scholarly journals A Glance of p53 Functions in Brain Development, Neural Stem Cells, and Brain Cancer

Biology ◽  
2020 ◽  
Vol 9 (9) ◽  
pp. 285
Author(s):  
Yuqing Xiong ◽  
Yun Zhang ◽  
Shunbin Xiong ◽  
Abie E. Williams-Villalobo
Keyword(s):  
Gene Expression ◽  
Brain Development ◽  
P53 Protein ◽  
P53 Gene ◽  
Stem Cell Regulation ◽  
Cellular Events ◽  
Damage Repair ◽  
Brain Tumor Cells ◽  
Metabolic Remodeling

p53 is one of the most intensively studied tumor suppressors. It transcriptionally regulates a broad range of genes to modulate a series of cellular events, including DNA damage repair, cell cycle arrest, senescence, apoptosis, ferroptosis, autophagy, and metabolic remodeling, which are fundamental for both development and cancer. This review discusses the role of p53 in brain development, neural stem cell regulation and the mechanisms of inactivating p53 in gliomas. p53 null or p53 mutant mice show female biased exencephaly, potentially due to X chromosome inactivation failure and/or hormone-related gene expression. Oxidative cellular status, increased PI3K/Akt signaling, elevated ID1, and metabolism are all implicated in p53-loss induced neurogenesis. However, p53 has also been shown to promote neuronal differentiation. In addition, p53 mutations are frequently identified in brain tumors, especially glioblastomas. Mechanisms underlying p53 inactivation in brain tumor cells include disruption of p53 protein stability, gene expression and transactivation potential as well as p53 gene loss or mutation. Loss of p53 function and gain-of-function of mutant p53 are both implicated in brain development and tumor genesis. Further understanding of the role of p53 in the brain may provide therapeutic insights for brain developmental syndromes and cancer.

scholarly journals Inhibition of polyamine synthesis induces p53 gene expression but not apoptosis

1999 ◽  
Vol 276 (4) ◽  
pp. C946-C954 ◽  
Author(s):  
Li Li ◽  
Ji Li ◽  
Jaladanki N. Rao ◽  
Minglin Li ◽  
Barbara L. Bass ◽  
...  
Keyword(s):  
Gene Expression ◽  
Growth Inhibition ◽  
P53 Protein ◽  
Specific Inhibitor ◽  
P53 Gene ◽  
Mrna Levels ◽  
Intestinal Epithelial ◽  
Polyamine Biosynthesis ◽  
Fetal Bovine ◽  
P53 Mrna

The nuclear phosphoprotein p53 acts as a transcription factor and is involved in growth inhibition and apoptosis. The present study was designed to examine the effect of decreasing cellular polyamines on p53 gene expression and apoptosis in small intestinal epithelial (IEC-6) cells. Cells were grown in DMEM containing 5% dialyzed fetal bovine serum in the presence or absence of α-difluoromethylornithine (DFMO), a specific inhibitor of polyamine biosynthesis, for 4, 6, and 12 days. The cellular polyamines putrescine, spermidine, and spermine in DFMO-treated cells decreased dramatically at 4 days and remained depleted thereafter. Polyamine depletion by DFMO was accompanied by a significant increase in expression of the p53 gene. The p53 mRNA levels increased 4 days after exposure to DFMO, and the maximum increases occurred at 6 and 12 days after exposure. Increased levels of p53 mRNA in DFMO-treated cells were paralleled by increases in p53 protein. Polyamines given together with DFMO completely prevented increased expression of the p53 gene. Increased expression of the p53 gene in DFMO-treated cells was associated with a significant increase in G1 phase growth arrest. In contrast, no features of programmmed cell death were identified after polyamine depletion: no internucleosomal DNA fragmentation was observed, and no morphological features of apoptosis were evident in cells exposed to DFMO for 4, 6, and 12 days. These results indicate that 1) decreasing cellular polyamines increases expression of the p53 gene and 2) activation of p53 gene expression after polyamine depletion does not induce apoptosis in intestinal crypt cells. These findings suggest that increased expression of the p53 gene may play an important role in growth inhibition caused by polyamine depletion.

scholarly journals IMMUNOHISTOPATHOLOGICAL ROLE OF BCL2 AND P53 GENE EXPRESSION IN HELICOBACTER PYLORI CYTOTOXIN-ASSOCIATED GENE A POSITIVE VERSUS CYTOTOXIN-ASSOCIATED GENE A NEGATIVE ANTRAL PREDOMINANT NON-ATROPHIC GASTRITIS IN IRAQI PATIENTS

2017 ◽  
Vol 10 (3) ◽  
pp. 142
Author(s):  
Ali Ibrahim Ali Al-ezzy
Keyword(s):  
Gene Expression ◽  
Helicobacter Pylori ◽  
Atrophic Gastritis ◽  
P53 Gene ◽  
P53 Expression ◽  
Positive Correlation ◽  
Urease Test ◽  
Cytotoxin Associated Gene A ◽  
Bcl2 Expression

ABSTRACTObjectives: To determine the role of Bcl2 and p53 gene expression in the pathogenesis of antral-predominant non-atrophic gastritis (APNG) accordingto Helicobacter pylori (HP) cytotoxin-associated gene A (CagA) status.Methods: Multiple antral biopsies were taken from 78 patients for rapid urease test, histopathology, Bcl2 and P53 immunohistochemistry and HPCagA in situ hybridization.Results: CagA was detected in 74.35% cases. There was no significant difference in Bcl2 expression among CagA+ and CagA− APNG cases. Significantdifferences in polymorphonuclear neutrophils (PMNs) and lymphocytes grades were detected among CagA+ and CagA− APNG cases. There was nosignificant correlation among patients’ age, inflammatory infiltrates, Bcl2, p53 expression. CagA has positive correlation with p53 (p=0.001), PMNsgrade (p=0.027), lymphocytes grade (p=0.003), inflammation intensity (p=0.006), and inflammation activity (p=0.007). Bcl2 has no significantcorrelation with p53, CagA, PMNs, and lymphocytes indexes. P53 expression has significant correlation with PMNs and lymphocyte grades (p=0.000),inflammation intensity (p=0.003), and inflammation activity (p=0.002). PMNs grade has positive correlation with lymphocyte grade, inflammationintensity, and activity (p=0.000). Lymphocyte grade has a significant correlation with inflammation intensity and activity (p=0.000). Inflammationintensity has a significant correlation with inflammation activity (p=0.000).Conclusions: CagA cytotoxin has direct effect on P53 gene and indirect effect on Bcl2 gene expression in APNG cases. Bcl2 and P53 expression donot get affected by patient’s age and gender. PMNs grade, lymphocytes grade, inflammation intensity, and inflammation activity affected directly byP53 and CagA cytotoxin expression and indirectly by Bcl2 expression. The balance of P53-Bcl2 pathways play a vital role in pathogenesis of HP andCagA-induced APNG.Keywords: Antral-predominant non-atrophic gastritis, Bcl2, p53, Helicobacter pylori, Cytotoxin-associated gene A.

scholarly journals Role of P53 protein in activation of atm- and parp-mediated dna damage repair (DDR) pathways induced by topoisomerase type II inhibitors

2016 ◽  
Vol 97 (2) ◽  
pp. 245-249
Author(s):  
B.R. Ramazanov ◽  
◽  
R.R. Khusnutdinov ◽  
A.R. Galembikova ◽  
P.D. Dunaev ◽  
...  
Keyword(s):  
Dna Damage ◽  
P53 Protein ◽  
Dna Damage Repair ◽  
Type Ii ◽  
Damage Repair

scholarly journals Inhibition of Stress-Inducible Kinase Pathways by Tumorigenic Mutant p53

2003 ◽  
Vol 23 (1) ◽  
pp. 322-334 ◽  
Author(s):  
Yoichi Ohiro ◽  
Anny Usheva ◽  
Shinichiro Kobayashi ◽  
Shannon L. Duffy ◽  
Regan Nantz ◽  
...  
Keyword(s):  
Tumor Cells ◽  
P53 Protein ◽  
Gene Mutations ◽  
P53 Gene ◽  
Mutant P53 ◽  
Inhibition Of Proliferation ◽  
Dependent Inhibition ◽  
Tumor Types ◽  
Precise Role

ABSTRACT More than 50% of human cancers contain p53 gene mutations and as a result accumulate altered forms of the full-length p53 protein. Although certain tumor types expressing mutant p53 protein have a poor prognostic process, the precise role of mutant p53 protein in highly malignant tumor cells is not well defined. Some p53 mutants, but not wild-type p53, are shown here to interact with Daxx, a Fas-binding protein that activates stress-inducible kinase pathways. Interaction of Daxx with p53 is highly dependent upon the specific mutation of p53. Tumorigenic mutants of p53 bind to Daxx and inhibit Daxx-dependent activation of the apoptosis signal-regulating kinase 1 stress-inducible kinases and Jun NH2-terminal kinase. Mutant p53 forms complexes with Daxx in cells, and consequently, mutant p53 is able to rescue cells from Daxx-dependent inhibition of proliferation. Thus, the accumulation of mutant p53 in tumor cells may contribute to tumorigenesis by inhibiting stress-inducible kinase pathways.

scholarly journals A constitutive active allele of the transcription factor Msn2 mimicking low PKA activity dictates metabolic remodeling in yeast

2018 ◽  
Vol 29 (23) ◽  
pp. 2848-2862 ◽  
Author(s):  
Vera Pfanzagl ◽  
Wolfram Görner ◽  
Martin Radolf ◽  
Alexandra Parich ◽  
Rainer Schuhmacher ◽  
...  
Keyword(s):  
Gene Expression ◽  
Gene Expression Signature ◽  
Metabolic Reprogramming ◽  
Diauxic Shift ◽  
Environmental Stress Response ◽  
Metabolic Switch ◽  
Metabolic Remodeling ◽  
Active Allele ◽  
Limited Degree

In yeast, protein kinase A (PKA) adjusts transcriptional profiles, metabolic rates, and cell growth in accord with carbon source availability. PKA affects gene expression mostly via the transcription factors Msn2 and Msn4, two key regulators of the environmental stress response. Here we analyze the role of the PKA-Msn2 signaling module using an Msn2 allele that harbors serine-to-alanine substitutions at six functionally important PKA motifs (Msn2A6) . Expression of Msn2A6 mimics low PKA activity, entails a transcription profile similar to that of respiring cells, and prevents formation of colonies on glucose-containing medium. Furthermore, Msn2A6 leads to high oxygen consumption and hence high respiratory activity. Substantially increased intracellular concentrations of several carbon metabolites, such as trehalose, point to a metabolic adjustment similar to diauxic shift. This partial metabolic switch is the likely cause for the slow-growth phenotype in the presence of glucose. Consistently, Msn2A6 expression does not interfere with growth on ethanol and tolerated is to a limited degree in deletion mutant strains with a gene expression signature corresponding to nonfermentative growth. We propose that the lethality observed in mutants with hampered PKA activity resides in metabolic reprogramming that is initiated by Msn2 hyperactivity.

scholarly journals POS0398 ADIPONECTIN INDUCES SYNOVIAL ANGIOGENESIS IN RHEUMATOID ARTHRITIS THROUGH METABOLIC REMODELING

2021 ◽  
Vol 80 (Suppl 1) ◽  
pp. 428.2-428
Author(s):  
L. Wang ◽  
W. Tan ◽  
F. Wang ◽  
M. Zhang
Keyword(s):  
Rheumatoid Arthritis ◽  
Gene Expression ◽  
Endothelial Cell ◽  
Bone Erosion ◽  
Aortic Ring ◽  
Tube Formation ◽  
Related Gene ◽  
Metabolic Remodeling ◽  
Angiogenesis Related Gene

Background:Our team have previously reported that Adiponectin correlates well with synovial inflammation and progressive bone erosion in rheumatoid arthritis (RA). Angiogenesis is another important part, which plays a critical role in the pathogenesis of RA.Objectives:We hypothesized that adiponectin induces synovial angiogenesis in RA.Methods:Single-cell RNA sequencing (scRNA-Seq) was used to screen cellular changes in local knee joint of collagen-induced arthritis (CIA) after intraarticularly injected of adiponectin. Chimera models of synovium-cartilage-NOD/SCID mice, matrigel plug assay and rat aortic ring assay were performed to demonstrate the pro-angiogenesis role of adiponectin. Cellular experiment, including proliferation, migration, apoptosis, tube formation and angiogenesis related gene expression profile, were detected with Human Umbilical Vein Endothelial Cells (HUVEC) and Mice Lung Microvessel Endothelial Cell (MLMEC) after adiponectin stimulation. Seahorse was performed to clear the influence of adiponectin to cell metabolism.Results:The synovium and pannus hyperplasia worse in CIA model after intraarticularly injected of adiponectin, along with more serious synovitis and bone erosion. ScRNA-Seq of synovial tissues separated from CIA reminded that endothelial cell barbarically grows via metabolic remodeling after stimulated with adiponectin. Synovial chimera, matrigel plug and rat aortic ring shows adiponectin accelerates angiogenesis significantly in different background conditions. In vitro, endothelial cell proliferation detecting by RCTA and CCK8, migration by wound healing and transwell, apoptosis by FACS, tube formation and angiogenesis related gene expression profile by PCR-ARRAY were promoted by adiponectin in both HUVEC and MLMEC. Seahorse showed HUVEC made more use of glycolysis after co-cultured with adiponectin, a method of cell energy supply that tumor cells possess called warburg effect, that drives endothelial cell hyperplasia in severe environment.Conclusion:As a classic metabolic regulator, adiponectin exacerbates CIA by promoting angiogenesis through metabolic remodeling. The findings not only provide a novel insight into the pathogenic role of adiponectin, but also reveals a potential therapeutical strategy to attenuate revascularization in RA.Disclosure of Interests:None declared

scholarly journals Acetylation of Mouse p53 at Lysine 317 Negatively Regulates p53 Apoptotic Activities after DNA Damage

2006 ◽  
Vol 26 (18) ◽  
pp. 6859-6869 ◽  
Author(s):  
Connie Chao ◽  
Zhiqun Wu ◽  
Sharlyn J. Mazur ◽  
Helena Borges ◽  
Matteo Rossi ◽  
...  
Keyword(s):  
Gene Expression ◽  
Dna Damage ◽  
Posttranslational Modifications ◽  
P53 Protein ◽  
P53 Gene ◽  
Carboxyl Terminus ◽  
Mouse Embryonic Fibroblasts ◽  
Embryonic Fibroblasts ◽  
Doxorubicin Treatment ◽  
Lysine Residues

ABSTRACT Posttranslational modifications of p53, including phosphorylation and acetylation, play important roles in regulating p53 stability and activity. Mouse p53 is acetylated at lysine 317 by PCAF and at multiple lysine residues at the extreme carboxyl terminus by CBP/p300 in response to genotoxic and some nongenotoxic stresses. To determine the physiological roles of p53 acetylation at lysine 317, we introduced a Lys317-to-Arg (K317R) missense mutation into the endogenous p53 gene of mice. p53 protein accumulates to normal levels in p53K317R mouse embryonic fibroblasts (MEFs) and thymocytes after DNA damage. While p53-dependent gene expression is largely normal in p53K317R MEFs after various types of DNA damage, increased p53-dependent apoptosis was observed in p53K317R thymocytes, epithelial cells from the small intestine, and cells from the retina after ionizing radiation (IR) as well as in E1A/Ras-expressing MEFs after doxorubicin treatment. Consistent with these findings, p53-dependent expression of several proapoptotic genes was significantly increased in p53K317R thymocytes after IR. These findings demonstrate that acetylation at lysine 317 negatively regulates p53 apoptotic activities after DNA damage.

scholarly journals The multifunctional role of EKLF/KLF1 during erythropoiesis

Blood ◽  
2011 ◽  
Vol 118 (8) ◽  
pp. 2044-2054 ◽  
Author(s):  
Miroslawa Siatecka ◽  
James J. Bieker
Keyword(s):  
Gene Expression ◽  
Erythroid Differentiation ◽  
Red Cell ◽  
Direct Role ◽  
Erythroid Progenitor ◽  
Cellular Events ◽  
Downstream Effects ◽  
Cell Phenotypes ◽  
Terminal Erythroid Differentiation

Abstract The cellular events that lead to terminal erythroid differentiation rely on the controlled interplay of extra- and intracellular regulatory factors. Their downstream effects are highly coordinated and result in the structural/morphologic and metabolic changes that uniquely characterize a maturing red blood cell. Erythroid Krüppel-like factor (EKLF/KLF1) is one of a very small number of intrinsic transcription factors that play a major role in regulating these events. This review covers 3 major aspects of erythropoiesis in which EKLF plays crucial functions: (1) at the megakaryocyte-erythroid progenitor stage, where it is involved in erythroid lineage commitment; (2) during the global expansion of erythroid gene expression in primitive and definitive lineages, where it plays a direct role in globin switching; and (3) during the terminal maturation of red cells, where it helps control exit from the cell cycle. We conclude by describing recent studies of mammalian EKLF/KLF1 mutations that lead to altered red cell phenotypes and disease.

Polyamine depletion stabilizes p53 resulting in inhibition of normal intestinal epithelial cell proliferation

2001 ◽  
Vol 281 (3) ◽  
pp. C941-C953 ◽  
Author(s):  
Li Li ◽  
Jaladanki N. Rao ◽  
Xin Guo ◽  
Lan Liu ◽  
Rachel Santora ◽  
...  
Keyword(s):  
Gene Expression ◽  
Cell Proliferation ◽  
Growth Inhibition ◽  
Intestinal Mucosa ◽  
P53 Protein ◽  
P53 Gene ◽  
Small Intestinal Mucosa ◽  
Small Intestinal ◽  
The Stability ◽  
P53 Mrna

The p53 nuclear phosphoprotein plays a critical role in transcriptional regulation of target genes involved in growth arrest and apoptosis. The natural polyamines, including spermidine, spermine, and their precursor putrescine, are required for cell proliferation, and decreasing cellular polyamines inhibits growth of the small intestinal mucosa. In the current study, we investigated the mechanisms of regulation of p53 gene expression by cellular polyamines and further determined the role of the gene product in the process of growth inhibition after polyamine depletion. Studies were conducted both in vivo and in vitro using rats and the IEC-6 cell line, derived from rat small intestinal crypt cells. Levels for p53 mRNA and protein, transcription and posttranscription of the p53 gene, and cell growth were examined. Depletion of cellular polyamines by treatment with α-difluoromethylornithine (DFMO) increased p53 gene expression and caused growth inhibition in the intact small intestinal mucosa and the cultured cells. Polyamine depletion dramatically increased the stability of p53 mRNA as measured by the mRNA half-life but had no effect on p53 gene transcription in IEC-6 cells. Induction of p53 mRNA levels in DFMO-treated cells was paralleled by an increase in the rate of newly synthesized p53 protein. The stability of p53 protein was also increased after polyamine depletion, which was associated with a decrease in Mdm2 expression. When polyamine-deficient cells were exposed to exogenous spermidine, a decrease in p53 gene expression preceded an increase in cellular DNA synthesis. Inhibition of the p53 gene expression by using p53 antisense oligodeoxyribonucleotides significantly promoted cell growth in the presence of DFMO. These findings indicate that polyamines downregulate p53 gene expression posttranscriptionally and that growth inhibition of small intestinal mucosa after polyamine depletion is mediated, at least partially, through the activation of p53 gene.

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