Bcl3-dependent stabilization of CtBP1 is crucial for the inhibition of apoptosis and tumor progression in breast cancer.
B-cell lymphoma 3 (Bcl3) is a proto-oncogene upregulated in a wide range of cancers, including breast cancer. Although Bcl3 is known to promote cell proliferation and inhibit apoptosis, the molecular mechanisms underlying the proto-oncogenic function of Bcl3 have not been completely elucidated. To gain insight into the oncogenic role of Bcl3, we applied a proteomic approach, which led to the identification of C-terminal binding protein 1 (CtBP1) as a binding partner of Bcl3. A PXDLS/R motif embedded in Bcl3 was found to mediate the interaction between Bcl3 and CtBP1, which caused the stabilization of CtBP1 by blocking proteasome-dependent degradation. Apoptotic stimuli-induced degradation of CtBP1 was significantly abolished by the upregulation of Bcl3, leading to the sustained repression of pro-apoptotic gene expression and subsequent inhibition of apoptosis. Intriguingly, a strong positive correlation between the protein levels of Bcl3 and CtBP1 was detected in breast cancer patient samples. Our study reveals a novel combinatorial role for Bcl3 and CtBP1, providing an explanation for the acquisition of resistance to apoptosis in cancer cells, which is a major requirement for cancer development.
Choi
Hee June
HJ
Department of Biological Sciences, Creative Research Initiative Center for Chromatin Dynamics, Seoul National University, Seoul 151-742, South Korea.
Lee
Ji Min
JM
Kim
Hyunkyung
H
Nam
Hye Jin
HJ
Shin
Hi-Jai R
HJ
Kim
Dongha
D
Ko
Enyoung
E
Noh
Dong-Young
DY
Kim
Keun Il
KI
Kim
Jung Hwa
JH
Baek
Sung Hee
SH
D000429:Alcohol Oxidoreductases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D017209:Apoptosis; D000081242:B-Cell Lymphoma 3 Protein; D001943:Breast Neoplasms / Q000378:metabolism / Q000473:pathology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D004795:Enzyme Stability; D005260:Female; D006801:Humans; D000090063:Proto-Oncogene Mas; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D014157:Transcription Factors / Q000378:metabolism*; D054875:Ubiquitination
D000081242:B-Cell Lymphoma 3 Protein; C000631344:BCL3 protein, human; D004268:DNA-Binding Proteins; C000715470:MAS1 protein, human; D000090063:Proto-Oncogene Mas; D011518:Proto-Oncogene Proteins; D014157:Transcription Factors; D000429:Alcohol Oxidoreductases; C096794:C-terminal binding protein