Expression of the human GADD45a gene is increased in TK6 cells exposed to mutagens, clastogens and aneugens. It is known to be regulated through both p53-dependent and p53-independent pathways and WT1 has been implicated in both cases. This article reports an investigation into the effect that mutations in the WT1 and p53 response elements of the gene have on GADD45a expression. This was conducted in both p53 wild-type (TK6) and mutant (WI-L2-NS) human B lymphoblastoid cell lines. Gene expression was monitored using a GADD45a-green fluorescent protein reporter assay. Mutant cell lines were exposed to the mechanistically diverse genotoxins methyl methanesulphonate, cisplatin and mitomycin C (direct acting), hydroxyurea, aphidicolin and 5'fluorouracil (inhibitors of nucleotide/DNA synthesis) and benomyl (aneugen). In all cases, the induction of the reporter was reduced in the mutants compared with wild-type. These results provide experimental evidence for the implied role of WT1 in both p53-dependent and p53-independent pathways of GADD45a regulation and further insight into the mechanism of GADD45a induction by genotoxins.
Download full-text PDF |
Source |
|---|---|
| http://dx.doi.org/10.1093/mutage/get015 | DOI Listing |
Publication Analysis
Top Keywords
Similar Publications
Design, synthesis, and antiproliferative activity evaluation of novel α-mangostin derivatives by ROS/MAPK signaling pathway.
Bioorg Chem
December 2024
Department of Pathophysiology, School of Basic Medical Sciences, College of Medicine, Zhengzhou University, Zhengzhou, Henan, 450001, China; China-US (Henan) Hormel Cancer Institute, No.127, Dongming Road, Jinshui District, Zhengzhou, Henan 450008, China; State Key Laboratory of Esophageal Cancer Prevention and Treatment, Zhengzhou University, Zhengzhou, Henan, China; The Hormel Institute, University of Minnesota, Austin, MN 55912, USA; Provincial Cooperative Innovation Center for Cancer Chemoprevention, Zhengzhou University, Zhengzhou 450000, China; Cancer Chemoprevention International Collaboration Laboratory, Zhengzhou 450000, China; Tianjian Laboratory of Advanced Biomedical Sciences, Institute of Advanced Biomedical Sciences, Zhengzhou University, Zhengzhou, Henan, China. Electronic address:
Novel hydroxamic acid and 3,6-amide modified α-mangostin derivatives were synthesized and evaluated their antiproliferative activities against KYSE 30 (esophageal cancer), HCT 116 (colon cancer), and HGC 27 (gastric cancer) cell lines. Most of the new derivatives displayed stronger anti-proliferative activities compared to α-mangostin. Among all the derivatives, compound 4a exhibited the most potent activity, with IC values of 0.
View Article and Find Full Text PDFHepatitis B Virus X Protein Induces Reactive Oxygen Species Generation via Activation of p53 in Human Hepatoma Cells.
Biomolecules
September 2024
Department of Integrated Biological Science, The Graduate School, Pusan National University, Busan 46241, Republic of Korea.
Hepatitis B virus (HBV), particularly through the HBx protein, induces oxidative stress during liver infections. This study reveals that HBx increases reactive oxygen species (ROS) via two distinct mechanisms. The first mechanism is p53-independent, likely involving mitochondrial dysfunction, as demonstrated by elevated ROS levels in p53-deficient Hep3B cells and p53-knocked-down HepG2 cells after HBx expression or HBV infection.
View Article and Find Full Text PDFThe mitochondrial enzyme pyruvate carboxylase restricts pancreatic β-cell senescence by blocking p53 activation.
Proc Natl Acad Sci U S A
October 2024
Department of Endocrinology and Metabolism, Zhongshan Hospital, Fudan University, Shanghai 200030, China.
Defective glucose-stimulated insulin secretion (GSIS) and β-cell senescence are hallmarks in diabetes. The mitochondrial enzyme pyruvate carboxylase (PC) has been shown to promote GSIS and β-cell proliferation in the clonal β-cell lines, yet its physiological relevance remains unknown. Here, we provide animal and human data showing a role of PC in protecting β-cells against senescence and maintaining GSIS under different physiological and pathological conditions.
View Article and Find Full Text PDFRibosomes are critical for cell function; their synthesis (known as ribosome biogenesis; "RiBi") is complex and energy-intensive. Surprisingly little is known about RiBi in differentiated cells in adult tissue. Here, we generated mice with conditional deletion of , an essential gene for RiBi and translation, to investigate effects of RiBi blockade We focused on RiBi in a long-lived, ribosome-rich cell population, pancreatic acinar cells, during homeostasis and tumorigenesis.
View Article and Find Full Text PDFIntegrated stress response (ISR) activation and apoptosis through HRI kinase by PG3 and other p53 pathway-restoring cancer therapeutics.
Oncotarget
September 2024
Laboratory of Translational Oncology and Experimental Cancer Therapeutics, Warren Alpert Medical School, Brown University, RI 02912, USA.
Restoration of the p53 pathway has been a long-term goal in the field of cancer research to treat tumors with mutated p53 and aggressive clinical behavior. p53 pathway restoration in p53-deficient cancers can be achieved by small molecules via p53-dependent or p53-independent processes. Hereafter p53-independent restoration of p53-pathway-signaling in p53-deficient/mutated tumors is referred to as 'restoration of the p53 pathway'.
View Article and Find Full Text PDFWant AI Summaries of new PubMed Abstracts delivered to your In-box?
Enter search terms and have AI summaries delivered each week - change queries or unsubscribe any time!