scholarly journals Regulation of p53 Target Gene Expression by Peptidylarginine Deiminase 4

2008 ◽  
Vol 28 (15) ◽  
pp. 4745-4758 ◽  
Author(s):  
Pingxin Li ◽  
Hongjie Yao ◽  
Zhiqiang Zhang ◽  
Ming Li ◽  
Yuan Luo ◽  
...  
Keyword(s):  
Target Gene ◽  
Target Genes ◽  
Peptidylarginine Deiminase ◽  
Uv Treatment ◽  
Rna Pol Ii ◽  
Pol Ii ◽  
Cycle Arrest ◽  
P53 Target Gene ◽  
P53 Target Genes ◽  
P21 Promoter

ABSTRACT Histone Arg methylation has been correlated with transcriptional activation of p53 target genes. However, whether this modification is reversed to repress the expression of p53 target genes is unclear. Here, we report that peptidylarginine deiminase 4, a histone citrullination enzyme, is involved in the repression of p53 target genes. Inhibition or depletion of PAD4 elevated the expression of a subset of p53 target genes, including p21/CIP1/WAF1, leading to cell cycle arrest and apoptosis. Moreover, the induction of p21, cell cycle arrest, and apoptosis by PAD4 depletion is p53 dependent. Protein-protein interaction studies showed an interaction between p53 and PAD4. Chromatin immunoprecipitation assays showed that PAD4 is recruited to the p21 promoter in a p53-dependent manner. RNA polymerase II (Pol II) activities and the association of PAD4 are dynamically regulated at the p21 promoter during UV irradiation. Paused RNA Pol II and high levels of PAD4 were detected before UV treatment. At early time points after UV treatment, an increase of histone Arg methylation and a decrease of citrullination were correlated with a transient activation of p21. At later times after UV irradiation, a loss of RNA Pol II and an increase of PAD4 were detected at the p21 promoter. The dynamics of RNA Pol II activities after UV treatment were further corroborated by permanganate footprinting. Together, these results suggest a role of PAD4 in the regulation of p53 target gene expression.

scholarly journals E2f1, E2f2, and E2f3 Control E2F Target Expression and Cellular Proliferation via a p53-Dependent Negative Feedback Loop

2007 ◽  
Vol 27 (1) ◽  
pp. 65-78 ◽  
Author(s):  
Cynthia Timmers ◽  
Nidhi Sharma ◽  
Rene Opavsky ◽  
Baidehi Maiti ◽  
Lizhao Wu ◽  
...  
Keyword(s):  
Gene Expression ◽  
Target Gene ◽  
Target Genes ◽  
Cellular Proliferation ◽  
Kinase Activity ◽  
Cyclin Dependent Kinase ◽  
Control Of Gene Expression ◽  
Target Gene Expression ◽  
Rb Phosphorylation ◽  
P53 Target Genes

ABSTRACT E2F-mediated control of gene expression is believed to have an essential role in the control of cellular proliferation. Using a conditional gene-targeting approach, we show that the targeted disruption of the entire E2F activator subclass composed of E2f1, E2f2, and E2f3 in mouse embryonic fibroblasts leads to the activation of p53 and the induction of p53 target genes, including p21 CIP1 . Consequently, cyclin-dependent kinase activity and retinoblastoma (Rb) phosphorylation are dramatically inhibited, leading to Rb/E2F-mediated repression of E2F target gene expression and a severe block in cellular proliferation. Inactivation of p53 in E2f1-, E2f2-, and E2f3-deficient cells, either by spontaneous mutation or by conditional gene ablation, prevented the induction of p21 CIP1 and many other p53 target genes. As a result, cyclin-dependent kinase activity, Rb phosphorylation, and E2F target gene expression were restored to nearly normal levels, rendering cells responsive to normal growth signals. These findings suggest that a critical function of the E2F1, E2F2, and E2F3 activators is in the control of a p53-dependent axis that indirectly regulates E2F-mediated transcriptional repression and cellular proliferation.

scholarly journals FLIP(L) determines p53 induced life or death

2019 ◽  
Author(s):  
Andrea Lees ◽  
Alexander J. McIntyre ◽  
Fiammetta Falcone ◽  
Nyree T. Crawford ◽  
Christopher McCann ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cell Cycle Arrest ◽  
Cell Fate ◽  
Target Genes ◽  
Hdac Inhibitors ◽  
Caspase 8 ◽  
Cycle Arrest ◽  
P53 Activation ◽  
P53 Target Genes ◽  
Mdm2 Inhibitor

AbstractHow p53 differentially activates cell cycle arrest versus cell death remains poorly understood. Here, we demonstrate that upregulation of canonical pro-apoptotic p53 target genes in colon cancer cells imposes a critical dependence on the long splice form of the caspase-8 regulator FLIP (FLIP(L)), which we identify as a direct p53 transcriptional target. Inhibiting FLIP(L) expression with siRNA or Class-I HDAC inhibitors promotes apoptosis in response to p53 activation by the MDM2 inhibitor Nutlin-3A, which otherwise predominantly induces cell-cycle arrest. When FLIP(L) upregulation is inhibited, apoptosis is induced in response to p53 activation via a novel ligand-independent TRAIL-R2/caspase-8 complex, which, by activating BID, induces mitochondrial-mediated apoptosis. Notably, FLIP(L) depletion inhibits p53-induced expression of the cell cycle regulator p21 and enhances p53-mediated upregulation of PUMA, with the latter activating mitochondrial-mediated apoptosis in FLIP(L)-depleted, Nutlin-3A-treated cells lacking TRAIL-R2/caspase-8. Thus, we report two previously undescribed, novel FLIP(L)-dependent mechanisms that determine cell fate following p53 activation.

The do's and don'ts of p53 isoforms

2009 ◽  
Vol 390 (10) ◽  
Author(s):  
Reiner U. Jänicke ◽  
Vilma Graupner ◽  
Wilfried Budach ◽  
Frank Essmann
Keyword(s):  
Decision Process ◽  
Target Genes ◽  
Decision Processes ◽  
Dominant Negative ◽  
Alternative Promoters ◽  
Selective Activation ◽  
Cycle Arrest ◽  
P53 Isoforms ◽  
Transcription Factor P53 ◽  
P53 Target Genes

Abstract Upon DNA damage and other stresses, the transcription factor p53 elicits numerous responses including DNA repair, cell cycle arrest and apoptosis, properties that make p53 the prototype tumor suppressor. In addition, p53 also transactivates genes whose products act in an anti-apoptotic manner providing strong evidence that p53 exhibits both tumor suppressive and tumorigenic functions. Although several events were postulated to contribute to the p53-mediated decision process, the precise mechanism(s) that governs p53 activities is still elusive. Recently, it was found that the p53 gene allows expression of at least nine different isoforms that arise from multiple splicing events and the usage of alternative promoters. Several of these isoforms were shown to critically interfere with the function of the full-length p53 mainly by acting in a dominant-negative manner. However, an isoform-dependent selective activation of p53 target genes was also observed. Furthermore, certain p53 isoforms are aberrantly expressed in various tumors strongly implying their involvement in tumorigenic events. Thus, p53 isoforms may represent crucial determinants in p53-mediated decision processes whose precise functions (their do's and don'ts) are only beginning to emerge.

scholarly journals β-Globin Intergenic Transcription and Histone Acetylation Dependent on an Enhancer

2007 ◽  
Vol 27 (8) ◽  
pp. 2980-2986 ◽  
Author(s):  
AeRi Kim ◽  
Hui Zhao ◽  
Ina Ifrim ◽  
Ann Dean
Keyword(s):  
Histone Acetylation ◽  
Rna Polymerase Ii ◽  
Target Gene ◽  
Globin Gene ◽  
Tata Box ◽  
Rna Pol Ii ◽  
Pol Ii ◽  
Transcription Complexes ◽  
And Function ◽  
H3 Acetylation

ABSTRACT Histone acetyltransferases are associated with the elongating RNA polymerase II (Pol II) complex, supporting the idea that histone acetylation and transcription are intertwined mechanistically in gene coding sequences. Here, we studied the establishment and function of histone acetylation and transcription in noncoding sequences by using a model locus linking the β-globin HS2 enhancer and the embryonic ε-globin gene in chromatin. An intact HS2 enhancer that recruits RNA Pol II is required for intergenic transcription and histone H3 acetylation and K4 methylation between the enhancer and target gene. RNA Pol II recruitment to the target gene TATA box is not required for the intergenic transcription or intergenic histone modifications, strongly implying that they are properties conferred by the enhancer. However, Pol II recruitment at HS2, intergenic transcription, and intergenic histone modification are not sufficient for transcription or modification of the target gene: these changes require initiation at the TATA box of the gene. The results suggest that intergenic and genic transcription complexes are independent and possibly differ from one another.

scholarly journals p53-Dependent p21 mRNA Elongation Is Impaired when DNA Replication Is Stalled

2006 ◽  
Vol 27 (4) ◽  
pp. 1309-1320 ◽  
Author(s):  
Melissa Mattia ◽  
Vanesa Gottifredi ◽  
Kristine McKinney ◽  
Carol Prives
Keyword(s):  
Dna Replication ◽  
Rna Polymerase Ii ◽  
Target Genes ◽  
Large Subunit ◽  
Transcriptional Elongation ◽  
Mrna Transcription ◽  
Rna Pol Ii ◽  
Pol Ii ◽  
Replication Checkpoint ◽  
Dna Replication Checkpoint

ABSTRACT We have previously reported that when DNA replication is blocked in some human cell lines, p53 is impaired in its ability to induce a subset of its key target genes, including p21 WAF1/CIP1 . Here, we investigated the reason for this impairment by comparing the effects of two agents, hydroxyurea (HU), which arrests cells in early S phase and impairs induction of p21, and daunorubicin, which causes a G2 block and leads to robust activation of p21 by p53. HU treatment was shown to inhibit p21 mRNA transcription rather than alter its mRNA stability. Nevertheless, chromatin immunoprecipitation assays revealed that HU impacts neither p53 binding nor acetylation of histones H3 and H4 within the p21 promoter. Furthermore, recruitment of the TFIID/TATA-binding protein complex and the large subunit of RNA polymerase II (RNA Pol II) are equivalent after HU and daunorubicin treatments. Relative to daunorubicin treatment, however, transcription elongation of the p21 gene is significantly impaired in cells treated with HU, as evidenced by reduced occupancy of RNA Pol II at regions downstream of the start site. Likewise, in the p21 downstream region after administration of HU, there is less of a specifically phosphorylated form of RNA Pol II (Pol II-C-terminal domain serine 2P) which occurs only when the polymerase is elongating RNA. We propose that while the DNA replication checkpoint is unlikely to regulate the assembly of a p21 promoter initiation complex, it signals to one or more factors involved in the process of transcriptional elongation.

scholarly journals c-Myc Is Required for the ChREBP-Dependent Activation of Glucose-Responsive Genes

2010 ◽  
Vol 24 (6) ◽  
pp. 1274-1286 ◽  
Author(s):  
Pili Zhang ◽  
Mallikarjurna R. Metukuri ◽  
Sharell M. Bindom ◽  
Edward V. Prochownik ◽  
Robert M. O'Doherty ◽  
...  
Keyword(s):  
Gene Expression ◽  
Rna Polymerase Ii ◽  
Time Course ◽  
Target Genes ◽  
Process Time ◽  
Glucose Response ◽  
Rna Pol Ii ◽  
Pol Ii ◽  
Molecular Events ◽  
Regulated Gene Expression

Abstract Glucose regulates programs of gene expression that orchestrate changes in cellular phenotype in several metabolically active tissues. Carbohydrate response element-binding protein (ChREBP) and its binding partner, Mlx, mediate glucose-regulated gene expression by binding to carbohydrate response elements on target genes, such as the prototypical glucose-responsive gene, liver-type pyruvate kinase (Pklr). c-Myc is also required for the glucose response of the Pklr gene, although the relationship between c-Myc and ChREBP has not been defined. Here we describe the molecular events of the glucose-mediated activation of Pklr and determine the effects of decreasing the activity or abundance of c-Myc on this process. Time-course chromatin immunoprecipitation revealed a set of transcription factors [hepatocyte nuclear factor (HNF)1α, HNF4α, and RNA polymerase II (Pol II)] constitutively resident on the Pklr promoter, with a relative enrichment of acetylated histones 3 and 4 in the same region of the gene. Glucose did not affect HNF1α binding or the acetylation of histones H3 or H4. By contrast, glucose promoted the recruitment of ChREBP and c-Myc and increased the occupancy of HNF4α and RNA Pol II, which were coincident with the glucose-mediated increase in transcription as determined by a nuclear run-on assay. Depletion of c-Myc activity using a small molecule inhibitor (10058-F4/1RH) abolished the glucose-mediated recruitment of HNF4α, ChREBP, and RNA Pol II, without affecting basal gene expression, histone acetylation, and HNF1α or basal HNF4α occupancy. The activation and recruitment of ChREBP to several glucose-responsive genes were blocked by 1RH, indicating a general necessity for c-Myc in this process.

scholarly journals Stress-mediated Sin3B activation leads to negative regulation of subset of p53 target genes

2015 ◽  
Vol 35 (4) ◽  
Author(s):  
Rama Kadamb ◽  
Shilpi Mittal ◽  
Nidhi Bansal ◽  
Daman Saluja
Keyword(s):  
Target Gene ◽  
Target Genes ◽  
Epigenetic Modifications ◽  
Negative Regulation ◽  
Stress Conditions ◽  
Gene Repression ◽  
Gene Promoters ◽  
P53 Target Genes

Sin3B expression and its interaction with phosphorylated p53 increases under stress conditions. Recruitment of Sin3B by p53 at its target gene promoters is essential for the maintenance of inhibitory chromatin environment by inducing epigenetic modifications that brings about their target gene repression.

scholarly journals In Vivo Mitochondrial p53 Translocation Triggers a Rapid First Wave of Cell Death in Response to DNA Damage That Can Precede p53 Target Gene Activation

2004 ◽  
Vol 24 (15) ◽  
pp. 6728-6741 ◽  
Author(s):  
Susan Erster ◽  
Motohiro Mihara ◽  
Roger H. Kim ◽  
Oleksi Petrenko ◽  
Ute M. Moll
Keyword(s):  
Target Gene ◽  
Caspase 3 ◽  
Target Genes ◽  
Cultured Cells ◽  
Gene Activation ◽  
Lag Phase ◽  
Cell Fractionation ◽  
Γ Irradiation ◽  
P53 Target Gene

ABSTRACT p53 promotes apoptosis in response to death stimuli by transactivation of target genes and by transcription-independent mechanisms. We recently showed that wild-type p53 rapidly translocates to mitochondria in response to multiple death stimuli in cultured cells. Mitochondrial p53 physically interacts with antiapoptotic Bcl proteins, induces Bak oligomerization, permeabilizes mitochondrial membranes, and rapidly induces cytochrome c release. Here we characterize the mitochondrial p53 response in vivo. Mice were subjected to γ irradiation or intravenous etoposide administration, followed by cell fractionation and immunofluorescence studies of various organs. Mitochondrial p53 accumulation occurred in radiosensitive organs like thymus, spleen, testis, and brain but not in liver and kidney. Of note, mitochondrial p53 translocation was rapid (detectable at 30 min in thymus and spleen) and triggered an early wave of marked caspase 3 activation and apoptosis. This caspase 3-mediated apoptosis was entirely p53 dependent, as shown by p53 null mice, and preceded p53 target gene activation. The transcriptional p53 program had a longer lag phase than the rapid mitochondrial p53 program. In thymus, the earliest apoptotic target gene products PUMA, Noxa, and Bax appeared at 2, 4, and 8 h, respectively, while Bid, Killer/DR5, and p53DinP1 remained uninduced even after 20 h. Target gene induction then led to further increase in active caspase 3. Similar biphasic kinetics was seen in cultured human cells. Our results suggest that in sensitive organs mitochondrial p53 accumulation in vivo occurs soon after a death stimulus, triggering a rapid first wave of apoptosis that is transcription independent and may precede a second slower wave that is transcription dependent.

scholarly journals Stress-induced expression of p53 target genes is insensitive to SNW1/SKIP downregulation

2011 ◽  
Vol 16 (3) ◽  
Author(s):  
Ondřej Tolde ◽  
Petr Folk
Keyword(s):  
Target Genes ◽  
Elongation Factor ◽  
Mrna Synthesis ◽  
Rna Pol Ii ◽  
Induced Expression ◽  
Stress Response Genes ◽  
Carboxy Terminal Domain ◽  
Carboxy Terminal ◽  
P53 Target Genes ◽  
Hiv 1

AbstractPharmacological inhibition of protein kinases that are responsible for the phosphorylation of the carboxy-terminal domain (CTD) of RNA Pol II during transcription by 5,6-dichloro-1-beta-D-ribofuranosyl-benzimidazole (DRB) leads to severe inhibition of mRNA synthesis and activates p53. Transcription of the p53 effectors that are induced under these conditions, such as p21 or PUMA, must bypass the requirement for CTD phosphorylation by the positive elongation factor P-TEFb. Here, we have downregulated SNW1/SKIP, a splicing factor and a transcriptional co-regulator, which was found to interact with P-TEFb and synergistically affect Tat-dependent transcription elongation of HIV 1. Using the colon cancer derived cell line HCT116, we have found that both doxorubicin- and DRB-induced expression of p21 or PUMA is insensitive to SNW1 downregulation by siRNA. This suggests that transcription of stress response genes, unlike, e.g., the SNW1-sensitive mitosis-specific genes, can proceed uncoupled from regulators that normally function under physiological conditions.

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