title: Functional effects of a pathogenic mutation in Cereblon (CRBN) on the regulation of protein synthesis via the AMPK-mTOR cascade.
abstract: Initially identified as a protein implicated in human mental deficit, cereblon (CRBN) was recently recognized as a negative regulator of adenosine monophosphate-activated protein kinase (AMPK) in vivo and in vitro. Here, we present results showing that CRBN can effectively regulate new protein synthesis through the mammalian target of rapamycin (mTOR) signaling pathway, a downstream target of AMPK. Whereas deficiency of Crbn repressed protein translation via activation of the AMPK-mTOR cascade in Crbn-knock-out mice, ectopic expression of the wild-type CRBN increased protein synthesis by inhibiting endogenous AMPK. Unlike the wild-type CRBN, a mutant CRBN found in human patients, which lacks the last 24 amino acids, failed to rescue mTOR-dependent repression of protein synthesis in Crbn-deficient mouse fibroblasts. These results provide the first evidence that Crbn can activate the protein synthesis machinery through the mTOR signaling pathway by inhibiting AMPK. In light of the fact that protein synthesis regulated by mTOR is essential for various forms of synaptic plasticity that underlie the cognitive functions of the brain, the results of this study suggest a plausible mechanism for CRBN involvement in higher brain function in humans, and they may help explain how a specific mutation in CRBN can affect the cognitive ability of patients.
authors.affiliation: From the School of Life Sciences, Cell Dynamics Research Center and National Leading Research Laboratory, Gwangju Institute Science and Technology (GIST), Gwangju, 500-712, The Republic of Korea.
authors.forename: Kwang Min
authors.initials: KM
authors.lastname: Lee
authors.affiliation: From the School of Life Sciences, Cell Dynamics Research Center and National Leading Research Laboratory, Gwangju Institute Science and Technology (GIST), Gwangju, 500-712, The Republic of Korea.
authors.forename: Seung-Joo
authors.initials: SJ
authors.lastname: Yang
authors.affiliation: From the School of Life Sciences, Cell Dynamics Research Center and National Leading Research Laboratory, Gwangju Institute Science and Technology (GIST), Gwangju, 500-712, The Republic of Korea.
authors.forename: Ja-Hyun
authors.initials: JH
authors.lastname: Choi
authors.affiliation: From the School of Life Sciences, Cell Dynamics Research Center and National Leading Research Laboratory, Gwangju Institute Science and Technology (GIST), Gwangju, 500-712, The Republic of Korea cspark@gist.ac.kr.
authors.forename: Chul-Seung
authors.initials: CS
authors.lastname: Park
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000263:Adenylate Kinase / Q000378:metabolism*; D000818:Animals; D001921:Brain / Q000201:enzymology / Q000378:metabolism; D007859:Learning Disabilities / Q000235:genetics; D008297:Male; D008569:Memory Disorders / Q000235:genetics; D051379:Mice; D018345:Mice, Knockout; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000235:genetics*; D010766:Phosphorylation; D014176:Protein Biosynthesis; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C549921:Crbn protein, mouse; D009419:Nerve Tissue Proteins; C546843:mTOR protein, mouse; D058570:TOR Serine-Threonine Kinases; D000263:Adenylate Kinase
keywords: AMP-activated Kinase (AMPK); Cereblon; Gene Knockout; Mammalian Target of Rapamycin (mTOR); Mental Deficit; Nonsense Mutation; Protein Synthesis; Signal Transduction