C/EBPβ Activates E2F-regulated Genes in Vivo via Recruitment of the Coactivator CREB-binding Protein/P300

Wang, Haitao; Larris, Brian; Peiris, T. Harshani; Zhang, Liping; Lay, John Le; Gao, Yan; Greenbaum, Linda E.

doi:10.1074/jbc.m705066200

Cited by 43 publications

(29 citation statements)

References 59 publications

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“…Three separate studies with mRNA array analysis have shown that genes involved in liver regeneration change in groups following different dynamic patterns (17)(18)(19). Most up-regulated genes are involved in stress responses, nutrition and energy metabolism, cell cycle, and proliferation (18,20). We used a quantitative RT-PCR array to verify up-regulation of genes involved in cell cycle and proliferation and found that many cyclins and CDKs were up-regulated 2 days after 50% PH, which was in accordance with positive staining of PCNA and Ki67 in both SSLG and remaining livers, and upregulated cyclin G1 expression.…”

Section: Discussionmentioning

confidence: 99%

miRNA Regulation of Liver Growth After 50% Partial Hepatectomy and Small Size Grafts in Rats

et al. 2011

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Background. The molecular mechanisms underlying the growth of small size grafts and the remaining livers are poorly understood. MicroRNAs (miRNAs) negatively modulate expression of genes that are involved in cellular function and metabolism. The aim of this study is to identify critical miRNA species that modulate the growth of small grafts and the remaining livers after partial hepatectomy (PH). Methods. Small size graft liver transplantation was performed in rats. Liver tissue was harvested after transplant or PH for the determination of miRNA expression profile, and the data were confirmed by quantitative reverse-transcriptase polymerase chain reaction. The genes involved in cell cycle and proliferation were analyzed by quantitative reversetranscriptase polymerase chain reaction and immunohistochemical staining. Results. Compared with control liver, miR_122a, Let_7b, and miR_26a were reduced by more than 90% in 45% volume grafts. In the remaining livers after 50% PH, 30 miRNAs were down-regulated by more than 50%, and among them, miR_22a, miR_26a, miR_30b, Let_7f, and Let_7g were markedly decreased. A negative correlation existed between down-regulated miRNAs and highly up-regulated genes involved in cell cycle and proliferation in the remaining livers. Moreover, overexpression of miR_26a markedly down-regulated cyclin E2 protein levels and significantly decreased proliferation of HepG2 cells. Conclusion. Down-regulated miRNAs play a pivotal role in promoting the growth of small size grafts and the remaining livers. The negative correlation between down-regulated miRNAs and up-regulated genes suggests that these specific miRNAs participate in the modulation of a growth response in both living donors and small size graft recipients.

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Section: Discussionmentioning

confidence: 99%

miRNA Regulation of Liver Growth After 50% Partial Hepatectomy and Small Size Grafts in Rats

et al. 2011

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“…Cells without NPAT fail to enter S phase from quiescence (20). CBP/p300 is another protein phosphorylated by cyclin E/Cdk2 at G 1 /S transition to activate its histone acetyltransferase activity (21) and may function as a cofactor for many transcription factors including E2F (22). Interestingly, cyclin E/Cdk2 phosphorylates E2F-5 and increases its transcriptional activity through CBP/p300 recruitment (23).…”

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confidence: 99%

Identification and Functional Analysis of a Novel Cyclin E/Cdk2 Substrate Ankrd17

Deng

Ballif

et al. 2009

Journal of Biological Chemistry

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Cyclin E/Cdk2 is a key regulator in G 1 -S transition. We have identified a novel cyclin E/Cdk2 substrate called Ankrd17 (ankyrin repeat protein 17) using the TAP tag purification technique. Ankrd17 protein contains two clusters of a total 25 ankyrin repeats at its N terminus, one NES (nuclear exporting signal) and one NLS (nuclear localization signal) in the middle, and one RXL motif at its C terminus. Ankrd17 is expressed in various tissues and associates with cyclin E/Cdk2 in an RXL-dependent manner. It can be phosphorylated by cyclin E/Cdk2 at 3 phosphorylation sites (Ser 1791 , Ser 1794 , and Ser 2150 ). Overexpression of Ankrd17 promotes S phase entry, whereas depletion of Ankrd17 expression by small interfering RNA inhibits DNA replication and blocks cell cycle progression as well as up-regulates the expression of p53 and p21. Ankrd17 is localized to the nucleus and interacts with DNA replication factors including MCM family members, Cdc6 and PCNA. Depletion of Ankrd17 results in decreased loading of Cdc6 and PCNA onto DNA suggesting that Ankrd17 may be directly involved in the DNA replication process. Taken together, these data indicate that Ankrd17 is an important downstream effector of cyclin E/Cdk2 and positively regulates G 1 /S transition.Progression through the cell cycle is driven by the sequential and periodic activation of cyclin/Cdk complexes. Cyclin D/Cdk4/6 4 complexes are active throughout the G 1 phase, cyclin E/Cdk2 at the G 1 /S boundary, cyclin A/Cdk2 during S phase, and cyclin A/Cdk1 and cyclin B/Cdk1 during the G 2 /M transition. Cyclin E/Cdk2 plays a central role in coordinating both the onset of S phase and centrosome duplication in cell cycle (1-4). It presumably exerts most of its biologic activities by phosphorylating its substrates, most frequently through the RXL motif in the substrate that interacts with the cyclin box (5-8). A number of RXL-containing proteins are themselves cell cycle regulatory proteins. In the case of pRb, cyclin E/Cdk2-mediated Rb phosphorylation inactivates Rb by derepressing E2F transcription factors (9, 10), whereas in the case of p27, phosphorylation of p27 by cyclin E/Cdk2 stimulates its degradation by the SCF-Skp2 ubiquitin ligase (11-15).There are a number of proteins identified as cyclin E/Cdk2 substrates that regulate cell division. NPAT is a transcription factor that controls cell cycle-dependent histone gene transcription. The phosphorylation of NPAT by cyclin E/Cdk2 promotes histone transcription (16 -19). Cells without NPAT fail to enter S phase from quiescence (20). CBP/p300 is another protein phosphorylated by cyclin E/Cdk2 at G 1 /S transition to activate its histone acetyltransferase activity (21) and may function as a cofactor for many transcription factors including E2F (22). Interestingly, cyclin E/Cdk2 phosphorylates E2F-5 and increases its transcriptional activity through CBP/p300 recruitment (23). Cyclin E/Cdk2 also phosphorylates centrosomal proteins that regulate centrosome duplication. Phosphorylation of nucleophosmin (NPM) by cyc...

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“…Previous studies have shown that C/EBP␤ may recruit other factors. C/EBP␤ binds to CREB binding protein/p300, and the complex regulates the expression of target genes, such as CD-RAP and E2F, by modifying chromatin structure via histone acetylation (40,41). It was also reported that C/EBP␤ can directly bind various regulators, such as NF-B, activating transcription factor, Fos, Jun, and Sp-1, by assisting other important transcription factors to bind DNA (42)(43)(44).…”

Section: Discussionmentioning

confidence: 99%

CCAAT/ENHANCER binding protein β mediates expression of matrix metalloproteinase 13 in human articular chondrocytes in inflammatory arthritis

Hayashida¹,

Okazaki²,

Fukushi³

et al. 2009

Arthritis & Rheumatism

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Objective. To determine the function of CCAAT/ enhancer binding protein ␤ (C/EBP␤) in the expression of matrix metalloproteinase 13 (MMP-13) in chondrocytes in inflammatory arthritis.Methods. Cartilage obtained from patients with rheumatoid arthritis and osteoarthritis was immunostained for expression of C/EBP␤ or MMP-13. Interleukin-1␤-or tumor necrosis factor ␣ (TNF␣)-stimulated chondrocytes were subjected to Western blotting and real-time reverse transcriptase-polymerase chain reaction (RT-PCR). MMP-13 promoter assays were conducted, and the C/EBP␤ response element was characterized by deletion and mutation analysis. C-28/I2 cells were treated with TNF␣ and subjected to chromatin immunoprecipitation (ChIP) assays. Finally, C/EBP␤-liver-enriched activator protein (LAP) was overexpressed in C-28/I2 cells or cartilage tissues, and MMP-13 expression was analyzed.Results. C/EBP␤ and MMP-13 expression was colocalized in chondrocytes in arthritic cartilage. MMP-13 promoter activity was stimulated by C/EBP␤ overexpression in a dose-dependent manner. Luciferase assays revealed that a -981-bp promoter had the greatest activity, while deletion to -936 bp strongly diminished promoter activity. Luciferase activity was repressed to basal levels by mutations in potential C/EBP binding sites. The stimulatory effects of C/EBP␤ overexpression were diminished by mutation. ChIP assays revealed that TNF␣ treatment enhanced the binding of C/EBP␤ to the MMP-13 promoter. When C/EBP␤-LAP was overexpressed in C-28/I2 cells, endogenous MMP-13 expression was stimulated up to 32-fold as detected by real-time RT-PCR. Furthermore, following adenoviral overexpression of C/EBP␤-LAP in organ culture of articular cartilage, stimulation of MMP-13 was also detected by immunohistochemistry. Conclusion. C/EBP␤ directly binds to the MMP-13 promoter region and stimulates the expression of MMP-13 in chondrocytes in inflammatory arthritis.Degeneration of articular cartilage is the principal process causing disability in patients with inflammatory arthritis, including those with rheumatoid arthritis (RA) (1,2) and osteoarthritis (OA) (3,4). Normally, maintenance of the cartilage extracellular matrix (ECM) is strictly regulated by the balance of anabolic and catabolic factors secreted by synovial cells or by chondrocytes themselves. Arthritic cartilage is characterized by excessive production of proteinases, such as matrix metalloproteinases (MMPs) and aggrecanases, and reduced synthesis of new matrix by chondrocytes, which disturbs the balance of anabolic and catabolic factors. Among the proteinases, MMP-13 cleaves a broad range of substrates, including fibrillar type II collagen and type II procollagen as well as gelatin, types I, III, IV, IX, X, and XIV collagen, tenascin, fibronectin, fibronectin fragments, and aggrecan (5-8). It has been reported that MMP-13 has the highest degradation activity for type II collagen (5,9). A recent study showed that up-regulated transgenic expression of MMP-13 in mouse articular cartilage resulted in pathologic chan...

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C/EBPβ Activates E2F-regulated Genes in Vivo via Recruitment of the Coactivator CREB-binding Protein/P300

Cited by 43 publications

References 59 publications

miRNA Regulation of Liver Growth After 50% Partial Hepatectomy and Small Size Grafts in Rats

miRNA Regulation of Liver Growth After 50% Partial Hepatectomy and Small Size Grafts in Rats

Identification and Functional Analysis of a Novel Cyclin E/Cdk2 Substrate Ankrd17

CCAAT/ENHANCER binding protein β mediates expression of matrix metalloproteinase 13 in human articular chondrocytes in inflammatory arthritis

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