title: Stabilization of MAPO1 by specific binding with folliculin and AMP-activated protein kinase in O⁶-methylguanine-induced apoptosis.
abstract: When DNA is damaged by alkylating agents, apoptosis is induced to exclude cells carrying DNA lesions in order to prevent mutations and cancer. MAPO1, identified as a component involved in the induction of apoptosis, interacts with AMP-activated protein kinase (AMPK) and folliculin (FLCN). We herein report that MAPO1 is stabilized during the course of apoptosis, triggered by alkylation-induced O(6)-methylguanine in DNA. An immunoblotting analysis revealed that the amount of MAPO1 increased gradually after treatment with N-methyl-N-nitrosourea (MNU), although the level of mRNA for MAPO1 was unchanged. When cells were exposed to a proteasome inhibitor, MG132, the MAPO1 level significantly increased. On the other hand, application of a protein synthesis inhibitor, cycloheximide, caused a decrease in the MAPO1 content, implying that proteasome-mediated degradation is involved. In FLCN-knockdown cells, the MAPO1 level decreased, and no increases occurred even after MNU treatment. In contrast, stabilization of MAPO1 occurred in AMPKα-knockdown cells even without MNU treatment. While MAPO1 retains its ability to stably bind to FLCN, it dissociates gradually from AMPK after exposure to MNU. It seems that the proapoptotic function of MAPO1 may be regulated by AMPK and FLCN through stabilization of MAPO1 itself.
authors.affiliation: Department of Odontology, Fukuoka Dental College, Fukuoka 814-0193, Japan.
authors.forename: Shiori
authors.initials: S
authors.lastname: Sano
authors.forename: Ryuji
authors.initials: R
authors.lastname: Sakagami
authors.forename: Mutsuo
authors.initials: M
authors.lastname: Sekiguchi
authors.forename: Masumi
authors.initials: M
authors.lastname: Hidaka
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism*; D000477:Alkylating Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D002352:Carrier Proteins / Q000378:metabolism*; D004247:DNA / Q000187:drug effects; D004970:Estrone / Q000235:genetics / Q000378:metabolism*; D055785:Gene Knockdown Techniques; D006147:Guanine / Q000031:analogs & derivatives / Q000494:pharmacology; D006367:HeLa Cells; D006801:Humans; D007976:Leupeptins / Q000494:pharmacology; D055550:Protein Stability
chemical_list: D000477:Alkylating Agents; D002352:Carrier Proteins; C529782:FNIP2 protein, human; D007976:Leupeptins; D004970:Estrone; D006147:Guanine; D004247:DNA; C008449:O-(6)-methylguanine; D055372:AMP-Activated Protein Kinases; C072553:benzyloxycarbonylleucyl-leucyl-leucine aldehyde