The RING domain of Mdm2 can inhibit cell proliferation.
Mdm2 is a p53-inducible phosphoprotein that negatively regulates p53 by binding to it and promoting its ubiquitin-mediated degradation. Alternatively spliced variants of Mdm2 have been isolated from human and mouse tumors, but their roles in tumorigenesis, if any, remain elusive. We cloned six alternatively spliced variants of Mdm2 from E(mu)-Myc-induced mouse lymphomas, all of which lacked the NH(2)-terminal p53-binding domain but conserved the remainder of the Mdm2 protein. Enforced expression of full-length Mdm2 in primary mouse embryo fibroblasts or bone marrow-derived, interleukin 7-dependent pre-B cells accelerated their proliferation, whereas unexpectedly, overexpression of truncated Mdm2 isoforms inhibited their growth. Truncated variants were active as inhibitors whether they localized predominantly to the nucleus or cytoplasm. Despite the absence of the p53-binding domain, growth inhibition remained strictly p53 dependent (but not p19(Arf) dependent) and could be overcome by full-length Mdm2. The intact RING finger domain at the Mdm2 COOH terminus (amino acids 399-489) was necessary and sufficient for growth inhibition by truncated Mdm2 proteins and could physically interact with either the RING finger domain or central acidic region of full-length Mdm2. However, such interactions do not inhibit Mdm2 E3 ubiquitin ligase activity in vitro using p53 as a substrate. Expression of growth-inhibitory Mdm2 isoforms in tumors remains an enigma.
Dang
Jinjun
J
Department of Tumor Cell Biology, St. Jude Children's Research Hospital, Memphis, Tennessee 38105, USA.
Kuo
Mei-Ling
ML
Eischen
Christine M
CM
Stepanova
Lilia
L
Sherr
Charles J
CJ
Roussel
Martine F
MF
D017398:Alternative Splicing; D000818:Animals; D002455:Cell Division / Q000502:physiology; D006131:Growth Inhibitors / Q000235:genetics / Q000502:physiology; D008223:Lymphoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D051379:Mice; D009687:Nuclear Proteins; D020033:Protein Isoforms; D017434:Protein Structure, Tertiary; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000502:physiology*; D051736:Proto-Oncogene Proteins c-mdm2; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D025801:Ubiquitin / Q000378:metabolism
D006131:Growth Inhibitors; D009687:Nuclear Proteins; D020033:Protein Isoforms; D011518:Proto-Oncogene Proteins; D016159:Tumor Suppressor Protein p53; D025801:Ubiquitin; C497207:Mdm2 protein, mouse; D051736:Proto-Oncogene Proteins c-mdm2