Stabilization and Enhancement of the Antiapoptotic Activity of Mcl-1 by TCTP

Abstract

Mcl-1 is one Bcl-2 family member that plays a pivotal role in animal development. The extremely labile nature of the Mcl-1 protein itself and the fact that the Mcl-1 level is a critical determinant in various cell survival pathways suggest that cellular processes that regulate Mcl-1 stability are as important as those that regulate Mcl-1 synthesis. Although transcriptional stimulation of Mcl-1 synthesis in response to various stimuli has been well documented, regulation of Mcl-1 stability has been hardly explored. In this study, we identified that the translationally controlled tumor protein (TCTP) was one cellular factor that interacted with Mcl-1 and modulated Mcl-1 stability. While overexpression of TCTP augmented the protein stability of Mcl-1, knockdown expression of TCTP by RNA interference destabilized Mcl-1. Furthermore, TCTP stabilized Mcl-1 through interfering with Mcl-1's degradation by the ubiquitin-dependent proteasome degradation pathway, and the TCTP binding-defective mutant of Mcl-1 (K257V) was much more susceptible to degradation and manifested a compromised antiapoptotic activity. Taken together, these results suggest that TCTP modulates Mcl-1's antiapoptotic activity by modulating its protein stability. The possible mechanism(s) involved in TCTP's modulation process is discussed.

ACKNOWLEDGMENTS

We thank Shiu-Ming Shih for his technical advice on the yeast two-hybrid screen, Yi-Ping Hsueh for the pSUPER-neo+gfp plasmid, and Cheng-Ting Chien for critical comments on the manuscript.

This study was supported in part by an intramural fund from Academia Sinica and by grants NHR1-EX91-9119BN, NSC90-2318-B-001-001-M51, NSC91-3112-B-001-004-M51, and NSC 92-3112-B-001-016 from National Health Research Institutes and the National Science Council of Taiwan to H.-F.Y.-Y.