p53 directly regulates the glycosidase FUCA1 to promote chemotherapy-induced cell death.
p53 is a central factor in tumor suppression as exemplified by its frequent loss in human cancer. p53 exerts its tumor suppressive effects in multiple ways, but the ability to invoke the eradication of damaged cells by programmed cell death is considered a key factor. The ways in which p53 promotes cell death can involve direct activation or engagement of the cell death machinery, or can be via indirect mechanisms, for example though regulation of ER stress and autophagy. We present here another level of control in p53-mediated tumor suppression by showing that p53 activates the glycosidase, FUCA1, a modulator of N-linked glycosylation. We show that p53 transcriptionally activates FUCA1 and that p53 modulates fucosidase activity via FUCA1 up-regulation. Importantly, we also report that chemotherapeutic drugs induce FUCA1 and fucosidase activity in a p53-dependent manner. In this context, while we found that over-expression of FUCA1 does not induce cell death, RNAi-mediated knockdown of endogenous FUCA1 significantly attenuates p53-dependent, chemotherapy-induced apoptotic death. In summary, these findings add an additional component to p53s tumor suppressive response and highlight another mechanism by which the tumor suppressor controls programmed cell death that could potentially be exploited for cancer therapy.
a Cancer Research UK Beatson Institute, Garscube Estate , Glasgow , Scotland , UK.
Alice D
AD
Baudot
a Cancer Research UK Beatson Institute, Garscube Estate , Glasgow , Scotland , UK.
Diane
D
Crighton
a Cancer Research UK Beatson Institute, Garscube Estate , Glasgow , Scotland , UK.
Jim
J
O'Prey
a Cancer Research UK Beatson Institute, Garscube Estate , Glasgow , Scotland , UK.
Joanna
J
Somers
a Cancer Research UK Beatson Institute, Garscube Estate , Glasgow , Scotland , UK.
Pablo
P
Sierra Gonzalez
a Cancer Research UK Beatson Institute, Garscube Estate , Glasgow , Scotland , UK.
Kevin M
KM
Ryan
D000970:Antineoplastic Agents / Q000494:pharmacology*; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D004249:DNA Damage; D006801:Humans; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*; D005644:alpha-L-Fucosidase / Q000235:genetics / Q000378:metabolism*
D000970:Antineoplastic Agents; C000593239:FUCA1 protein, human; D016159:Tumor Suppressor Protein p53; D005644:alpha-L-Fucosidase
FUCA1; cell death; chemotherapy; glycosylation; p53