Enigma negatively regulates p53 through MDM2 and promotes tumor cell survival in mice.
The human E3 ubiquitin ligase murine double minute 2 (MDM2) targets the tumor suppressor p53 for ubiquitination and degradation but also promotes its own ubiquitination and subsequent degradation. As the balance between MDM2 and p53 levels plays a crucial role in regulating cell proliferation and apoptosis, we sought to identify factors selectively inhibiting MDM2 self-ubiquitination. Here we have shown that the LIM domain protein Enigma directly interacts with MDM2 to form a ternary complex with p53 in vitro and in human hepatoma and colon carcinoma cell lines and mouse embryonic fibroblasts. We found that Enigma elicited p53 degradation by inhibiting MDM2 self-ubiquitination and increasing its ubiquitin ligase activity toward p53 in cells. Moreover, mitogenic stimuli such as serum, FGF, and HGF increased Enigma transcription via induction of serum response factor (SRF), leading to MDM2 stabilization and subsequent p53 degradation. We observed similar results in the livers of mice treated with HGF. In humans, we found SRF and Enigma coexpressed with MDM2 but not p53 in several liver and stomach tumors. Finally, we showed that Enigma promoted cell survival and chemoresistance by suppressing p53-mediated apoptosis in both cell lines and a mouse xenograft model. Our findings suggest a role for Enigma in tumorigenesis and uncover a mechanism whereby mitogens attenuate p53 antiproliferative activity through an SRF/Enigma/MDM2 pathway.
Gene Therapy Research Unit, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon, South Korea.
Cho-Rok
CR
Jung
Jung Hwa
JH
Lim
Yoonjung
Y
Choi
Dae-Ghon
DG
Kim
Koo Jeong
KJ
Kang
Seung-Moo
SM
Noh
Dong-Soo
DS
Im
D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D017209:Apoptosis; D001483:Base Sequence; D045744:Cell Line, Tumor; D002470:Cell Survival; D002478:Cells, Cultured; D015179:Colorectal Neoplasms / Q000378:metabolism / Q000473:pathology; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism; D003598:Cytoskeletal Proteins; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D060588:LIM Domain Proteins; D051379:Mice; D018345:Mice, Knockout; D009369:Neoplasms / Q000378:metabolism* / Q000473:pathology; D051736:Proto-Oncogene Proteins c-mdm2 / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000235:genetics; D015398:Signal Transduction; D013274:Stomach Neoplasms / Q000378:metabolism / Q000473:pathology; D016159:Tumor Suppressor Protein p53 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D054875:Ubiquitination
D048868:Adaptor Proteins, Signal Transducing; C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D003598:Cytoskeletal Proteins; D047908:Intracellular Signaling Peptides and Proteins; D060588:LIM Domain Proteins; C484380:PDLIM7 protein, human; C484381:Pdlim7 protein, mouse; D034741:RNA, Small Interfering; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; C497206:MDM2 protein, human; C497207:Mdm2 protein, mouse; D051736:Proto-Oncogene Proteins c-mdm2