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Role of cdk2 in the sequential phosphorylation/activation of C/EBPbeta during adipocyte differentiation.

ABSTRACT: Upon induction of differentiation, growth-arrested (G(1) phase) 3T3-L1 preadipocytes express CCAAT/enhancer binding protein-beta (C/EBPbeta), initiating a transcriptional cascade. C/EBPbeta immediately undergoes a priming phosphorylation (on Thr(188)) by MAPK/ERK. However, the acquisition of DNA binding and transactivation capacity of C/EBPbeta is delayed until further phosphorylation (on Ser(184) or Thr(179)) by GSK3beta occurs. Phosphorylation by glycogen synthase kinase-3beta (GSK3beta) induces S phase entry and thereby mitotic clonal expansion (MCE), a requirement for terminal differentiation. Because MAPK activity is down-regulated before S phase is completed, we sought to identify the kinase that maintains C/EBPbeta in the primed phosphorylated state throughout S phase and MCE. We show here that cdk2/cyclinA, whose expression is activated at the onset of S phase, functions in this capacity. Ex vivo and in vitro experiments show that cdk2/cyclinA catalyzes this delayed priming phosphorylation. Mass spectrometric analysis revealed that cdk2/cyclinA phosphorylates C/EBPbeta on Thr(188) and is required for phosphorylation (on Ser(184) or Thr(179)) of C/EBPbeta by GSK3beta and maintenance of DNA binding activity. Suppression of cdk2 activity by RNA interference or pharmacologic inhibitor disrupts subsequent events in the differentiation program. Thus, MAPK and cdk2/cyclinA act sequentially to maintain Thr(188) of C/EBPbeta in the primed phosphorylated state during MCE and thereby progression of terminal differentiation.

SUBMITTER: Li X

PROVIDER: S-EPMC1913868 | biostudies-other | 2007 Jul

REPOSITORIES: biostudies-other

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Role of cdk2 in the sequential phosphorylation/activation of C/EBPbeta during adipocyte differentiation.

Li Xi X Kim Jae Woo JW Grønborg Mads M Urlaub Henning H Lane M Daniel MD Tang Qi-Qun QQ

Proceedings of the National Academy of Sciences of the United States of America 20070629 28

Upon induction of differentiation, growth-arrested (G(1) phase) 3T3-L1 preadipocytes express CCAAT/enhancer binding protein-beta (C/EBPbeta), initiating a transcriptional cascade. C/EBPbeta immediately undergoes a priming phosphorylation (on Thr(188)) by MAPK/ERK. However, the acquisition of DNA binding and transactivation capacity of C/EBPbeta is delayed until further phosphorylation (on Ser(184) or Thr(179)) by GSK3beta occurs. Phosphorylation by glycogen synthase kinase-3beta (GSK3beta) induc ...[more]

PMID: 17601773

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Project description:The yak (Bos grunniens) is subjected to nutritional deficiency during the whole winter grazing season; deciphering the adipose metabolism and energy homeostasis under cold and nutrients stress conditions could be a novel way to understand the specific mechanism of energy metabolism. Circular RNAs (circRNAs) have elucidated that they play a key role in many biological events, but the regulatory function of adipose development remains mostly unknown. Therefore, the expression pattern of circRNAs were identified for the first time during yak adipocyte differentiation to gain insight into their potential functional involvement in bovine adipogenesis. We detected 7203 circRNA candidates, most of them contained at least two exons, and multiple circRNA isoforms could be generated from one parental gene. Analysis of differential expression circRNAs displayed that 136 circRNAs were differentially expressed at day 12 (Ad) after adipocyte differentiation, compared with the control at day 0 (Pread 0), while 7 circRNAs were detected on day 2. Sanger sequencing validated that six circRNAs had head-to-tail junction, and quantitative real-time PCR (qPCR) results revealed that the expression patterns of ten circRNAs were consistent with their expression levels from RNA-sequencing (RNA-seq) data. We further predicted the networks of circRNA-miRNA-gene based on miRNAs sponging by circRNAs, in which genes were participated in the adipocyte differentiation-related signaling pathways. After that, we constructed several adipocyte differentiation-related ceRNAs and revealed six circRNAs (novel_circ_0009127, novel_circ_0000628, novel_circ_0011513, novel_circ_0010775, novel_circ_0006981 and novel_circ_0001494) were related to adipogenesis. Furthermore, we analyzed the homology among yak, human and mouse circRNAs and found that 3536 yak circRNAs were homologous to human and mouse circRNAs. In conclusion, these findings provide a solid basis for the investigation of yak adipocyte differentiation-related circRNAs and serve as a great reference to study the energy metabolism of high-altitude animals.

Dataset Information

Role of cdk2 in the sequential phosphorylation/activation of C/EBPbeta during adipocyte differentiation.

Publications

Role of cdk2 in the sequential phosphorylation/activation of C/EBPbeta during adipocyte differentiation.

Similar Datasets

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