TY - JOUR
T1 - The Ski protein negatively regulates Siah2-mediated HDAC3 degradation
AU - Zhao, Hong Ling
AU - Ueki, Nobuhide
AU - Hayman, Michael J.
N1 - Funding Information:
The authors thank the members of the Hayman laboratory for helpful discussions and criticisms on the manuscript. This work was supported by US Public Health Service Grant CA42573 from the National Cancer Institute to M.J.H. and T32-CA009176 (N.U.). The authors also thank Dr. D. Bar-Sagi from New York University for kindly providing Flag-Siah2 and Flag-Siah2 (RM) constructs.
PY - 2010/9
Y1 - 2010/9
N2 - Ski acts as a transcriptional co-repressor by multiple direct and indirect interactions with several distinct repression complexes. Ski represses retinoic acid (RA) signaling by interacting with, and stabilizing, key components of the co-repressor complex, namely, HDAC3. However, little is known as to how the Ski protein can stabilize HDAC3. In the present study, we identified the Siah2 protein as a potential E3 ubiquitin ligase that mediated proteasomal degradation of HDAC3. Reciprocal co-immunoprecipitation assays further revealed that Ski interacts with Siah2. Furthermore, co-expression of the Ski protein stabilized the level of Siah2 protein. Since Siah2 regulates its own level of expression by self-degradation, the stabilization of Siah2 by Ski is an indication that Ski association leads to inhibition of Siah2 E3 ubiquitin ligase activity. Only wild-type Ski and Ski truncation mutants that were in the same complex with Siah2 could stabilize HDAC3 levels. Taken together, the results suggest that association with Ski leads to inhibition of Siah2 E3 ubiquitin ligase activity and in this way, the Ski protein inhibits Siah2-mediated proteasomal degradation of HDAC3.
AB - Ski acts as a transcriptional co-repressor by multiple direct and indirect interactions with several distinct repression complexes. Ski represses retinoic acid (RA) signaling by interacting with, and stabilizing, key components of the co-repressor complex, namely, HDAC3. However, little is known as to how the Ski protein can stabilize HDAC3. In the present study, we identified the Siah2 protein as a potential E3 ubiquitin ligase that mediated proteasomal degradation of HDAC3. Reciprocal co-immunoprecipitation assays further revealed that Ski interacts with Siah2. Furthermore, co-expression of the Ski protein stabilized the level of Siah2 protein. Since Siah2 regulates its own level of expression by self-degradation, the stabilization of Siah2 by Ski is an indication that Ski association leads to inhibition of Siah2 E3 ubiquitin ligase activity. Only wild-type Ski and Ski truncation mutants that were in the same complex with Siah2 could stabilize HDAC3 levels. Taken together, the results suggest that association with Ski leads to inhibition of Siah2 E3 ubiquitin ligase activity and in this way, the Ski protein inhibits Siah2-mediated proteasomal degradation of HDAC3.
KW - Co-repressor complex
KW - HDAC3
KW - Proteasomal degradation
KW - Siah2
KW - Ski
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U2 - 10.1016/j.bbrc.2010.07.127
DO - 10.1016/j.bbrc.2010.07.127
M3 - Article
C2 - 20691163
AN - SCOPUS:77956262579
SN - 0006-291X
VL - 399
SP - 623
EP - 628
JO - Biochemical and Biophysical Research Communications
JF - Biochemical and Biophysical Research Communications
IS - 4
ER -