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

J Biol Chem. 2013 May 3;288(18):12615-26. doi: 10.1074/jbc.M112.435701. Epub 2013 Mar 29.

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.

Keywords: Cancer; Cell Growth; Cell Proliferation; Cyclin-dependent Kinase (CDK); Protein Complexes; Protein-Protein Interactions; Tumor Marker; UCH-L1.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

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

Substances

  • 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