Sp1 is involved in the transcriptional activation of p16<sup>INK4</sup> by p21<sup>Waf1</sup> in HeLa cells

Xue, Lixiang; Wu, Junfeng; Zheng, Wenjie; Wang, Peichang; Li, Jun; Zhang, Zongyu; Tong, Tanjun

doi:10.1016/s0014-5793(04)00352-7

Cited by 26 publications

(20 citation statements)

References 28 publications

(31 reference statements)

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“…It is possible, therefore, that the cdk complex may be mediating DNA interaction. Others have shown that p53 works through p21 and Rb to downregulate Chk1 (17) and that p21 activates p16 INK4 through Sp1 (47). It is interesting to note that p21 was not able to fully repress the cB 1 promoter in our studies.…”

Section: Discussioncontrasting

confidence: 72%

The histone deacetylase inhibitor butyrate downregulates cyclin B₁gene expression via a p21/WAF-1-dependent mechanism in human colon cancer cells

Archer

Johnson

Kim

et al. 2005

American Journal of Physiology-Gastrointestinal and Liver Physi

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Histone deacetylase (HDAC) inhibitors are showing promise as treatment for a variety of human cancers, but their precise mechanism of action has not been elucidated. We examined the effects of the HDAC inhibitor butyrate on colon cancer cells, focusing on its effect on the cell cycle promoter cyclin B(1). In HT-29 cells, sodium butyrate-mediated growth inhibition is associated with a marked decrease in cyclin B(1) mRNA levels. The decrease in cyclin B(1) occurred in a delayed fashion (at 24 h), is completely blocked by concomitant treatment with protein synthesis inhibitors, and appears to be dependent on changes in transcription. Cyclin B(1) repression is linked to the differentiation process in colon cancer cells, not merely with growth arrest. The mechanism of cyclin B(1) repression by butyrate requires prolonged histone hyperacetylation and is at least partly dependent on p21 expression. In fact, p21/WAF-1 appears to directly repress a minimal cyclin B(1) promoter (-90 bp), a process that can be mediated by the amino-terminal portion of the p21 protein. These findings highlight key molecular mechanisms by which HDAC inhibitors mediate their beneficial effects on human cancer cells.

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Section: Discussioncontrasting

confidence: 72%

The histone deacetylase inhibitor butyrate downregulates cyclin B₁gene expression via a p21/WAF-1-dependent mechanism in human colon cancer cells

Archer

Johnson

Kim

et al. 2005

American Journal of Physiology-Gastrointestinal and Liver Physi

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“…Some transcription factors interact with p53 and p16 INK4a promoters and regulate gene promoter activity through these promoter regions (Furlong et al , 1996; Kirch et al , 1999; Myöhänen and Baylin, 2001; Xue et al , 2004; Wu et al , 2007). The polymorphic sites identified in these promoters in the present study were not located within their transcription factor-binding sites.…”

Section: Discussionmentioning

confidence: 99%

Polymorphisms in promoter sequences of MDM2, p53, and p16INK4a genes in normal Japanese individuals

Ohsaka

Nishino

2010

Genet. Mol. Biol.

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Research has been conducted to identify sequence polymorphisms of gene promoter regions in patients and control subjects, including normal individuals, and to determine the influence of these polymorphisms on transcriptional regulation in cells that express wild-type or mutant p53. In this study we isolated genomic DNA from whole blood of healthy Japanese individuals and sequenced the promoter regions of the MDM2, p53, and p16INK4a genes. We identified polymorphisms comprising 3 nucleotide substitutions at exon 1 and intron 1 regions of the MDM2 gene and 1 nucleotide insertion at a poly(C) nucleotide position in the p53 gene. The Japanese individuals also exhibited p16INK4a polymorphisms at several positions, including position -191. Reporter gene analysis by using luciferase revealed that the polymorphisms of MDM2, p53, and p16INK4a differentially altered luciferase activities in several cell lines, including the Colo320DM, U251, and T98G cell lines expressing mutant p53. Our results indicate that the promoter sequences of these genes differ among normal Japanese individuals and that polymorphisms can alter gene transcription activity.

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“…These data suggest that the region of 133 bp between positions Ϫ378 and Ϫ510 is important in mediating the inhibitory effect of HDACis on the human INK4a promoter. Of note, previous investigations have demonstrated that this region contains functional binding sites for Sp1 and Sp3 transcription factors (52,53). Transcription factors Sp1 and Sp3 have been identified in numerous promoters as mediators of both HDACi-induced activation (see Ref.…”

Section: Effect Of Hdacis On P19mentioning

confidence: 98%

Regulation of the INK4a/ARF Locus by Histone Deacetylase Inhibitors

Matheu

Klatt

Serrano

2005

Journal of Biological Chemistry

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Histone deacetylase inhibitors (HDACis)3 have emerged as a promising class of anti-neoplastic agents (reviewed in Refs. 1-3). Trichostatin A (TSA) and sodium butyrate (NaB) are prototypical of two different classes of chemical inhibitors of histone deacetylases (HDACs) that interfere with the activity of HDAC classes I and II; the remaining class of HDACs, class III, also known as the Sir2 family, is TSA resistant but nicotinamide sensitive (reviewed in Refs. 1, 2; see also Refs. 4,5). The molecular events that mediate the biological effects of HDACis are incompletely understood. HDACs can be recruited to chromatin through interaction with a large variety of DNA-binding proteins, and upon recruitment deacetylate histones, generally resulting in heterochromatinization and transcriptional silencing (6). An additional layer of complexity derives from the fact that the substrates of HDACs are not restricted to histones but include transcriptional regulators, such as p53 or E2F-1, and may extend to general transcription factors, such as TFIIB or TFIIF (1, 7-15). Because of the complexity and variety of transcriptional processes that involve HDACs, it is anticipated that a multitude of mechanisms underlie the transcriptional effects of HDACis. In this regard, global gene expression analyses have shown that HDACis affect the expression levels of 2-20% of genes in the genome, of which about half are up-regulated and half down-regulated (Refs. 16, 17, and references therein).Given the key role of cell cycle integrity in tumor suppression (reviewed in Refs. 18,19) INK4a and p14 ARF /p19 ARF (p14 when referred to the human protein and p19 when referred to the murine protein), which share common exons 2 and 3 but differ in their first exons and their respective promoters. Protein p16INK4a inhibits the activity of the CDK4,6/cycD kinases, thus contributing to the maintenance of the active, growthsuppressive form of the retinoblastoma family of proteins (31). On the other hand, the tumor suppressor ARF contributes to the stability of p53 by inhibiting the p53-degrading activity of MDM2 (31). A large amount of accumulated evidence indicates that the INK4a/ARF locus is a sensor of oncogenic stress, its expression being up-regulated upon the detection of aberrant oncogenic signals (32-34). Given the importance of the INK4a/ARF locus in tumor suppression, it is of obvious interest to understand the effects of HDACis on these two genes and their encoded proteins. Few studies have addressed the impact of HDACis on the expression of the INK4a/ARF locus. Specifically, HDACis can cooperate with DNA methylation inhibitors to reactivate a silenced, aberrantly methylated p16INK4a promoter (35). In a different context, HDACis can up-regulate p16INK4a in rat synovial fibroblasts from arthritic joints, but not from normal ones (36). Finally, long-term exposure of human fibroblasts to low concentrations of HDACis affects their subsequent proliferative potential, shortening their replicative lifespan and eventually entering into premature se...

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Sp1 is involved in the transcriptional activation of p16^INK4 by p21^Waf1 in HeLa cells

Cited by 26 publications

References 28 publications

The histone deacetylase inhibitor butyrate downregulates cyclin B₁gene expression via a p21/WAF-1-dependent mechanism in human colon cancer cells

The histone deacetylase inhibitor butyrate downregulates cyclin B₁gene expression via a p21/WAF-1-dependent mechanism in human colon cancer cells

Polymorphisms in promoter sequences of MDM2, p53, and p16INK4a genes in normal Japanese individuals

Regulation of the INK4a/ARF Locus by Histone Deacetylase Inhibitors

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Sp1 is involved in the transcriptional activation of p16INK4 by p21Waf1 in HeLa cells

Cited by 26 publications

References 28 publications

The histone deacetylase inhibitor butyrate downregulates cyclin B1gene expression via a p21/WAF-1-dependent mechanism in human colon cancer cells

The histone deacetylase inhibitor butyrate downregulates cyclin B1gene expression via a p21/WAF-1-dependent mechanism in human colon cancer cells

Polymorphisms in promoter sequences of MDM2, p53, and p16INK4a genes in normal Japanese individuals

Regulation of the INK4a/ARF Locus by Histone Deacetylase Inhibitors

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Sp1 is involved in the transcriptional activation of p16^INK4 by p21^Waf1 in HeLa cells

The histone deacetylase inhibitor butyrate downregulates cyclin B₁gene expression via a p21/WAF-1-dependent mechanism in human colon cancer cells

The histone deacetylase inhibitor butyrate downregulates cyclin B₁gene expression via a p21/WAF-1-dependent mechanism in human colon cancer cells