Cdk2-dependent Phosphorylation of the NF-Y Transcription Factor and Its Involvement in the p53-p21 Signaling Pathway

Yun, Jeanho; Chae, Hee-Don; Choi, Tae-Saeng; Kim, Eunhee; Bang, Yung‐Jue; Chung, JongkyeongK; Choi, Kyeong-Sook; Mantovani, Roberto; Shin, Deug Y.

doi:10.1074/jbc.m305178200

Cited by 78 publications

(78 citation statements)

References 40 publications

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“…immunoprecipitation (IP)-kinase assay showed that while both Cdk2 and Cdc2 were not detected in HCT116 cells, both kinases remain unchanged in p53-and p21-knockout cells following PTX-2 treatment (Figure 1c). Therefore, inactivation of Cdk2 and Cdc2 kinases in p53-positive cells should be due to p21-mediated inhibition, supporting our previous report that p21-mediated Cdk2 inhibition lead to Cdc2 inactivation (Yun et al, 2003;Chae et al, 2004).…”

Section: Actin Inhibitors Activate P53-signaling Pathwaysupporting

confidence: 88%

Deregulation of Cdk2 causes Bim-mediated apoptosis in p53-deficient tumors following actin damage

et al. 2008

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Section: Actin Inhibitors Activate P53-signaling Pathwaysupporting

confidence: 88%

Deregulation of Cdk2 causes Bim-mediated apoptosis in p53-deficient tumors following actin damage

et al. 2008

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“…To confirm whether the expression of YA or YA-aa affects DNA-binding activity of NF-Y, we performed a gel shift assay ( Figure (Yun et al, 2003).…”

Section: Resultsmentioning

confidence: 99%

“…Furthermore, the DNA-binding activity of NF-Y is decreased by p53 (Jung et al, 2001). Moreover, we recently reported that cdk2 phosphorylates two serine residues near DNA-binding domain of YA subunit of NF-Y (Yun et al, 2003). Although YA phosphorylation had no effect on heterotrimer formation with the YB-YC dimer, it is necessary for efficient DNA binding of NF-Y (Yun et al, 2003).…”

mentioning

confidence: 95%

“…Moreover, we recently reported that cdk2 phosphorylates two serine residues near DNA-binding domain of YA subunit of NF-Y (Yun et al, 2003). Although YA phosphorylation had no effect on heterotrimer formation with the YB-YC dimer, it is necessary for efficient DNA binding of NF-Y (Yun et al, 2003). In this study, we examined the effects of a phosphorylation-deficient mutant form of YA, YA-aa, in which the two serine residues that are phosphorylated by cdk2 are replaced with alanine.…”

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confidence: 99%

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Cdk2-dependent phosphorylation of the NF-Y transcription factor is essential for the expression of the cell cycle-regulatory genes and cell cycle G1/S and G2/M transitions

et al. 2004

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We previously reported that cdk2 phosphorylates two serine residues near the DNA-binding domain of the YA subunit of NF-Y transcription factor and this phosphorylation is essential for DNA binding of NF-Y. In this study, we examined the effects of a phosphorylationdeficient mutant form of YA, YA-aa, in which the two serine residues are replaced with alanine, on the cell cycle and expression of the NF-Y target genes. Transient transfection assays show that YA-aa inhibits transcription from the NF-Y target promoters, such as cdc2, cyclin A, and cdc25C. Moreover, this inhibitory function of YA-aa can be suppressed by the expression of wild-type YA, implying that YA-aa inhibits transcription of those NF-Y target genes by inactivating wild-type YA. Since NF-Y target genes include the cell cycle-regulatory genes that ensure orderly progression of the cell cycle, we examined the effects of YA-aa in cell cycle progression. We constructed a recombinant adenovirus encoding YA-aa and found that YA-aa expression leads to repression of cell cycle-regulatory genes, such as cyclin A, RNR R2, DNA polymerase a, cdc2, cyclin B, and cdc25C. Consistently, YA-aa expression results in the inactivation of both cdc2 and cdk2. Furthermore, cell cycle analysis reveals that YA-aa induces cell cycle arrest at both G1 and G2/M. These results suggest that cdk2-dependent phosphorylation of NF-Y is essential for the expression of the cell cycle-regulatory genes and therefore for cell cycle progression at both G1/S and G2/M.

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“…Cyclin A/Cdk2 complex is required during S phase, 38 which coincides with increasing topoIIa expression. Cyclin A has been shown to phosphorylate and activate NF-YA, 43 the transcription factor that binds to ICBs and activates topoIIa promoter. 44 Furthermore, interrupting the association between cyclin A and cdk2 can specifically suppress breast cancer cell growth.…”

Section: Discussionmentioning

confidence: 99%

Mutant Bik expression mediated by the enhanced minimal topoisomerase IIα promoter selectively suppressed breast tumors in an animal model

et al. 2006

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To ensure the success of systemic gene therapy, it is critical to enhance the tumor specificity and activity of the promoter. In the current study, we determined that topoisomerase IIa promoter is selectively activated in breast cancer cells. An element containing an inverted CCAAT box (ICB) was shown to be responsible for the breast cancer specificity. When the ICB-harboring topoisomerase IIa minimal promoter was linked with an enhancer sequence from the cytomegalovirus immediate early gene promoter (CMV promoter), this composite promoter, CT90, exhibited activity comparable to or higher than the CMV promoter in breast cancer cells in vitro and in vivo, yet expresses much lower activity in normal cell lines and normal organs than the CMV promoter. A CT90-driven construct expressing BikDD, a potent proapoptotic gene, was shown to selectively kill breast cancer cells in vitro, and to suppress mammary tumor development in an animal model of intravenously administrated, liposome-delivered gene therapy. Expression of BikDD was readily detectable in the tumors but not in the normal organs (such as heart) of CT90-BikDD-treated animals. The results indicate that liposomal CT90-BikDD is an effective systemic breast cancer-targeting gene therapy.

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Cdk2-dependent Phosphorylation of the NF-Y Transcription Factor and Its Involvement in the p53-p21 Signaling Pathway

Cited by 78 publications

References 40 publications

Deregulation of Cdk2 causes Bim-mediated apoptosis in p53-deficient tumors following actin damage

Deregulation of Cdk2 causes Bim-mediated apoptosis in p53-deficient tumors following actin damage

Cdk2-dependent phosphorylation of the NF-Y transcription factor is essential for the expression of the cell cycle-regulatory genes and cell cycle G1/S and G2/M transitions

Mutant Bik expression mediated by the enhanced minimal topoisomerase IIα promoter selectively suppressed breast tumors in an animal model

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