Nature Cell Biology
- 8, 1424 - 1431 (2006)
Published online: 5 November 2006; | doi:10.1038/ncb1512
SUMO-specific protease SUSP4 positively regulates p53 by promoting Mdm2 self-ubiquitinationMoon Hee Lee1, Sung Won Lee1, Eun Joo Lee1, Soo Joon Choi1, Sung Soo Chung1, Jae Il Lee2, Joong Myung Cho2, Jae Hong Seol1, Sung Hee Baek1, Keun Il Kim3, Tomoki Chiba4, Keiji Tanaka4, Ok Sun Bang1 & Chin Ha Chung1
NRL of Protein Biochemistry, School of Biological Sciences, Seoul National University, Seoul 151-742, Korea.
Crystalgenomics Inc., Seoul 138-736, Korea.
Department of Biological Sciences, Sookmyung Woman's University, Seoul 140-742, Korea.
Tokyo Metropolitan Institute of Medical Sciences, Tokyo 113, Japan.
Correspondence should be addressed to Chin Ha Chung chchung@snu.ac.kr or Ok Sun Bang osbang@snu.ac.kr The p53 tumour suppressor has a key role in the control of cell growth and differentiation, and in the maintenance of genome integrity1,
2. 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 degradation3,
4,
5. 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.
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