TY - JOUR
T1 - Posttranscriptional regulation of per1 underlies the oncogenic function of IREα
AU - Pluquet, Olivier
AU - Dejeans, Nicolas
AU - Bouchecareilh, Marion
AU - Lhomond, Stephanie
AU - Pineau, Raphael
AU - Higa, Arisa
AU - Delugin, Maylis
AU - Combe, Chantal
AU - Loriot, Sandrine
AU - Cubel, Gaelle
AU - Dugot-Senant, Nathalie
AU - Vital, Anne
AU - Loiseau, Hugues
AU - Gosline, Sara J.C.
AU - Taouji, Said
AU - Hallett, Michael
AU - Sarkaria, Jann N.
AU - Anderson, Keith
AU - Wu, Wenting
AU - Rodriguez, Fausto J.
AU - Rosenbaum, Jean
AU - Saltel, Frederic
AU - Fernandez-Zapico, Martin E.
AU - Chevet, Eric
PY - 2013/8/1
Y1 - 2013/8/1
N2 - Growing evidence supports a role for the unfolded protein response (UPR) in carcinogenesis; however, the precise molecular mechanisms underlying this phenomenon remain elusive. Herein, we identified the circadian clock PER1 mRNA as a novel substrate of the endoribonuclease activity of the UPR sensor IRE1a. Analysis of the mechanism shows that IRE1a endoribonuclease activity decreased PER1 mRNA in tumor cells without affecting PER1 gene transcription. Inhibition of IRE1a signaling using either siRNA-mediated silencing or a dominantnegative strategy prevented PER1 mRNA decay, reduced tumorigenesis, and increased survival, features that were reversed upon PER1 silencing. Clinically, patients showing reduced survival have lower levels of PER1 mRNA expression and increased splicing of XBP1, a known IRE-a substrate, thereby pointing toward an increased IRE1a activity in these patients. Hence, we describe a novel mechanism connecting the UPR and circadian clock components in tumor cells, thereby highlighting the importance of this interplay in tumor development.
AB - Growing evidence supports a role for the unfolded protein response (UPR) in carcinogenesis; however, the precise molecular mechanisms underlying this phenomenon remain elusive. Herein, we identified the circadian clock PER1 mRNA as a novel substrate of the endoribonuclease activity of the UPR sensor IRE1a. Analysis of the mechanism shows that IRE1a endoribonuclease activity decreased PER1 mRNA in tumor cells without affecting PER1 gene transcription. Inhibition of IRE1a signaling using either siRNA-mediated silencing or a dominantnegative strategy prevented PER1 mRNA decay, reduced tumorigenesis, and increased survival, features that were reversed upon PER1 silencing. Clinically, patients showing reduced survival have lower levels of PER1 mRNA expression and increased splicing of XBP1, a known IRE-a substrate, thereby pointing toward an increased IRE1a activity in these patients. Hence, we describe a novel mechanism connecting the UPR and circadian clock components in tumor cells, thereby highlighting the importance of this interplay in tumor development.
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U2 - 10.1158/0008-5472.CAN-12-3989
DO - 10.1158/0008-5472.CAN-12-3989
M3 - Article
C2 - 23752693
AN - SCOPUS:84881436099
SN - 0008-5472
VL - 73
SP - 4732
EP - 4743
JO - Cancer Research
JF - Cancer Research
IS - 15
ER -