title: SUMO regulates proteasome-dependent degradation of FLASH/Casp8AP2.
abstract: FLASH/Casp8AP2 is a huge multifunctional protein involved in multiple cellular processes, reaching from death receptor signaling to regulation of histone gene transcription and histone mRNA processing. Previous work has shown that FLASH localizes to Cajal bodies and promyelocytic leukemia (PML) bodies. However, the function of its nuclear body association remains unclear. Here we demonstrate that murine FLASH is covalently modified by SUMO at Lys residue 1792. Interestingly, ectopic expression of SUMO results in proteasome-dependent degradation of FLASH. A point mutant of FLASH with a mutated SUMO acceptor lysine residue, FLASH(K1792R), is resistant to SUMO-induced degradation. Finally, we show that arsenic trioxide, a drug known to potentiate SUMO modification and degradation of PML, triggers recruitment of FLASH to PML bodies and concomitant loss of FLASH protein. Our data suggest that SUMO targets FLASH for proteasome-dependent degradation, which is associated with recruitment of FLASH to PML bodies.
authors.affiliation: German Cancer Research Center (DKFZ), Research Group Cellular Senescence, DKFZ-ZMBH Alliance, Heidelberg, Germany.
authors.forename: Astrid
authors.initials: A
authors.lastname: Vennemann
authors.forename: Thomas G
authors.initials: TG
authors.lastname: Hofmann
mesh_terms: D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000378:metabolism*; D000077237:Arsenic Trioxide; D001152:Arsenicals / Q000494:pharmacology; D001692:Biological Transport / Q000187:drug effects; D002135:Calcium-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D006801:Humans; D015151:Immunoblotting; D051379:Mice; D018613:Microscopy, Confocal; D010087:Oxides / Q000494:pharmacology; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D025842:SUMO-1 Protein / Q000235:genetics / Q000378:metabolism*
chemical_list: D051017:Apoptosis Regulatory Proteins; D001152:Arsenicals; C485604:CASP8AP2 protein, human; D002135:Calcium-Binding Proteins; C119301:Casp8ap2 protein, mouse; D010087:Oxides; D025842:SUMO-1 Protein; D046988:Proteasome Endopeptidase Complex; D000077237:Arsenic Trioxide
keywords: FLASH/Casp8AP2; SUMO; proteasome-dependent degradation