TY - JOUR
T1 - C/EBPδ targets cyclin D1 for proteasome-mediated degradation via induction of CDC27/APC3 expression
AU - Pawar, Snehalata A.
AU - Sarkar, Tapasree Roy
AU - Balamurugan, Kuppusamy
AU - Sharan, Shikha
AU - Wang, Jun
AU - Zhang, Youhong
AU - Dowdy, Steven F.
AU - Huang, A. Mei
AU - Sterneck, Esta
PY - 2010/5/18
Y1 - 2010/5/18
N2 - The transcription factor CCAAT/enhancer binding protein δ (C/EBPδ, CEBPD, NFIL-6δ) has tumor suppressor function; however, the molecular mechanism(s) by which C/EBPδ exerts its effect are largely unknown. Here, we report that C/EBPδ induces expression of the Cdc27 (APC3) subunit of the anaphase promoting complex/cyclosome (APC/C), which results in the polyubiquitination and degradation of the prooncogenic cell cycle regulator cyclin D1, and also down-regulates cyclin B1, Skp2, and Plk-1. In C/EBPδ knockout mouse embryo fibroblasts (MEF) Cdc27 levels were reduced, whereas cyclin D1 levels were increased even in the presence of activated GSK-3β. Silencing of C/EBPδ, Cdc27, or the APC/C coactivator Cdh1 (FZR1) in MCF-10A breast epithelial cells increased cyclin D1 protein expression. Like C/EBPδ, and in contrast to cyclin D1, Cdc27 was down-regulated in several breast cancer cell lines, suggesting that Cdc27 itself may be a tumor suppressor. Cyclin D1 is a known substrate of polyubiquitination complex SKP1/CUL1/F-box (SCF), and our studies show that Cdc27 directs cyclin D1 to alternative degradation by APC/C. These findings shed light on the role and regulation of APC/C, which is critical for most cellular processes.
AB - The transcription factor CCAAT/enhancer binding protein δ (C/EBPδ, CEBPD, NFIL-6δ) has tumor suppressor function; however, the molecular mechanism(s) by which C/EBPδ exerts its effect are largely unknown. Here, we report that C/EBPδ induces expression of the Cdc27 (APC3) subunit of the anaphase promoting complex/cyclosome (APC/C), which results in the polyubiquitination and degradation of the prooncogenic cell cycle regulator cyclin D1, and also down-regulates cyclin B1, Skp2, and Plk-1. In C/EBPδ knockout mouse embryo fibroblasts (MEF) Cdc27 levels were reduced, whereas cyclin D1 levels were increased even in the presence of activated GSK-3β. Silencing of C/EBPδ, Cdc27, or the APC/C coactivator Cdh1 (FZR1) in MCF-10A breast epithelial cells increased cyclin D1 protein expression. Like C/EBPδ, and in contrast to cyclin D1, Cdc27 was down-regulated in several breast cancer cell lines, suggesting that Cdc27 itself may be a tumor suppressor. Cyclin D1 is a known substrate of polyubiquitination complex SKP1/CUL1/F-box (SCF), and our studies show that Cdc27 directs cyclin D1 to alternative degradation by APC/C. These findings shed light on the role and regulation of APC/C, which is critical for most cellular processes.
KW - Anaphase promoting complex
KW - Breast cancer
KW - Cdh1/FZR1
KW - Cell cycle
KW - Tumor suppressor
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U2 - 10.1073/pnas.0913813107
DO - 10.1073/pnas.0913813107
M3 - Article
C2 - 20439707
AN - SCOPUS:77952718207
SN - 0027-8424
VL - 107
SP - 9210
EP - 9215
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
IS - 20
ER -