C/EBP{delta} targets cyclin D1 for proteasome-mediated degradation via induction of CDC27/APC3 expression.
The transcription factor CCAAT/enhancer binding protein delta (C/EBPdelta, CEBPD, NFIL-6beta) has tumor suppressor function; however, the molecular mechanism(s) by which C/EBPdelta exerts its effect are largely unknown. Here, we report that C/EBPdelta 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/EBPdelta knockout mouse embryo fibroblasts (MEF) Cdc27 levels were reduced, whereas cyclin D1 levels were increased even in the presence of activated GSK-3beta. Silencing of C/EBPdelta, Cdc27, or the APC/C coactivator Cdh1 (FZR1) in MCF-10A breast epithelial cells increased cyclin D1 protein expression. Like C/EBPdelta, 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.
Pawar
Snehalata A
SA
Center for Cancer Research, National Cancer Institute, Frederick, MD 21702-1201, USA.
Sarkar
Tapasree Roy
TR
Balamurugan
Kuppusamy
K
Sharan
Shikha
S
Wang
Jun
J
Zhang
Youhong
Y
Dowdy
Steven F
SF
Huang
A-Mei
AM
Sterneck
Esta
E
D000818:Animals; D064191:Apc3 Subunit, Anaphase-Promoting Complex-Cyclosome; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000378:metabolism*; D051743:CCAAT-Enhancer-Binding Protein-delta / Q000235:genetics / Q000378:metabolism*; D018797:Cell Cycle Proteins / Q000378:metabolism*; D045744:Cell Line, Tumor; D056744:Cyclin B1 / Q000378:metabolism; D019938:Cyclin D1 / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics* / Q000502:physiology; D047468:Immunoprecipitation; D051379:Mice; D018345:Mice, Knockout; D008856:Microscopy, Fluorescence; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D034622:RNA Interference; D020133:Reverse Transcriptase Polymerase Chain Reaction; D044786:S-Phase Kinase-Associated Proteins / Q000378:metabolism; D000097869:Polo-Like Kinase 1
D064191:Apc3 Subunit, Anaphase-Promoting Complex-Cyclosome; D051743:CCAAT-Enhancer-Binding Protein-delta; D018797:Cell Cycle Proteins; D056744:Cyclin B1; D019938:Cyclin D1; D046988:Proteasome Endopeptidase Complex; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D044786:S-Phase Kinase-Associated Proteins; D000097869:Polo-Like Kinase 1; C577367:CDC27 protein, mouse; C534700:Ccnb1 protein, mouse; C497253:Cebpd protein, mouse