title: Apoptotic-induced cleavage shifts HuR from being a promoter of survival to an activator of caspase-mediated apoptosis.
abstract: 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 α (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.
authors.affiliation: Department of Biochemistry, Rosalind and Morris Goodman Cancer Center, McGill University, Montreal, Quebec, Canada.
authors.forename: C
authors.initials: C
authors.lastname: von Roretz
authors.forename: X Jin
authors.initials: XJ
authors.lastname: Lian
authors.forename: A M
authors.initials: AM
authors.lastname: Macri
authors.forename: N
authors.initials: N
authors.lastname: Punjani
authors.forename: E
authors.initials: E
authors.lastname: Clair
authors.forename: O
authors.initials: O
authors.lastname: Drouin
authors.forename: V
authors.initials: V
authors.lastname: Dormoy-Raclet
authors.forename: J F
authors.initials: JF
authors.lastname: Ma
authors.forename: I-E
authors.initials: IE
authors.lastname: Gallouzi
mesh_terms: D017209:Apoptosis / Q000502:physiology*; D053453:Caspase 9 / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D020169:Caspases / Q000378:metabolism*; D002470:Cell Survival / Q000502:physiology; D051959:ELAV Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D006367:HeLa Cells; D006801:Humans; D011498:Protein Precursors / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D013947:Thymosin / Q000031:analogs & derivatives / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D014162:Transfection
chemical_list: D051959:ELAV Proteins; D011498:Protein Precursors; C040782:prothymosin alpha; D013947:Thymosin; D053453:Caspase 9; D020169:Caspases