title: Ret finger protein 2 enhances ionizing radiation-induced apoptosis via degradation of AKT and MDM2.
abstract: Ret finger protein 2 (RFP2), a gene frequently deleted in multiple tumor types, encodes a protein with a RING finger, B-box, and coiled-coil domain that belongs to the RBCC/TRIM protein family. Although RBCC proteins are involved in diverse cellular processes such as apoptosis, proliferation, differentiation, and transcriptional regulation, the biological function of RFP2 has not been well defined. Here, we demonstrate that overexpression of RFP2 in cells induced apoptosis through proteasomal degradation of MDM2 and AKT. The expression of RFP2, which possesses RING domain-dependent E3 ubiquitin ligase activity, was increased by ionizing radiation dose- and time-dependently, and RFP2 overexpression induced cell death with increased expression of apoptotic molecules (p53, p21, and Bax). These results depended on the E3 ubiquitin ligase activity of RFP2 because mutant RFP2, which contains a mutated RING domain, failed to drive apoptosis compared with wild-type RFP2. We observed that RFP2 formed a complex with MDM2, a negative regulator of the p53 tumor suppressor, and AKT, a regulator of apoptosis inhibition at the cellular level. Additionally, we found that the interaction of RFP2 with MDM2 and AKT resulted in ubiquitination and proteasomal degradation of MDM2 and AKT in vivo and in vitro. Thus, these data suggest that irradiation causes RFP2 overexpression, which enhances ionizing radiation-induced apoptosis by increasing p53 stability and decreasing AKT kinase activity through MDM2 and AKT degradation.
authors.affiliation: Radiation Health Research Institute, Korea Hydro & Nuclear Power Co., Ltd., Seoul 132-703, Republic of Korea.
authors.forename: Hae Mi
authors.initials: HM
authors.lastname: Joo
authors.forename: Ji Young
authors.initials: JY
authors.lastname: Kim
authors.forename: Jae Boon
authors.initials: JB
authors.lastname: Jeong
authors.forename: Ki Moon
authors.initials: KM
authors.lastname: Seong
authors.forename: Seon Young
authors.initials: SY
authors.lastname: Nam
authors.forename: Kwang Hee
authors.initials: KH
authors.lastname: Yang
authors.forename: Cha Soon
authors.initials: CS
authors.lastname: Kim
authors.forename: Hee Sun
authors.initials: HS
authors.lastname: Kim
authors.forename: Meeseon
authors.initials: M
authors.lastname: Jeong
authors.forename: Sungkwan
authors.initials: S
authors.lastname: An
authors.forename: Young Woo
authors.initials: YW
authors.lastname: Jin
mesh_terms: D017209:Apoptosis / Q000528:radiation effects*; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D057809:HEK293 Cells; D006801:Humans; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism*; D051736:Proto-Oncogene Proteins c-mdm2 / Q000235:genetics / Q000378:metabolism*; D011839:Radiation, Ionizing; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D004268:DNA-Binding Proteins; D011993:Recombinant Fusion Proteins; C112217:TRIM13 protein, human; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2; D051057:Proto-Oncogene Proteins c-akt; D046988:Proteasome Endopeptidase Complex