Abstract
Stra6 is the retinoic acid (RA)-inducible gene encoding the cellular receptor for holo-retinol binding protein. This transmembrane protein mediates the internalization of retinol, which then upregulates RA-responsive genes in target cells. Here, we show that Stra6 can be upregulated by DNA damage in a p53-dependent manner, and it has an important role in cell death responses. Stra6 expression induced significant amounts of apoptosis in normal and cancer cells, and it was also able to influence p53-mediated cell fate decisions by turning an initial arrest response into cell death. Moreover, inhibition of Stra6 severely compromised p53-induced apoptosis. We also found that Stra6 induced mitochondria depolarization and accumulation of reactive oxygen species, and that it was present not only at the cellular membrane but also in the cytosol. Finally, we show that these novel functions of Stra6 did not require downstream activation of RA signalling. Our results present a previously unknown link between the RA and p53 pathways and provide a rationale to use retinoids to upregulate Stra6, and thus enhance the tumour suppressor functions of p53. This may have implications for the role of vitamin A metabolites in cancer prevention and treatment.
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Abbreviations
- ATRA:
-
all-trans retinoic acid
- DAPI:
-
4′,6-diamidino-2-phenylindole, dihydrochloride
- DCF:
-
2′,7′-dichlorodihydrofluorescein diacetate
- Dox:
-
doxorubicin
- Fpg:
-
formamidopyrimidine DNA glycosylase
- hOGG1:
-
human 8-oxoguanine DNA glycosylase 1
- PI:
-
propidium iodide
- RA:
-
retinoic acid
- RBP:
-
retinol binding protein
- ROS:
-
reactive oxygen species
- tBH:
-
tert-butyl-hydroxyperoxide
- TRAIL:
-
TNF-related apoptosis-inducing ligand
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Acknowledgements
We thank S A Aaronson for his help in the initial stages of this project. We thank S Cowley and M J Dyer for useful discussions and critical reading of the manuscript. We also thank K Straatman and the Advanced Image Facilities for assistance with immunofluorescence experiments. This work was funded by the MRC (www.mrc.ac.uk, New Blood Lectureship Research Support Funding). S Carrera held a predoctoral fellowship from CONACYT (www.conacyt.mx, fellow no.200721). Work in the lab of GDDJ is supported by the European Union (ECNIS, www.ecnis.org), Hope Against Cancer (www.hfcr.org) and Cancer Research UK (www.cancerresearchuk.org). S Cuadrado was a predoctoral fellowship holder from Junta de Castilla y León, ConsejerÃa de Educación (www.educa.jcyl.es). This work was also partially supported by grants from Fondo de Investigaciones Sanitarias (FIS, PI08/1813) from the Spanish Government (www.mineco.gob.es/) to E.V.
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Carrera, S., Cuadrado-Castano, S., Samuel, J. et al. Stra6, a retinoic acid-responsive gene, participates in p53-induced apoptosis after DNA damage. Cell Death Differ 20, 910–919 (2013). https://doi.org/10.1038/cdd.2013.14
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DOI: https://doi.org/10.1038/cdd.2013.14
