期刊
CELL DEATH AND DIFFERENTIATION
卷 20, 期 1, 页码 154-168出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/cdd.2012.111
关键词
caspases; HuR; apoptosis; mRNA stability
资金
- Canadian Institutes of Health Research (CIHR)
- Natural Sciences and Engineering Research Council of Canada
- Maysie MacSporran Graduate Studentship
- CIHR/FRSQ (Fonds de Recherche en Sante du Quebec) of the McGill Integrated Cancer Research Training Program (MICRTP) [FRN53888]
- CIHR Master's Training Award
- National Cancer Institute of Canada (NCIC)
- MICRTP fellowship
- NCIC [016247]
- CIHR [MOP-89798]
- TierII Canada Research Chair
Little is known about the cellular mechanisms modulating the shift in balance from a state of survival to cell death by caspase-mediated apoptosis in response to a lethal stress. Here we show that the RNA-binding protein HuR has an important function in mediating this switch. During caspase-mediated apoptosis, HuR is cleaved to generate two cleavage products (CPs). Our data demonstrate that the cleavage of HuR switches its function from being a prosurvival factor under normal conditions to becoming a promoter of apoptosis in response to a lethal stress. In the absence of an apoptotic stimuli, HuR associates with and promotes the expression of caspase-9 and prothymosin alpha (ProT) mRNAs, and pro- and antiapoptotic factors, respectively, both of which have been characterized as important players in determining cell fate. During the early steps of caspase-mediated apoptosis, however, the level of caspase-9 protein increases, while ProT remains unchanged. Under these conditions, the two HuR-CPs selectively bind to and stabilize caspase-9 mRNA, but do not bind to ProT. Hence, taken together, our data show that by maintaining a threshold of expression of proapoptotic factors such as caspase-9 in response to a lethal stress, the HuR-CPs help a cell to switch from resisting death to undergoing apoptosis. Cell Death and Differentiation (2013) 20, 154-168; doi:10.1038/cdd.2012.111; published online 7 September 2012
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