Anoikis effector Bit1 negatively regulates Erk activity.
Bcl-2 inhibitor of transcription (Bit1) is a mitochondrial protein that functions as a peptidyl-tRNA hydrolase, but, when released into the cytoplasm, it elicits apoptosis. The proapoptotic function is uniquely counteracted by integrin-mediated cell attachment. We generated a conditional KO mouse of the Bit1 gene by using the Cre-LoxP recombination system. Bit1-null mice were born alive but with some developmental abnormalities. They developed a runting syndrome after birth and died within the first 2 weeks. Cultured fibroblasts from the Bit1-null embryos [mouse embryo fibroblasts (MEFs)] were more resistant to cell death induced by loss of attachment to extracellular matrix (anoikis) than cells from the wild-type or heterozygous littermates. MEFs and tissues from Bit1 KO mice displayed a marked increase in Erk phosphorylation. Knocking down Bit1 expression in cultured cells resulted in increased Erk activation, and partially knocking down Erk reversed the increased anoikis resistance of Bit1 knockdown. The enhanced Erk activation was associated with decreased Erk phosphatase activity. These studies establish the physiological significance of Bit1 activity and begin to delineate a Bit1 signaling pathway that acts through Erk regulation.
Kairouz-Wahbe
Rania
R
Burnham Institute for Medical Research, 10901 North Torrey Pines Road, La Jolla, CA 92037, USA.
Biliran
Hector
H
Luo
Xiuquan
X
Khor
Ingwei
I
Wankell
Miriam
M
Besch-Williford
Cynthia
C
Pascual
Jaime
J
Oshima
Robert
R
Ruoslahti
Erkki
E
D000818:Animals; D023102:Anoikis / Q000235:genetics*; D001259:Ataxia / Q000235:genetics; D002265:Carboxylic Ester Hydrolases / Q000235:genetics / Q000502:physiology*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000235:genetics / Q000378:metabolism*; D047109:Fetal Development / Q000235:genetics; D051379:Mice; D018345:Mice, Knockout; D009136:Muscular Dystrophies / Q000235:genetics; D009503:Neutropenia / Q000235:genetics; D010766:Phosphorylation; D013577:Syndrome
D048049:Extracellular Signal-Regulated MAP Kinases; D002265:Carboxylic Ester Hydrolases; C527112:Ptrh2 protein, mouse