Differential Transcriptional Regulation of Polymorphic p53 Codon 72 in Metabolic Pathways

p53 is a transcription factor that is activated under DNA damage stress and regulates the expression of proapoptotic genes including the expression of growth arrest genes to subsequently determine the fate of cells. To investigate the functional differences of polymorphic p53 codon 72, we constructed isogenic lines encoding each polymorphic p53 codon 72 based on induced pluripotent stem cells, which can endogenously express each polymorphic p53 protein only, encoding either the arginine 72 (R72) variant or proline 72 (P72) variant, respectively. We found that there was no significant functional difference between P72 and R72 cells in growth arrest or apoptosis as a representative function of p53. In the comprehensive analysis, the expression pattern of the common p53 target genes, including cell cycle arrest or apoptosis, was also increased regardless of the polymorphic p53 codon 72 status, whereas the expression pattern involved in metabolism was decreased and more significant in R72 than in P72 cells. This study noted that polymorphic p53 codon 72 differentially regulated the functional categories of metabolism and not the pathways that determine cell fate, such as growth arrest and apoptosis in cells exposed to genotoxic stress.

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Laboratory Science. Effect of p53 codon 72 polymorphism on p53 protein expression in pterygium

Clinical and Experimental Ophthalmology ◽

10.1111/j.1442-9071.2005.00943.x ◽

2005 ◽

Vol 33 (1) ◽

pp. 60-62 ◽

Cited By ~ 1

Author(s):

Yi-Yu Tsai ◽

Kong-Chao Chang ◽

Huei Lee ◽

Ya-Wen Cheng ◽

Fuu-Jen Tsai ◽

...

Keyword(s):

Protein Expression ◽

P53 Protein ◽

P53 Codon 72 ◽

Codon 72 ◽

Laboratory Science ◽

P53 Protein Expression ◽

Codon 72 Polymorphism ◽

P53 Codon 72 Polymorphism

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Regulation of p53 by Hypoxia: Dissociation of Transcriptional Repression and Apoptosis from p53-Dependent Transactivation

Molecular and Cellular Biology ◽

10.1128/mcb.21.4.1297-1310.2001 ◽

2001 ◽

Vol 21 (4) ◽

pp. 1297-1310 ◽

Cited By ~ 232

Author(s):

Constantinos Koumenis ◽

Rodolfo Alarcon ◽

Ester Hammond ◽

Patrick Sutphin ◽

William Hoffman ◽

...

Keyword(s):

Dna Damage ◽

Transcriptional Repression ◽

Histone Deacetylases ◽

Target Genes ◽

P53 Protein ◽

Genotoxic Stress ◽

Protein Accumulation ◽

Dependent Cell ◽

Apoptotic Activity ◽

Induced Apoptosis

ABSTRACT Hypoxic stress, like DNA damage, induces p53 protein accumulation and p53-dependent apoptosis in oncogenically transformed cells. Unlike DNA damage, hypoxia does not induce p53-dependent cell cycle arrest, suggesting that p53 activity is differentially regulated by these two stresses. Here we report that hypoxia induces p53 protein accumulation, but in contrast to DNA damage, hypoxia fails to induce endogenous downstream p53 effector mRNAs and proteins. Hypoxia does not inhibit the induction of p53 target genes by ionizing radiation, indicating that p53-dependent transactivation requires a DNA damage-inducible signal that is lacking under hypoxic treatment alone. At the molecular level, DNA damage induces the interaction of p53 with the transcriptional activator p300 as well as with the transcriptional corepressor mSin3A. In contrast, hypoxia primarily induces an interaction of p53 with mSin3A, but not with p300. Pretreatment of cells with an inhibitor of histone deacetylases that relieves transcriptional repression resulted in a significant reduction of p53-dependent transrepression and hypoxia-induced apoptosis. These results led us to propose a model in which different cellular pools of p53 can modulate transcriptional activity through interactions with transcriptional coactivators or corepressors. Genotoxic stress induces both kinds of interactions, whereas stresses that lack a DNA damage component as exemplified by hypoxia primarily induce interaction with corepressors. However, inhibition of either type of interaction can result in diminished apoptotic activity.

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The Discrepancy Between Genetic Polymorphism of p53 Codon 72 and the Expression of p53 Protein in Helicobacter pylori-Associated Gastric Cancer in Korea

Digestive Diseases and Sciences ◽

10.1007/s10620-008-0688-x ◽

2009 ◽

Vol 55 (1) ◽

pp. 101-110 ◽

Cited By ~ 8

Author(s):

Nayoung Kim ◽

Sung-Il Cho ◽

Hye Seung Lee ◽

Ji Hyun Park ◽

Jee Hyun Kim ◽

...

Keyword(s):

Gastric Cancer ◽

Helicobacter Pylori ◽

Genetic Polymorphism ◽

P53 Protein ◽

P53 Codon 72 ◽

Codon 72

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TBP-like Protein (TLP) Disrupts the p53-MDM2 Interaction and Induces Long-lasting p53 Activation

Journal of Biological Chemistry ◽

10.1074/jbc.m116.763318 ◽

2017 ◽

Vol 292 (8) ◽

pp. 3201-3212 ◽

Cited By ~ 4

Author(s):

Ryo Maeda ◽

Hiroyuki Tamashiro ◽

Kazunori Takano ◽

Hiro Takahashi ◽

Hidefumi Suzuki ◽

...

Keyword(s):

Cell Fate ◽

Nuclear Export ◽

Cellular Response ◽

P53 Protein ◽

Genotoxic Stress ◽

Negative Control ◽

Cell Fate Decisions ◽

Single Cell Imaging ◽

P53 Activation ◽

Induced Apoptosis

Stress-induced activation of p53 is an essential cellular response to prevent aberrant cell proliferation and cancer development. The ubiquitin ligase MDM2 promotes p53 degradation and limits the duration of p53 activation. It remains unclear, however, how p53 persistently escapes MDM2-mediated negative control for making appropriate cell fate decisions. Here we report that TBP-like protein (TLP), a member of the TBP family, is a new regulatory factor for the p53-MDM2 interplay and thus for p53 activation. We found that TLP acts to stabilize p53 protein to ensure long-lasting p53 activation, leading to potentiation of p53-induced apoptosis and senescence after genotoxic stress. Mechanistically, TLP interferes with MDM2 binding and ubiquitination of p53. Moreover, single cell imaging analysis shows that TLP depletion accelerates MDM2-mediated nuclear export of p53. We further show that a cervical cancer-derived TLP mutant has less p53 binding ability and lacks a proliferation-repressive function. Our findings uncover a role of TLP as a competitive MDM2 blocker, proposing a novel mechanism by which p53 escapes the p53-MDM2 negative feedback loop to modulate cell fate decisions.

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p53 pro-apoptotic activity is regulated by the G2/M promoting factor Cdk1 in response to DNA damage

10.1101/2021.02.13.431094 ◽

2021 ◽

Author(s):

Mireya Ruiz-Losada ◽

Raul González ◽

Ana Peropadre ◽

Antonio Baonza ◽

Carlos Estella

Keyword(s):

Cell Cycle ◽

Dna Damage ◽

Cell Fate ◽

Cell Cycle Progression ◽

P53 Protein ◽

Genotoxic Stress ◽

Suppressor Gene ◽

Cell Fate Decisions ◽

Apoptotic Activity ◽

Induced Apoptosis

SummaryExposure to genotoxic stress promotes cell-cycle arrest and DNA repair or apoptosis. These “life” or “death” cell fate decisions often rely on the activity of the tumor suppressor gene p53. Therefore, how p53 activity is precisely regulated is essential to maintain tissue homeostasis and to prevent cancer development. Here we demonstrate that Drosophila p53 pro-apoptotic activity is regulated by the G2/M kinase Cdk1. We find that cell cycle arrested or endocycle-induced cells are refractory to ionizing radiation induced apoptosis. We show that the p53 protein is not able to bind to and to activate the expression of the pro-apoptotic genes in experimentally arrested cells. Our results indicate that p53 genetically and physically interacts with Cdk1 and that p53 pro-apoptotic role is regulated by the cell cycle status of the cell. We propose a model in which cell cycle progression and p53 pro-apoptotic activity are molecularly connected to coordinate the appropriate response after DNA damage.

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Identification of the Regulatory Elements and Target Genes of Megakaryopoietic Transcription Factor MEF2C

Thrombosis and Haemostasis ◽

10.1055/s-0039-1678694 ◽

2019 ◽

Vol 119 (05) ◽

pp. 716-725 ◽

Cited By ~ 2

Author(s):

Xianguo Kong ◽

Lin Ma ◽

Edward Chen ◽

Chad Shaw ◽

Leonard Edelstein

Keyword(s):

Gene Expression ◽

Stem Cells ◽

Genetic Variation ◽

Transcription Factors ◽

Cell Fate ◽

Target Genes ◽

Regulatory Elements ◽

Haematopoietic Stem Cells ◽

Platelet Production ◽

Induced Pluripotent

AbstractMegakaryopoiesis produces specialized haematopoietic stem cells in the bone marrow that give rise to megakaryocytes which ultimately produce platelets. Defects in megakaryopoiesis can result in altered platelet counts and physiology, leading to dysfunctional haemostasis and thrombosis. Additionally, dysregulated megakaryopoiesis is also associated with myeloid pathologies. Transcription factors play critical roles in cell differentiation by regulating the temporal and spatial patterns of gene expression which ultimately decide cell fate. Several transcription factors have been described as regulating megakaryopoiesis including myocyte enhancer factor 2C (MEF2C); however, the genes regulated by MEF2C that influence megakaryopoiesis have not been reported. Using chromatin immunoprecipitation-sequencing and Gene Ontology data we identified five candidate genes that are bound by MEF2C and regulate megakaryopoiesis: MOV10, AGO3, HDAC1, RBBP5 and WASF2. To study expression of these genes, we silenced MEF2C gene expression in the Meg01 megakaryocytic cell line and in induced pluripotent stem cells by CRISPR/Cas9 editing. We also knocked down MEF2C expression in cord blood-derived haematopoietic stem cells by siRNA. We found that absent or reduced MEF2C expression resulted in defects in megakaryocytic differentiation and reduced levels of the candidate target genes. Luciferase assays confirmed that genomic sequences within the target genes are regulated by MEF2C levels. Finally, we demonstrate that small deletions linked to a platelet count-associated single nucleotide polymorphism alter transcriptional activity, suggesting a mechanism by which genetic variation in MEF2C alters platelet production. These data help elucidate the mechanism behind MEF2C regulation of megakaryopoiesis and genetic variation driving platelet production.

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ZBP-89 Promotes Growth Arrest through Stabilization of p53

Molecular and Cellular Biology ◽

10.1128/mcb.21.14.4670-4683.2001 ◽

2001 ◽

Vol 21 (14) ◽

pp. 4670-4683 ◽

Cited By ~ 69

Author(s):

Longchuan Bai ◽

Juanita L. Merchant

Keyword(s):

Cell Proliferation ◽

Dna Binding ◽

Nuclear Export ◽

Target Genes ◽

Kinase Inhibitor ◽

P53 Protein ◽

Growth Arrest ◽

Serum Starvation ◽

Physical Interaction ◽

Induce Growth Arrest

ABSTRACT Transcription factor p53 can induce growth arrest and/or apoptosis in cells through activation or repression of downstream target genes. Recently, we reported that ZBP-89 cooperates with histone acetyltransferase coactivator p300 in the regulation of p21waf1, a cyclin-dependent kinase inhibitor whose associated gene is a target gene of p53. Therefore, we examined whether ZBP-89 might also inhibit cell growth by activating p53. In the present study, we demonstrate that elevated levels of ZBP-89 induce growth arrest and apoptosis in human gastrointestinal cell lines. The ZBP-89 protein accumulated within 4 h, and the p53 protein accumulated within 16 h, of serum starvation without changes in p14ARF levels, demonstrating a physiological increase in the cellular levels of these two proteins. Overexpression of ZBP-89 stabilized the p53 protein and enhanced its transcriptional activity through direct protein-protein interactions. The DNA binding and C-terminal domains of p53 and the zinc finger domain of ZBP-89 mediated the interaction. A point mutation in the p53 DNA binding domain, R273H, greatly reduced ZBP-89-mediated stabilization but not their physical interaction. Furthermore, ZBP-89 formed a complex with p53 and MDM2 and therefore did not prevent the MDM2-p53 interaction. However, heterokaryon assays demonstrated that ZBP-89 retained p53 in the nucleus. Collectively, these data indicate that ZBP-89 regulates cell proliferation in part through its ability to directly bind the p53 protein and retard its nuclear export. Our findings further our understanding of how ZBP-89 modulates cell proliferation and reveals a novel mechanism by which the p53 protein is stabilized.

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Analysis of miRNAs Targeted Storage Regulatory Genes during Soybean Seed Development Based on Transcriptome Sequencing

Genes ◽

10.3390/genes10060408 ◽

2019 ◽

Vol 10 (6) ◽

pp. 408 ◽

Cited By ~ 2

Author(s):

Jing-Yao Yu ◽

Zhan-Guo Zhang ◽

Shi-Yu Huang ◽

Xue Han ◽

Xin-Yu Wang ◽

...

Keyword(s):

Expression Pattern ◽

Seed Development ◽

Small Rna ◽

Target Genes ◽

Soybean Seed ◽

Regulatory Genes ◽

Small Rna Sequencing ◽

Grain Development ◽

Regulatory Relationship ◽

Novel Mirna

Soybeans are an important cash crop and are widely used as a source of vegetable protein and edible oil. MicroRNAs (miRNA) are endogenous small RNA that play an important regulatory role in the evolutionarily conserved system of gene expression. In this study, we selected four lines with extreme phenotypes, as well as high or low protein and oil content, from the chromosome segment substitution line (CSSL) constructed from suinong (SN14) and ZYD00006, and planted and sampled at three stages of grain development for small RNA sequencing and expression analysis. The sequencing results revealed the expression pattern of miRNA in the materials, and predicted miRNA-targeted regulatory genes, including 1967 pairs of corresponding relationships between known-miRNA and their target genes, as well as 597 pairs of corresponding relationships between novel-miRNA and their target genes. After screening and annotating genes that were targeted for regulation, five specific genes were identified to be differentially expressed during seed development and subsequently analyzed for their regulatory relationship with miRNAs. The expression pattern of the targeted gene was verified by Real-time Quantitative PCR (RT-qPCR). Our research provides more information about the miRNA regulatory network in soybeans and further identifies useful genes that regulate storage during soy grain development, providing a theoretical basis for the regulation of soybean quality traits.

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Mutated p53 in HGSC—From a Common Mutation to a Target for Therapy

Cancers ◽

10.3390/cancers13143465 ◽

2021 ◽

Vol 13 (14) ◽

pp. 3465

Author(s):

Aya Saleh ◽

Ruth Perets

Keyword(s):

Cancer Progression ◽

Target Genes ◽

P53 Protein ◽

Genetic Alterations ◽

Common Mutation ◽

Missense Mutations ◽

P53 Expression ◽

Histologic Subtype ◽

Tp53 Mutations

Mutations in tumor suppressor gene TP53, encoding for the p53 protein, are the most ubiquitous genetic variation in human ovarian HGSC, the most prevalent and lethal histologic subtype of epithelial ovarian cancer (EOC). The majority of TP53 mutations are missense mutations, leading to loss of tumor suppressive function of p53 and gain of new oncogenic functions. This review presents the clinical relevance of TP53 mutations in HGSC, elaborating on several recently identified upstream regulators of mutant p53 that control its expression and downstream target genes that mediate its roles in the disease. TP53 mutations are the earliest genetic alterations during HGSC pathogenesis, and we summarize current information related to p53 function in the pathogenesis of HGSC. The role of p53 is cell autonomous, and in the interaction between cancer cells and its microenvironment. We discuss the reduction in p53 expression levels in tumor associated fibroblasts that promotes cancer progression, and the role of mutated p53 in the interaction between the tumor and its microenvironment. Lastly, we discuss the potential of TP53 mutations to serve as diagnostic biomarkers and detail some more advanced efforts to use mutated p53 as a therapeutic target in HGSC.

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Linking metabolic dysfunction with cardiovascular diseases: Brn-3b/POU4F2 transcription factor in cardiometabolic tissues in health and disease

Cell Death and Disease ◽

10.1038/s41419-021-03551-9 ◽

2021 ◽

Vol 12 (3) ◽

Author(s):

Vishwanie S. Budhram-Mahadeo ◽

Matthew R. Solomons ◽

Eeshan A. O. Mahadeo-Heads

Keyword(s):

Transcription Factor ◽

Cardiovascular Diseases ◽

Cell Fate ◽

Target Genes ◽

Cardiovascular Responses ◽

Normal Function ◽

Valuable Insight ◽

Metabolic Dysfunction ◽

Pathological Changes ◽

Cardiac Responses

AbstractMetabolic and cardiovascular diseases are highly prevalent and chronic conditions that are closely linked by complex molecular and pathological changes. Such adverse effects often arise from changes in the expression of genes that control essential cellular functions, but the factors that drive such effects are not fully understood. Since tissue-specific transcription factors control the expression of multiple genes, which affect cell fate under different conditions, then identifying such regulators can provide valuable insight into the molecular basis of such diseases. This review explores emerging evidence that supports novel and important roles for the POU4F2/Brn-3b transcription factor (TF) in controlling cellular genes that regulate cardiometabolic function. Brn-3b is expressed in insulin-responsive metabolic tissues (e.g. skeletal muscle and adipose tissue) and is important for normal function because constitutive Brn-3b-knockout (KO) mice develop profound metabolic dysfunction (hyperglycaemia; insulin resistance). Brn-3b is highly expressed in the developing hearts, with lower levels in adult hearts. However, Brn-3b is re-expressed in adult cardiomyocytes following haemodynamic stress or injury and is necessary for adaptive cardiac responses, particularly in male hearts, because male Brn-3b KO mice develop adverse remodelling and reduced cardiac function. As a TF, Brn-3b regulates the expression of multiple target genes, including GLUT4, GSK3β, sonic hedgehog (SHH), cyclin D1 and CDK4, which have known functions in controlling metabolic processes but also participate in cardiac responses to stress or injury. Therefore, loss of Brn-3b and the resultant alterations in the expression of such genes could potentially provide the link between metabolic dysfunctions with adverse cardiovascular responses, which is seen in Brn-3b KO mutants. Since the loss of Brn-3b is associated with obesity, type II diabetes (T2DM) and altered cardiac responses to stress, this regulator may provide a new and important link for understanding how pathological changes arise in such endemic diseases.

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