Ubiquitin C-terminal hydrolase L1 (UCH-L1) acts as a novel potentiator of cyclin-dependent kinases to enhance cell proliferation independently of its hydrolase activity.

Abstract

Dysregulation of cell proliferation and the cell cycle are associated with various diseases, such as cancer. Cyclin-dependent kinases (CDKs) play central roles in cell proliferation and the cell cycle. Ubiquitin C-terminal hydrolase L1 (UCH-L1) is expressed in a restricted range of tissues, including the brain and numerous types of cancer. However, the molecular functions of UCH-L1 remain elusive. In this study, we found that UCH-L1 physically interacts with CDK1, CDK4, and CDK5, enhancing their kinase activity. Using several mutants of UCH-L1, we showed that this enhancement is dependent upon interaction levels between UCH-L1 and CDKs but is independent of the known ubiquitin-related functions of UCH-L1. Gain- and loss-of-function studies revealed that UCH-L1 enhances proliferation of multiple cell types, including human cancer cells. Inhibition of the interaction between UCH-L1 and cell cycle-associated CDK resulted in the abolishment of UCH-L1-induced enhancement of cell proliferation. RNA interference of UCH-L1 reduced the growth of human xenograft tumors in mice. We concluded that UCH-L1 is a novel regulator of the kinase activities of CDKs. We believe that our findings from this study will significantly contribute to our understanding of cell cycle-associated diseases.

• Authors: Tomohiro Kabuta, Takeshi Mitsui, Masaki Takahashi, Yuuki Fujiwara, Chihana Kabuta, Chiho Konya, Yukihiro Tsuchiya, Yusuke Hatanaka, Kenko Uchida, Hirohiko Hohjoh, Keiji Wada
• Journal: The Journal of biological chemistry (J Biol Chem) Vol. 288 Issue 18 Pg. 12615-26 (May 03 2013) ISSN: 1083-351X [Electronic] United States
• PMID: 23543736 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Neoplasm Proteins
• UCHL1 protein, human
• Ubiquitin carboxyl-Terminal Hydrolase L-1, mouse
• Cyclin-Dependent Kinase 5
• CDC2 Protein Kinase
• CDK4 protein, human
• CDK5 protein, human
• Cdk4 protein, mouse
• Cdk5 protein, mouse
• Cyclin-Dependent Kinase 4
• Ubiquitin Thiolesterase

Topics

• Animals
• CDC2 Protein Kinase (genetics, metabolism)
• COS Cells
• Cell Proliferation
• Chlorocebus aethiops
• Cyclin-Dependent Kinase 4 (genetics, metabolism)
• Cyclin-Dependent Kinase 5 (genetics, metabolism)
• HeLa Cells
• Humans
• Mice
• Mutation
• NIH 3T3 Cells
• Neoplasm Proteins (genetics, metabolism)
• Neoplasm Transplantation
• Neoplasms (enzymology, genetics, pathology)
• Transplantation, Heterologous
• Ubiquitin Thiolesterase (genetics, metabolism)