Abstract
TSAP6 (tumor suppressor-activated pathway 6), also known as Steap3, is a direct p53 transcriptional target gene. It regulates protein secretion, for example translationally controlled tumor protein (TCTP), which is implicated in tumor reversion. In keeping with the latter, we show herein that TSAP6 is a glycosylated protein present in the trans-Golgi network, endosomal–vesicular compartment and cytoplasmic membrane. To further investigate the physiological function of TSAP6, we have generated TSAP6-deficient mice. These mice exhibit microcytic anemia with abnormal reticulocyte maturation and deficient transferrin receptor downregulation, a process known to be dependent on exosomal secretion. Moreover, we provide direct evidence that exosome production is severely compromised in TSAP6-null cells. Finally, we show that the DNA damage-induced p53-dependent nonclassical exosomal secretory pathway is abrogated in TSAP6-null cells. Given the fact that exosomes are used as cell-free vaccines against cancer and that they could be involved in the biogenesis and spread of human immunodeficiency virus, it is important to understand their regulation. The results presented here provide the first genetic demonstration that exosome formation is a tightly controlled biological process dependent of TSAP6.
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Abbreviations
- TSAP6:
-
tumor suppressor-activated pathway 6
- TCTP:
-
translationally controlled tumor protein
- MEFs:
-
mouse embryo fibroblasts
- PARP:
-
poly (ADP-ribose) polymerase
- TUNEL:
-
terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling
- PHZ:
-
Phenylhydrazine
- PFT:
-
Pifithrin
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Acknowledgements
This study is part of the PhD thesis of Alexandra Lespagnol (Université Paris VII), and Dominique Duflaut (Université Paris XI). We are grateful to Tania Sorg and Daniel Metzger for their advice in the generation of the TSAP6 knockout mice, to Alain Schmitt, Marie-Claude Gendron, Myriam Garfa, and Evelyne Souil for their expertize, Naomi Taylor for her scientific and technical help and Marie-Claude Guillemin for the bone marrow analysis and Pierre Hainaut for his constructive comments. We thank Séverine Beaucourt for her involvement in the initial experiments (see PhD thesis online: These_Severine_Beaucourt.pdf). CB is supported by grants from the Belgian Foundation for Cancer Research. This work was supported by grants from ARC (no. 3444) to MV, Conticanet (Network of Excellence) and Eureka from the European Commission to AT and RA.
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Supplementary Information accompanies the paper on Cell Death and Differentiation website (http://www.nature.com/cdd)
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Lespagnol, A., Duflaut, D., Beekman, C. et al. Exosome secretion, including the DNA damage-induced p53-dependent secretory pathway, is severely compromised in TSAP6/Steap3-null mice. Cell Death Differ 15, 1723–1733 (2008). https://doi.org/10.1038/cdd.2008.104
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DOI: https://doi.org/10.1038/cdd.2008.104
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