SUMO-specific protease SUSP4 positively regulates p53 by promoting Mdm2 self-ubiquitination.
The p53 tumour suppressor has a key role in the control of cell growth and differentiation, and in the maintenance of genome integrity. p53 is kept labile under normal conditions, but in response to stresses, such as DNA damage, it accumulates in the nucleus for induction of cell-cycle arrest, DNA repair or apoptosis. Mdm2 is an ubiquitin ligase that promotes p53 ubiquitination and degradation. Mdm2 is also self-ubiquitinated and degraded. Here, we identified a novel cascade for the increase in p53 level in response to DNA damage. A new SUMO-specific protease, SUSP4, removed SUMO-1 from Mdm2 and this desumoylation led to promotion of Mdm2 self-ubiquitination, resulting in p53 stabilization. Moreover, SUSP4 competed with p53 for binding to Mdm2, also resulting in p53 stabilization. Overexpression of SUSP4 inhibited cell growth, whereas knockdown of susp4 by RNA interference (RNAi) promoted of cell growth. UV damage induced SUSP4 expression, leading to an increase in p53 levels in parallel with a decrease in Mdm2 levels. These findings establish a new mechanism for the elevation of cellular p53 levels in response to UV damage.
Lee
Moon Hee
MH
NRL of Protein Biochemistry, School of Biological Sciences, Seoul National University, Seoul 151-742, Korea.
Lee
Sung Won
SW
Lee
Eun Joo
EJ
Choi
Soo Joon
SJ
Chung
Sung Soo
SS
Lee
Jae Il
JI
Cho
Joong Myung
JM
Seol
Jae Hong
JH
Baek
Sung Hee
SH
Kim
Keun Il
KI
Chiba
Tomoki
T
Tanaka
Keiji
K
Bang
Ok Sun
OS
Chung
Chin Ha
CH
D000818:Animals; D048708:Cell Growth Processes / Q000528:radiation effects; D003546:Cysteine Endopeptidases / Q000235:genetics / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000528:radiation effects; D006801:Humans; D051379:Mice; D008954:Models, Biological; D008969:Molecular Sequence Data; D041681:NIH 3T3 Cells; D011485:Protein Binding / Q000528:radiation effects; D021381:Protein Transport / Q000528:radiation effects; D051736:Proto-Oncogene Proteins c-mdm2 / Q000172:deficiency / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D025841:Small Ubiquitin-Related Modifier Proteins / Q000378:metabolism*; D013816:Thermodynamics; D016159:Tumor Suppressor Protein p53 / Q000172:deficiency / Q000378:metabolism*; D025801:Ubiquitin / Q000378:metabolism*; D014466:Ultraviolet Rays
D012333:RNA, Messenger; D025841:Small Ubiquitin-Related Modifier Proteins; D016159:Tumor Suppressor Protein p53; D025801:Ubiquitin; C497207:Mdm2 protein, mouse; D051736:Proto-Oncogene Proteins c-mdm2; D003546:Cysteine Endopeptidases; C515978:SUSP4 protein, mouse