Abstract
Translationally controlled tumor protein (TCTP) is a potential target for cancer therapy. It functions as a growth regulating protein implicated in the TSC1–TSC2 –mTOR pathway or a guanine nucleotide dissociation inhibitor for the elongation factors EF1A and EF1Bβ. Accumulating evidence indicates that TCTP also functions as an antiapoptotic protein, through a hitherto unknown mechanism. In keeping with this, we show here that loss of tctp expression in mice leads to increased spontaneous apoptosis during embryogenesis and causes lethality between E6.5 and E9.5. To gain further mechanistic insights into this apoptotic function, we solved and refined the crystal structure of human TCTP at 2.0 Å resolution. We found a structural similarity between the H2–H3 helices of TCTP and the H5–H6 helices of Bax, which have been previously implicated in regulating the mitochondrial membrane permeability during apoptosis. By site-directed mutagenesis we establish the relevance of the H2–H3 helices in TCTP's antiapoptotic function. Finally, we show that TCTP antagonizes apoptosis by inserting into the mitochondrial membrane and inhibiting Bax dimerization. Together, these data therefore further confirm the antiapoptotic role of TCTP in vivo and provide new mechanistic insights into this key function of TCTP.
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Accession codes
Abbreviations
- TCTP:
-
translationally controlled tumor protein
- MEFs:
-
mouse embryo fibroblasts
- PARP:
-
poly (ADP-ribose) polymerase
- TUNEL:
-
terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling
- IVT:
-
in vitro translation
- TSC:
-
tuberous sclerosis complex
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Acknowledgements
This study is part of the PhD thesis of Dominique Duflaut (Université Paris XI) and Alexandra Lespagnol (Université Paris VII). We thank the staff of the European Synchrotron Radiation Facility beam line ID14-1 for use of their synchrotron instrumentation and help during data collection. We are in debt to Pierre Chambon for his longstanding support and grateful to Tania Sorg and Daniel Metzger for their help and advice in the generation of the tctp knockout mice. CB is supported by a grant from the Belgian Foundation for Cancer Research.
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Susini, L., Besse, S., Duflaut, D. et al. TCTP protects from apoptotic cell death by antagonizing bax function. Cell Death Differ 15, 1211–1220 (2008). https://doi.org/10.1038/cdd.2008.18
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DOI: https://doi.org/10.1038/cdd.2008.18
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