Direct p53 Transcriptional Repression: In Vivo Analysis of CCAAT-Containing G<sub>2</sub>/M Promoters

Imbriano, Carol; Gurtner, Aymone; Cocchiarella, Fabienne; Agostino, Silvia Di; Basile, Valentina; Gostissa, Monica; Dobbelstein, Matthias; Sal, Giannino Del; Piaggio, Giulia; Mantovani, Roberto

doi:10.1128/mcb.25.9.3737-3751.2005

Cited by 203 publications

(250 citation statements)

References 65 publications

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“…Previous reports showed that HDAC4 is a key mediator of p53-dependent cancer cell growth arrest in response to DNA damage (Kao et al, 2003;Imbriano et al, 2005;Basile et al, 2006). Here, we demonstrated that HDAC4 represses p21 WAF1/Cip1 expression in proliferating unstressed cancer cells through a p53-independent mechanism.…”

Section: Hdac4 Represses P21waf1/cip1 Expression In Human Cancer Cellsupporting

confidence: 60%

HDAC4 represses p21WAF1/Cip1 expression in human cancer cells through a Sp1-dependent, p53-independent mechanism

et al. 2008

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Cancer cells have complex, unique characteristics that distinguish them from normal cells, such as increased growth rates and evasion of anti-proliferative signals. Global inhibition of class I and II histone deacetylases (HDACs) stops cancer cell proliferation in vitro and has proven effective against cancer in clinical trials, at least in part, through transcriptional reactivation of the p21 WAF1/Cip1 gene. The HDACs that regulate p21 WAF1/Cip1 are not fully identified. Using small interfering RNAs, we found that HDAC4 participates in the repression of p21 WAF1/Cip1 through Sp1/Sp3-, but not p53-binding sites. HDAC4 interacts with Sp1, binds and reduces histone H3 acetylation at the Sp1/Sp3 binding site-rich p21 WAF1/Cip1 proximal promoter, suggesting a key role for Sp1 in HDAC4-mediated repression of p21 WAF1/Cip1 . Induction of p21 WAF1/Cip1 mediated by silencing of HDAC4 arrested cancer cell growth in vitro and inhibited tumor growth in an in vivo human glioblastoma model. Thus, HDAC4 could be a useful target for new anti-cancer therapies based on selective inhibition of specific HDACs.

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Section: Hdac4 Represses P21waf1/cip1 Expression In Human Cancer Cellsupporting

confidence: 60%

HDAC4 represses p21WAF1/Cip1 expression in human cancer cells through a Sp1-dependent, p53-independent mechanism

et al. 2008

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“…Interestingly, unlike the mechanisms discussed earlier, transactivation by the mutp53-NF-Y complex does not require the N terminus of mutp53, implying that this activity of mutp53 utilizes other domains of the protein. In support of this, wtp53 interacts with NF-Y, p300 and HDAC1 through its C-terminal domain (Imbriano et al, 2005).…”

Section: Mutp53: Role Of Residual Wtp53 Activity?mentioning

confidence: 81%

Transcription regulation by mutant p53

2007

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“…The protein p53 interacts with Sp1 and NF-Y transcription factor (Imbriano et al, 2005;Koutsodontis et al, 2005). This interaction either reduces the ability of these factors to bind to DNA, resulting in insufficient (Imbriano et al, 2005;Jin et al, 2008).…”

Section: Resultsmentioning

confidence: 99%

“…This interaction either reduces the ability of these factors to bind to DNA, resulting in insufficient (Imbriano et al, 2005;Jin et al, 2008). To elucidate the mechanism by which p53 downregulates Cdc25B, we performed chromatin immunoprecipitation (ChIP) analyses.…”

Section: Resultsmentioning

confidence: 99%

Cdc25B is negatively regulated by p53 through Sp1 and NF-Y transcription factors

et al. 2011

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Cdc25B phosphatases function as key players in G2/M cell cycle progression by activating the CDK1-cyclinB1 complexes. They also have an essential role in recovery from the G2/M checkpoint activated in response to DNA damage. Overexpression of Cdc25B results in bypass of the G2/M checkpoint and illegitimate entry into mitosis, and also causes replicative stress, leading to genomic instability. Thus, fine-tuning of Cdc25B expression level is critical for correct cell cycle progression and G2 checkpoint recovery. However, the transcriptional regulation of Cdc25B remains largely unknown. Earlier studies have shown that the tumor suppressor p53 overexpression transcriptionally represses Cdc25B; however, the molecular mechanism of this repression has not yet been elucidated, although it was suggested to occur through the induction of p21. Here we show that Cdc25B is downregulated by the basal level of p53 in multiple cell types. This downregulation also occurs in p21À/À cell lines, indicating that p21 is not required for p53-mediated regulation of Cdc25B. Deletion and mutation analyses of the Cdc25B promoter revealed that downregulation by p53 is dependent on the presence of functional Sp1/Sp3 and NF-Y binding sites. Furthermore, chromatin immunoprecipitation analyses show that p53 binds to the Cdc25B promoter and mediates transcriptional attenuation through the Sp1 and NF-Y transcription factors. Our results suggest that the inability to downregulate Cdc25B after loss of p53 might contribute to tumorigenesis.

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Direct p53 Transcriptional Repression: In Vivo Analysis of CCAAT-Containing G₂/M Promoters

Abstract: Promoters and enhancers are a combinatorial puzzle of DNA elements recognized by sequence-specific regulators that act in a chromatin context. The CCAAT box is a common promoter element, usually positioned in either orientation between Ϫ60 and Ϫ100.

Cited by 203 publications

References 65 publications

HDAC4 represses p21WAF1/Cip1 expression in human cancer cells through a Sp1-dependent, p53-independent mechanism

HDAC4 represses p21WAF1/Cip1 expression in human cancer cells through a Sp1-dependent, p53-independent mechanism

Transcription regulation by mutant p53

Cdc25B is negatively regulated by p53 through Sp1 and NF-Y transcription factors

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Direct p53 Transcriptional Repression: In Vivo Analysis of CCAAT-Containing G2/M Promoters

Abstract: Promoters and enhancers are a combinatorial puzzle of DNA elements recognized by sequence-specific regulators that act in a chromatin context. The CCAAT box is a common promoter element, usually positioned in either orientation between Ϫ60 and Ϫ100.

Cited by 203 publications

References 65 publications

HDAC4 represses p21WAF1/Cip1 expression in human cancer cells through a Sp1-dependent, p53-independent mechanism

HDAC4 represses p21WAF1/Cip1 expression in human cancer cells through a Sp1-dependent, p53-independent mechanism

Transcription regulation by mutant p53

Cdc25B is negatively regulated by p53 through Sp1 and NF-Y transcription factors

Contact Info

Product

Resources

About

Direct p53 Transcriptional Repression: In Vivo Analysis of CCAAT-Containing G₂/M Promoters