title: AT motif binding factor 1 (ATBF1) is highly phosphorylated in embryonic brain and protected from cleavage by calpain-1.
abstract: ATBF1 is a transcription factor that regulates genes responsible for repairing tissues and the protection of cells from oxidative stress. Therefore reduction of ATBF1 promotes susceptibility to varieties of human diseases including neurodegenerative diseases and malignant tumors. The instability of the protein was found to be an important background of diseases. Because ATBF1 is composed of a large 404-kDa protein, it can be easily targeted by proteinases. The protein instability should be a serious problem for the function in the cells and practically for our biochemical study of ATBF1. We have found that calpain-1 is a protease responsible for the degeneration of ATBF1. We observed distinct difference between embryo and adult brain derived ATBF1 regarding the sensitivity to calpain-1. The comparative study showed that eight phosphorylated serine residues (Ser1600, Ser2634, Ser2795, Ser2804, Ser2900, Ser3431, Ser3613, Ser3697) in embryonic brain, but only one site (Ser2634) in adult brain. As long as these amino acids were phosphorylated, ATBF1 derived from embryonic mouse brain showed resistance to cleavage; however, treatment with calf intestine alkaline phosphatase sensitized ATBF1 to be digested by calpain-1. An inhibitor (FK506) against calcineurin, which is a serine/threonine specific phosphatase enhanced the resistance of ATBF1 against the digestion by calpain-1. Taken together, these results demonstrate that these phosphorylation sites on ATBF1 function as a defensive shield to calpain-1.
authors.affiliation: Department of Pathology and Laboratory Medicine, Kanazawa Medical University, Japan.
authors.forename: Sheng
authors.initials: S
authors.lastname: Zhang
authors.forename: Tae-Sun
authors.initials: TS
authors.lastname: Kim
authors.forename: Yu
authors.initials: Y
authors.lastname: Dong
authors.forename: Satoshi
authors.initials: S
authors.lastname: Kanazawa
authors.forename: Makoto
authors.initials: M
authors.lastname: Kawaguchi
authors.forename: Nan
authors.initials: N
authors.lastname: Gao
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Minato
authors.forename: Tsutomu
authors.initials: T
authors.lastname: Takegami
authors.forename: Takayuki
authors.initials: T
authors.lastname: Nojima
authors.forename: Kiyofumi
authors.initials: K
authors.lastname: Asai
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Miura
mesh_terms: D000818:Animals; D001921:Brain / Q000196:embryology* / Q000378:metabolism*; D065095:Calcineurin Inhibitors; D002154:Calpain / Q000037:antagonists & inhibitors / Q000378:metabolism*; D005260:Female; D018398:Homeodomain Proteins / Q000378:metabolism*; D051379:Mice; D008813:Mice, Inbred ICR; D010766:Phosphorylation; D055550:Protein Stability; D059748:Proteolysis; D015842:Serine Proteinase Inhibitors / Q000494:pharmacology; D016559:Tacrolimus / Q000494:pharmacology
chemical_list: D065095:Calcineurin Inhibitors; D018398:Homeodomain Proteins; D015842:Serine Proteinase Inhibitors; C489511:Zfhx3 protein, mouse; D002154:Calpain; C112682:Capn1 protein, mouse; D016559:Tacrolimus