Stabilization and enhancement of the antiapoptotic activity of mcl-1 by TCTP.
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.
Liu
Hsuan
H
Institute of Molecular Biology, Academia Sinica, 128 Yen-Jiou Yuan Rd., Section 2, Nankang, Taipei 11529, Taiwan.
Peng
Hsien-Wei
HW
Cheng
Yi-Sheng
YS
Yuan
Hanna S
HS
Yang-Yen
Hsin-Fang
HF
D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D001665:Binding Sites / Q000235:genetics; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D002460:Cell Line; D015536:Down-Regulation; D008239:Lysine / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D009363:Neoplasm Proteins / Q000378:metabolism*; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism / Q000502:physiology*; D025941:Protein Interaction Mapping; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism*; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000235:genetics / Q000494:pharmacology; D015533:Transcriptional Activation; D000090324:Tumor Protein, Translationally-Controlled 1; D020798:Two-Hybrid System Techniques; D025801:Ubiquitin / Q000378:metabolism
D014408:Biomarkers, Tumor; C579094:Mcl1 protein, mouse; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D009363:Neoplasm Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D034741:RNA, Small Interfering; C000715648:Tpt1 protein, mouse; D000090324:Tumor Protein, Translationally-Controlled 1; D025801:Ubiquitin; D046988:Proteasome Endopeptidase Complex; D008239:Lysine