p53 and Cell Cycle Dependent Transcription of kinesin family member 23 (KIF23) Is Controlled Via a CHR Promoter Element Bound by DREAM and MMB Complexes

Fischer, Martin; Grundke, Inga; Sohr, Sindy; Quaas, Marianne; Hoffmann, Saskia; Knörck, Arne; Gumhold, Catalina; Rother, Karen

doi:10.1371/journal.pone.0063187

Cited by 46 publications

(64 citation statements)

References 64 publications

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“…408 Importantly, p53-dependent repression of these genes is controlled by DREAM binding to CDE and CHR sites. [355][356][357] Consistently, instead of losing activity by altering the CCAAT-boxes, destruction of CDE and CHR elements leads to derepression of genes such as CCNB2, 355 CDK1 (CDC2), 349,360 CDC20, 363 and TOP2A. 349 In addition to NF-Y, Sp1 has also repeatedly been implicated in mediating p53-dependent repression (Table S5).…”

Section: Evaluating Alternative Models Of Indirect Repressionmentioning

confidence: 87%

“…332,335,348,[350][351][352][353] Recently, attention has shifted to the p53-p21-DREAM pathway. [354][355][356][357] The mammalian DREAM complex consists of the pocket proteins p107 or p130, the transcription factors E2F4 or E2F5 and the dimerization partner DP1, as well as the MuvB core composed of RBBP4 and the LIN proteins LIN9, LIN37, LIN52 and LIN54. 341,358,359 The DREAM components E2F4 and p107/p130 have repeatedly been reported to participate in p53-dependent downregulation of cell cycle genes.…”

Section: Experimental Validation Of Meta-analysis Datamentioning

confidence: 99%

“…335,345,346,350,352,360,361 In order to evaluate the proposed indirect repression mechanism involving p21, DREAM, or RB/E2F, we searched the literature and found 88 genes that were described to be indirectly regulated by p53 through this mechanism (Table S4). 9,98,248,257,[330][331][332][333][334][335][345][346][347][348][349][350][351][352][353][354][355][356][357][360][361][362][363][364][365][366][367][368][369][370][371] Impressively, 83 (94.3%) genes were confirmed as repressed (Expression Score 2-1) (Table S4). Therefore, in contrast to the direct repression models, the mechanism of indirect repression employing p21, DREAM, or RB/E2F is supported by the genome-wide expression studies.…”

Section: Experimental Validation Of Meta-analysis Datamentioning

confidence: 99%

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The transcription factor p53: Not a repressor, solely an activator

2014

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The predominant function of the tumor suppressor p53 is transcriptional regulation. It is generally accepted that p53-dependent transcriptional activation occurs by binding to a specific recognition site in promoters of target genes. Additionally, several models for p53-dependent transcriptional repression have been postulated. Here, we evaluate these models based on a computational meta-analysis of genome-wide data. Surprisingly, several major models of p53-dependent gene regulation are implausible. Meta-analysis of large-scale data is unable to confirm reports on directly repressed p53 target genes and falsifies models of direct repression. This notion is supported by experimental re-analysis of representative genes reported as directly repressed by p53. Therefore, p53 is not a direct repressor of transcription, but solely activates its target genes. Moreover, models based on interference of p53 with activating transcription factors as well as models based on the function of ncRNAs are also not supported by the meta-analysis. As an alternative to models of direct repression, the meta-analysis leads to the conclusion that p53 represses transcription indirectly by activation of the p53-p21-DREAM/RB pathway.

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Section: Evaluating Alternative Models Of Indirect Repressionmentioning

confidence: 87%

Section: Experimental Validation Of Meta-analysis Datamentioning

confidence: 99%

Section: Experimental Validation Of Meta-analysis Datamentioning

confidence: 99%

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The transcription factor p53: Not a repressor, solely an activator

2014

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“…For example, p53 precludes entry into S phase by imposing transcriptional and translational blocks to cell cycle progression in response to serum starvation (77) and prevents inappropriate entry into mitosis by suppressing expression of the chromosome alignment protein Kif23 (17). Perhaps p53 is altered in the adenovirus-infected cell, and this altered form of p53 permits cells to slip past the G 2 checkpoint despite DNA damage or chromosomal abnormalities.…”

Section: Discussionmentioning

confidence: 99%

“…However, p53 also inhibits cell cycle progression immediately before mitosis. p53 can prevent entry into mitosis by inhibiting a kinesin involved in the arrangement of condensed chromosomes (17). Polo-like kinase 1 (Plk1) promotes the transition from G 2 into mitosis.…”

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confidence: 99%

Adenovirus Replaces Mitotic Checkpoint Controls

Turner

Groitl

Dobner

et al. 2015

J Virol

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Infection with adenovirus triggers the cellular DNA damage response, elements of which include cell death and cell cycle arrest. Early adenoviral proteins, including the E1B-55K and E4orf3 proteins, inhibit signaling in response to DNA damage. A fraction of cells infected with an adenovirus mutant unable to express the E1B-55K and E4orf3 genes appeared to arrest in a mitotic-like state. Cells infected early in G 1 of the cell cycle were predisposed to arrest in this state at late times of infection. This arrested state, which displays hallmarks of mitotic catastrophe, was prevented by expression of either the E1B-55K or the E4orf3 genes. However, E1B-55K mutant virus-infected cells became trapped in a mitotic-like state in the presence of the microtubule poison colcemid, suggesting that the two viral proteins restrict entry into mitosis or facilitate exit from mitosis in order to prevent infected cells from arresting in mitosis. The E1B-55K protein appeared to prevent inappropriate entry into mitosis through its interaction with the cellular tumor suppressor protein p53. The E4orf3 protein facilitated exit from mitosis by possibly mislocalizing and functionally inactivating cyclin B1. When expressed in noninfected cells, E4orf3 overcame the mitotic arrest caused by the degradation-resistant R42A cyclin B1 variant. IMPORTANCECells that are infected with adenovirus type 5 early in G 1 of the cell cycle are predisposed to arrest in a mitotic-like state in a p53-dependent manner. The adenoviral E1B-55K protein prevents entry into mitosis. This newly described activity for the E1B-55K protein appears to depend on the interaction between the E1B-55K protein and the tumor suppressor p53. The adenoviral E4orf3 protein facilitates exit from mitosis, possibly by altering the intracellular distribution of cyclin B1. By preventing entry into mitosis and by promoting exit from mitosis, these adenoviral proteins act to prevent the infected cell from arresting in a mitoticlike state.

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The landscape of human p53‐regulated long non‐coding RNAs reveals critical host gene co‐regulation

2023

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The role of long non-coding RNAs (lncRNAs) in p53-mediated tumor suppression has become increasingly appreciated in the past decade. Thus, the identification of p53-regulated lncRNAs can be a promising starting point to select and prioritize lncRNAs for functional analyses. By integrating transcriptome and transcription factor-binding data, we identified 379 lncRNAs that are recurrently differentially regulated by p53. Dissecting the mechanisms by which p53 regulates many of them, we identified sets of lncRNAs regulated either directly by p53 or indirectly through the p53-RFX7 and p53-p21-DREAM/RB:E2F pathways. Importantly, we identified multiple p53-responsive lncRNAs that are co-regulated with their protein-coding host genes, revealing an important mechanism by which p53 may regulate lncRNAs. Further analysis of transcriptome data and clinical data from cancer patients showed that recurrently p53-regulated lncRNAs are associated with patient survival. Together, the integrative analysis of the landscape of p53-regulated lncRNAs provides a powerful resource facilitating the identification of lncRNA function and displays the mechanisms of p53-dependent regulation that could be exploited for developing anticancer approaches.

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p53 and Cell Cycle Dependent Transcription of kinesin family member 23 (KIF23) Is Controlled Via a CHR Promoter Element Bound by DREAM and MMB Complexes

Cited by 46 publications

References 64 publications

The transcription factor p53: Not a repressor, solely an activator

The transcription factor p53: Not a repressor, solely an activator

Adenovirus Replaces Mitotic Checkpoint Controls

The landscape of human p53‐regulated long non‐coding RNAs reveals critical host gene co‐regulation

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