Caspase-dependent apoptosis induction by targeted expression of DEK in Drosophila involves histone acetylation inhibition.
As a nuclear phosphoprotein, proto-oncogene protein DEK is capable to changing chromatin structure. DEK was recently identified as an inhibitor of histone acetylation mediated by p300 and PCAF and to facilitate transcriptional repression. To elucidate the biological functions of DEK in vivo, we have constructed transgenic flies that overexpress the human DEK in the developing eye. Transgenic flies developed a severe rough eye phenotype, which is indicative of ectopically induced apoptosis. Genetic and biochemical analyses, including the rescue of the apoptotic phenotype by pan-caspase inhibitor protein p35 and caspase activity analyses, suggested that DEK induces apoptotic cell death through a caspases-9 and -3 dependent pathway. Using extracts from larval salivary glands, we have determined that the global histone acetylation levels of histone H3 Lys9 and H4 Lys5 were decreased upon DEK overexpression. Using chromatin immunoprecipitation assays, we have demonstrated that overexpression of DEK induced the histone H3 and H4 hypoacetylation of promoter of the antiapoptotic gene bcl-2. Co-expression of bcl-2 also rescued apoptosis and the reduced expression of bcl-2 gene was analyzed by real-time PCR. Our results indicate that acidic domain containing protein DEK might have a role in modulating both transcriptional regulation and apoptosis through HAT inhibitory activity.
Department of Life Science, College of Natural Sciences, Chung-Ang University, Seoul 156-756, Korea.
Kyu-Sun
KS
Lee
Dong-Wook
DW
Kim
Ji-Young
JY
Kim
Jong-Kil
JK
Choo
Kweon
K
Yu
Sang-Beom
SB
Seo
D000107:Acetylation; D000818:Animals; D030801:Animals, Genetically Modified; D017209:Apoptosis / Q000502:physiology*; D020169:Caspases / Q000378:metabolism*; D016923:Cell Death; D002868:Chromosomal Proteins, Non-Histone / Q000235:genetics / Q000502:physiology*; D054910:Compound Eye, Arthropod / Q000254:growth & development / Q000378:metabolism; D004330:Drosophila / Q000166:cytology / Q000254:growth & development / Q000378:metabolism*; D004789:Enzyme Activation; D006367:HeLa Cells; D006657:Histones / Q000378:metabolism*; D006801:Humans; D015513:Oncogene Proteins / Q000235:genetics / Q000502:physiology*; D000075223:Poly-ADP-Ribose Binding Proteins; D000090063:Proto-Oncogene Mas; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism
D002868:Chromosomal Proteins, Non-Histone; C084738:DEK protein, human; D006657:Histones; C000715470:MAS1 protein, human; D015513:Oncogene Proteins; D000075223:Poly-ADP-Ribose Binding Proteins; D000090063:Proto-Oncogene Mas; D019253:Proto-Oncogene Proteins c-bcl-2; D020169:Caspases