SENP3-mediated de-conjugation of SUMO2/3 from promyelocytic leukemia is correlated with accelerated cell proliferation under mild oxidative stress.
Small ubiquitin-like modifier (SUMO) 2/3 is known to conjugate to substrates in response to a variety of cellular stresses. However, whether and how SUMO2/3-specific proteases are involved in de-conjugation under cell stress is unclear. Here, we show that low doses of hydrogen peroxide (H(2)O(2)) induce an increase of the SENP3 protein, which removes SUMO2/3 from promyelocytic leukemia (PML). Low dose H(2)O(2) causes SENP3 to co-localize with PML bodies and reduces the number of PML bodies in a SENP3-dependent manner. Furthermore, de-conjugation of SUMO2/3 from PML is responsible for the accelerated cell proliferation caused by low dose H(2)O(2). Knocking down PML promotes basal cell proliferation as expected. This can be reversed by reconstitution with wild-type PML but not its mutant lacking SUMOylation, indicating that only the SUMOylated PML can play an inhibitory role for cell proliferation. Thus, SENP3 appears to be a key mediator in mild oxidative stress-induced cell proliferation via regulation of the SUMOylation status of PML. Furthermore, SENP3 is over-accumulated in a variety of primary human cancers including colon adenocarcinoma in which PML is hypo-SUMOylated. These results reveal an important role of SENP3 and the SUMOylation status of PML in the regulation of cell proliferation under oxidative stress.
Han
Yan
Y
Department of Cell Biology, Key Laboratory of the Education Ministry for Cell Differentiation and Apoptosis, Institutes of Medical Sciences, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.
Huang
Chao
C
Sun
Xuxu
X
Xiang
Binggang
B
Wang
Ming
M
Yeh
Edward T H
ET
Chen
Yuying
Y
Li
Hui
H
Shi
Guiying
G
Cang
Hui
H
Sun
Yueping
Y
Wang
Jian
J
Wang
Wei
W
Gao
Fei
F
Yi
Jing
J
D000230:Adenocarcinoma / Q000235:genetics / Q000378:metabolism; D000818:Animals; D049109:Cell Proliferation; D003110:Colonic Neoplasms / Q000235:genetics / Q000378:metabolism; D003546:Cysteine Endopeptidases / Q000235:genetics / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D055785:Gene Knockdown Techniques; D006367:HeLa Cells; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology; D051379:Mice; D041681:NIH 3T3 Cells; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D016877:Oxidants / Q000494:pharmacology; D018384:Oxidative Stress; D000071156:Promyelocytic Leukemia Protein; D011499:Protein Processing, Post-Translational; D025841:Small Ubiquitin-Related Modifier Proteins / Q000235:genetics / Q000378:metabolism*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism*; D014452:Ubiquitins / Q000235:genetics / Q000378:metabolism*
D009687:Nuclear Proteins; D016877:Oxidants; D000071156:Promyelocytic Leukemia Protein; C117909:SUMO2 protein, human; C492189:SUMO3 protein, human; D025841:Small Ubiquitin-Related Modifier Proteins; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins; D014452:Ubiquitins; C070576:PML protein, human; D006861:Hydrogen Peroxide; D003546:Cysteine Endopeptidases; C499718:SENP3 protein, human