Editorial: [Exciting Discoveries About New p53 Target Genes, Cancer Drugs and Diagnostic Tools, and Mechanisms of Various Human Diseases]

2012 ◽  
Vol 12 (8) ◽  
pp. 899-900
Author(s):  
David Wan-Cheng
Keyword(s):  
Target Genes ◽  
Human Diseases ◽  
Diagnostic Tools ◽  
Cancer Drugs ◽  
P53 Target Genes

381: Promoter Hypermethylation Profile of Kidney Cancer with New Pro-Apoptotic P53 Target Genes and Possible Clinical Implications

2006 ◽  
Vol 175 (4S) ◽  
pp. 125-125
Author(s):  
Frank Christoph ◽  
Steffen Weikert ◽  
Carsten Kempkensteffen ◽  
Martin Schostak ◽  
Hans Krause ◽  
...  
Keyword(s):  
Kidney Cancer ◽  
Target Genes ◽  
Promoter Hypermethylation ◽  
Clinical Implications ◽  
P53 Target Genes

scholarly journals Nuclear Pore Component Nup98 Is a Potential Tumor Suppressor and Regulates Posttranscriptional Expression of Select p53 Target Genes

2012 ◽  
Vol 48 (5) ◽  
pp. 799-810 ◽  
Author(s):  
Stephan Singer ◽  
Ruiying Zhao ◽  
Anthony M. Barsotti ◽  
Anette Ouwehand ◽  
Mina Fazollahi ◽  
...  
Keyword(s):  
Tumor Suppressor ◽  
Target Genes ◽  
Nuclear Pore ◽  
P53 Target Genes ◽  
Potential Tumor Suppressor

scholarly journals CK1α ablation in keratinocytes induces p53-dependent, sunburn-protective skin hyperpigmentation

2017 ◽  
Vol 114 (38) ◽  
pp. E8035-E8044 ◽  
Author(s):  
Chung-Hsing Chang ◽  
Che-Jung Kuo ◽  
Takamichi Ito ◽  
Yu-Ya Su ◽  
Si-Tse Jiang ◽  
...  
Keyword(s):  
Target Genes ◽  
Neutralizing Antibody ◽  
Double Knockout ◽  
Melanocyte Stimulating Hormone ◽  
Kit Ligand ◽  
Skin Physiology ◽  
P53 Activation ◽  
P53 Target Genes ◽  
Single Knockout

Casein kinase 1α (CK1α), a component of the β-catenin destruction complex, is a critical regulator of Wnt signaling; its ablation induces both Wnt and p53 activation. To characterize the role of CK1α (encoded byCsnk1a1) in skin physiology, we crossed mice harboring floxedCsnk1a1with mice expressing K14–Cre–ERT2to generate mice in which tamoxifen induces the deletion ofCsnk1a1exclusively in keratinocytes [single-knockout (SKO) mice]. As expected, CK1α loss was accompanied by β-catenin and p53 stabilization, with the preferential induction of p53 target genes, but phenotypically most striking was hyperpigmentation of the skin, importantly without tumorigenesis, for at least 9 mo afterCsnk1a1ablation. The number of epidermal melanocytes and eumelanin levels were dramatically increased in SKO mice. To clarify the putative role of p53 in epidermal hyperpigmentation, we established K14–Cre–ERT2CK1α/p53 double-knockout (DKO) mice and found that coablation failed to induce epidermal hyperpigmentation, demonstrating that it was p53-dependent. Transcriptome analysis of the epidermis revealed p53-dependent up-regulation of Kit ligand (KitL). SKO mice treated with ACK2 (a Kit-neutralizing antibody) or imatinib (a Kit inhibitor) abrogated the CK1α ablation-induced hyperpigmentation, demonstrating that it requires the KitL/Kit pathway. Pro-opiomelanocortin (POMC), a precursor of α-melanocyte–stimulating hormone (α-MSH), was not activated in the CK1α ablation-induced hyperpigmentation, which is in contrast to the mechanism of p53-dependent UV tanning. Nevertheless, acute sunburn effects were successfully prevented in the hyperpigmented skin of SKO mice. CK1α inhibition induces skin-protective eumelanin but no carcinogenic pheomelanin and may therefore constitute an effective strategy for safely increasing eumelanin via UV-independent pathways, protecting against acute sunburn.

scholarly journals Bcor insufficiency promotes initiation and progression of myelodysplastic syndrome

Blood ◽  
2018 ◽  
Vol 132 (23) ◽  
pp. 2470-2483 ◽  
Author(s):  
Shiro Tara ◽  
Yusuke Isshiki ◽  
Yaeko Nakajima-Takagi ◽  
Motohiko Oshima ◽  
Kazumasa Aoyama ◽  
...  
Keyword(s):  
Myelodysplastic Syndrome ◽  
Target Genes ◽  
Myeloproliferative Neoplasms ◽  
Lymphoblastic Leukemia ◽  
Transcriptional Profiling ◽  
Hoxa Cluster ◽  
Carboxyl Terminal ◽  
Regulator Genes ◽  
The Impact ◽  
P53 Target Genes

Abstract BCOR, encoding BCL-6 corepressor (BCOR), is X-linked and targeted by somatic mutations in various hematological malignancies including myelodysplastic syndrome (MDS). We previously reported that mice lacking Bcor exon 4 (BcorΔE4/y) in the hematopoietic compartment developed NOTCH-dependent acute T-cell lymphoblastic leukemia (T-ALL). Here, we analyzed mice lacking Bcor exons 9 and 10 (BcorΔE9-10/y), which express a carboxyl-terminal truncated BCOR that fails to interact with core effector components of polycomb repressive complex 1.1. BcorΔE9-10/y mice developed lethal T-ALL in a similar manner to BcorΔE4/y mice, whereas BcorΔE9-10/y hematopoietic cells showed a growth advantage in the myeloid compartment that was further enhanced by the concurrent deletion of Tet2. Tet2Δ/ΔBcorΔE9-10/y mice developed lethal MDS with progressive anemia and leukocytopenia, inefficient hematopoiesis, and the morphological dysplasia of blood cells. Tet2Δ/ΔBcorΔE9-10/y MDS cells reproduced MDS or evolved into lethal MDS/myeloproliferative neoplasms in secondary recipients. Transcriptional profiling revealed the derepression of myeloid regulator genes of the Cebp family and Hoxa cluster genes in BcorΔE9-10/y progenitor cells and the activation of p53 target genes specifically in MDS erythroblasts where massive apoptosis occurred. Our results reveal a tumor suppressor function of BCOR in myeloid malignancies and highlight the impact of Bcor insufficiency on the initiation and progression of MDS.

Haematotoxicology: Scientific Basis and Regulatory Aspects

2002 ◽  
Vol 30 (2_suppl) ◽  
pp. 111-113 ◽  
Author(s):  
Laura Gribaldo
Keyword(s):  
Target Genes ◽  
Cell Types ◽  
Scientific Basis ◽  
Cancer Drugs ◽  
Experimental Conditions ◽  
Clinical Drug Development ◽  
Anti Cancer ◽  
Starting Dose ◽  
Life Threatening

Haematopoietic tissues are the targets of numerous xenobiotics. The purpose of in vitro haematotoxicology is the prediction of adverse haematological effects from toxicants on human haematopoietic targets under controlled experimental conditions in the laboratory. Building on its foundations in experimental haematology and the wealth of haematotoxicological data found in experimental oncology, this field of alternatives toxicology has developed rapidly during the past decade. Preclinical and clinical drug development for anti-cancer drugs differs from that for other pharmaceuticals, because of the life-threatening nature of the disease. Treatment with anti-cancer drugs at clinically efficacious doses usually induces serious side-effects. The design of preclinical toxicology studies for anti-cancer drugs is intended to identify a safe clinical starting dose, characterise toxicities that could be encountered in human clinical trials, and determine whether these toxicities are reversible, manageable, and predictable. Although the myeloid colony-forming unit (CFU-GM) progenitor is most frequently evaluated, other defined progenitors and stem cells, as well as cell types found in the bone-marrow stroma, can now be evaluated in vitro. Genetic damage to haematopoietic cells can occur in the absence of any overt haematological signs. The development of tissue-specific screening systems that are able to give information about the toxic effects of chemicals, drugs and environmental hazards on target genes is needed, in order to make preliminary decisions or to set priorities for selection among large groups of chemicals and possible drugs.

scholarly journals Anticancer Agents from Diverse Natural Sources

2014 ◽  
Vol 9 (11) ◽  
pp. 1934578X1400901 ◽  
Author(s):  
Jabeena Khazir ◽  
Darren L. Riley ◽  
Lynne A. Pilcher ◽  
Pieter De-Maayer ◽  
Bilal Ahmad Mir
Keyword(s):  
Clinical Trials ◽  
Natural Products ◽  
Anticancer Agents ◽  
Marine Organisms ◽  
New Drugs ◽  
Human Diseases ◽  
Cancer Drugs ◽  
Natural Sources ◽  
Anti Cancer ◽  
Ancient Times

This review attempts to portray the discovery and development of anticancer agents/drugs from diverse natural sources. Natural molecules from these natural sources including plants, microbes and marine organisms have been the basis of treatment of human diseases since the ancient times. Compounds derived from nature have been important sources of new drugs and also serve as templates for synthetic modification. Many successful anti-cancer drugs currently in use are naturally derived or their analogues and many more are under clinical trials. This review aims to highlight the invaluable role that natural products have played, and continue to play, in the discovery of anticancer agents.

p53-Dependent acinar cell apoptosis triggers epithelial proliferation in duct-ligated murine pancreas

2000 ◽  
Vol 279 (4) ◽  
pp. G827-G836 ◽  
Author(s):  
Charles R. Scoggins ◽  
Ingrid M. Meszoely ◽  
Michihiko Wada ◽  
Anna L. Means ◽  
Liying Yang ◽  
...  
Keyword(s):  
Acinar Cell ◽  
Cell Apoptosis ◽  
Target Genes ◽  
P53 Protein ◽  
Acinar Cells ◽  
Epithelial Proliferation ◽  
Pancreatic Duct Ligation ◽  
Duct Ligation ◽  
The Relationship ◽  
P53 Target Genes

The mechanisms linking acinar cell apoptosis and ductal epithelial proliferation remain unknown. To determine the relationship between these events, pancreatic duct ligation (PDL) was performed on p53(+/+) and p53(−/−) mice. In mice bearing a wild-type p53 allele, PDL resulted in upregulation of p53 protein in both acinar cells and proliferating duct-like epithelium. In contrast, upregulation of Bcl-2 occurred only in duct-like epithelium. Both p21WAF1/CIP1 and Bax were also upregulated in duct-ligated lobes. After PDL in p53(+/+) mice, acinar cells underwent widespread apoptosis, while duct-like epithelium underwent proliferative expansion. In the absence of p53, upregulation of p53 target genes and acinar cell apoptosis did not occur. The absence of acinar cell apoptosis in p53(−/−) mice also eliminated the proliferative response to duct ligation. These data demonstrate that PDL-induced acinar cell apoptosis is a p53-dependent event and suggest a direct link between acinar cell apoptosis and proliferation of duct-like epithelium in duct-ligated pancreas.

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 Maximal killing of lymphoma cells by DNA damage–inducing therapy requires not only the p53 targets Puma and Noxa, but also Bim

Blood ◽  
2010 ◽  
Vol 116 (24) ◽  
pp. 5256-5267 ◽  
Author(s):  
Lina Happo ◽  
Mark S. Cragg ◽  
Belinda Phipson ◽  
Jon M. Haga ◽  
Elisa S. Jansen ◽  
...  
Keyword(s):  
Dna Damage ◽  
Drug Resistance ◽  
Target Genes ◽  
B Cell Lymphoma ◽  
Chemotherapeutic Agents ◽  
Lymphoid Cells ◽  
Lymphoma Cells ◽  
P53 Target Genes

Abstract DNA-damaging chemotherapy is the backbone of cancer treatment, although it is not clear how such treatments kill tumor cells. In nontransformed lymphoid cells, the combined loss of 2 proapoptotic p53 target genes, Puma and Noxa, induces as much resistance to DNA damage as loss of p53 itself. In Eμ-Myc lymphomas, however, lack of both Puma and Noxa resulted in no greater drug resistance than lack of Puma alone. A third B-cell lymphoma-2 homology domain (BH)3-only gene, Bim, although not a direct p53 target, was up-regulated in Eμ-Myc lymphomas incurring DNA damage, and knockdown of Bim levels markedly increased the drug resistance of Eμ-Myc/Puma−/−Noxa−/− lymphomas both in vitro and in vivo. Remarkably, c-MYC–driven lymphoma cell lines from Noxa−/−Puma−/−Bim−/− mice were as resistant as those lacking p53. Thus, the combinatorial action of Puma, Noxa, and Bim is critical for optimal apoptotic responses of lymphoma cells to 2 commonly used DNA-damaging chemotherapeutic agents, identifying Bim as an additional biomarker for treatment outcome in the clinic.

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