title: Anoikis effector Bit1 negatively regulates Erk activity.
abstract: 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.
authors.affiliation: Burnham Institute for Medical Research, 10901 North Torrey Pines Road, La Jolla, CA 92037, USA.
authors.forename: Rania
authors.initials: R
authors.lastname: Kairouz-Wahbe
authors.forename: Hector
authors.initials: H
authors.lastname: Biliran
authors.forename: Xiuquan
authors.initials: X
authors.lastname: Luo
authors.forename: Ingwei
authors.initials: I
authors.lastname: Khor
authors.forename: Miriam
authors.initials: M
authors.lastname: Wankell
authors.forename: Cynthia
authors.initials: C
authors.lastname: Besch-Williford
authors.forename: Jaime
authors.initials: J
authors.lastname: Pascual
authors.forename: Robert
authors.initials: R
authors.lastname: Oshima
authors.forename: Erkki
authors.initials: E
authors.lastname: Ruoslahti
mesh_terms: 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
chemical_list: D048049:Extracellular Signal-Regulated MAP Kinases; D002265:Carboxylic Ester Hydrolases; C527112:Ptrh2 protein, mouse