaw Liu7,8, Hui-Chih Hung1,6,9

1Department of Life Sciences, National Chung Hsing University (NCHU), Taichung, Taiwan

2Graduate Institute of Biotechnology, National Chung-Hsing University (NCHU), Taichung, Taiwan

3Molecular and Biological Agricultural Sciences Program, Taiwan International Graduate Program, Academia Sinica, Taipei, Taiwan

4Institute of Medicine, Chung Shan Medical University, Taichung, Taiwan

5Biotechnology Center, National Chung-Hsing University (NCHU), Taichung, Taiwan

6Agricultural Biotechnology Center (ABC), National Chung-Hsing University (NCHU), Taichung, Taiwan

7Institute of Microbiology & Immunology, Chung Shan Medical University, Taichung, Taiwan

8Division of Allergy, Immunology, and Rheumatology, Chung Shan Medical University Hospital, Taichung, Taiwan

9Institute of Genomics and Bioinformatics, National Chung Hsing University (NCHU), Taichung, Taiwan

*These authors have contributed equally to this work

Correspondence to:

Hui-Chih Hung, e-mail: [email protected]

Guang-Yaw Liu, e-mail: [email protected]

Keywords: biochemistry, molecular and cellular biology, signal transduction, cell cycle, oncogene

Abbreviations: AZ, antizyme; CCND1, cyclin D1; ODC, ornithine decarboxylase; AZI, antizyme inhibitor; AUC, analytical ultracentrifugation

Received: March 06, 2015     Accepted: June 16, 2015     Published: June 26, 2015

ABSTRACT

Ornithine decarboxylase (ODC), cyclin D1 (CCND1) and antizyme inhibitor (AZI) promote cell growth. ODC and CCND1 can be degraded through antizyme (AZ)-mediated 26S proteasomal degradation. This paper describes a mechanistic study of the molecular interactions between AZ and its interacting proteins. The dissociation constant (Kd) of the binary AZ-CCND1 complex and the respective binding sites of AZ and CCND1 were determined. Our data indicate that CCND1 has a 4-fold lower binding affinity for AZ than does ODC and an approximately 40-fold lower binding affinity for AZ than does AZI. The Kd values of AZ-CCND1, AZ-ODC and AZ-AZI were 0.81, 0.21 and 0.02 μM, respectively. Furthermore, the Kd values for CCND1 binding to the AZ N-terminal peptide (AZ34–124) and AZ C-terminal peptide (AZ100–228) were 0.92 and 8.97 μM, respectively, indicating that the binding site of CCND1 may reside at the N-terminus of AZ, rather than the C-terminus. Our data also show that the ODC-AZ-CCND1 ternary complex may exist in equilibrium. The Kd values of the [AZ-CCND1]-ODC and [AZ-ODC]-CCND1 complexes were 1.26 and 4.93 μM, respectively. This is the first paper to report the reciprocal regulation of CCND1 and ODC through AZ-dependent 26S proteasomal degradation.


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