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The RelA/p65 subunit of NF‐κB specifically regulates cyclin D1 protein stability: Implications for cell cycle withdrawal and skeletal myogenesis
Author(s) -
Dahlman Jason M.,
Wang Jingxin,
Bakkar Nadine,
Guttridge Denis C.
Publication year - 2008
Publication title -
journal of cellular biochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.028
H-Index - 165
eISSN - 1097-4644
pISSN - 0730-2312
DOI - 10.1002/jcb.21976
Subject(s) - cyclin d1 , cyclin a2 , cyclin d , cyclin a , cyclin b , microbiology and biotechnology , cell cycle , biology , cyclin , downregulation and upregulation , cyclin e , protein subunit , cancer research , cell , genetics , gene
Studies support that NF‐κB functions in cellular growth through the transcriptional regulation of cyclin D1, but whether such regulation is attributed to a single NF‐κB subunit remains unclear. To address this issue we examined endogenous cyclin D1 levels during cell cycle re‐entry in mouse embryonic fibroblasts (MEFs) lacking specific NF‐κB signaling subunits. Results showed that each of these subunits were dispensable for regulating cyclin D1 transcription. However, we found that resulting cyclin D1 protein was severely reduced in MEFs lacking only RelA/p65. Cyclohexamide treatment revealed that this regulation was due to an increase in protein turnover. Similar downregulation of cyclin D1 protein, but not RNA, was observed in vivo in multiple tissues lacking RelA/p65. Co‐immunoprecipitation analysis also showed that RelA/p65 and cyclin D1 were capable of interacting, thus providing a possible explanation for cyclin D1 protein stability. In addition, although the decrease in cyclin D1 in RelA/p65 −/− MEFs was concomitant with lower CDK4 activity during cell cycle re‐entry, this was not sufficient to affect S phase progression. Nevertheless, similar decreases in cyclin D1 protein in primary RelA/p65 −/− myoblasts was adequate to accelerate cell cycle exit and differentiation of these cells. Based on these findings we conclude that RelA/p65 functions as a specific regulator of cyclin D1 protein stability, necessary for proper cell cycle withdrawal during skeletal myogenesis. J. Cell. Biochem. 106: 42–51, 2009. © 2008 Wiley‐Liss, Inc.