title: Posttranscriptional Upregulation of p53 by Reactive Oxygen Species in Chronic Lymphocytic Leukemia.
abstract: Chronic lymphocytic leukemia (CLL) cells multiply and become more resistant to immunochemotherapy in "proliferation centers" within tissues, whereas apoptosis occurs in the periphery. Various models recapitulate these microenvironments in vitro, such as stimulation with CD154 and IL4. Using this system, we observed a 30- to 40-fold induction of wild-type p53 protein in 50 distinct human CLL specimens tested, without the induction of either cell-cycle arrest or apoptosis. In contrast, the mRNA levels for p53 did not increase, indicating that its elevation occurred posttranscriptionally. Mechanistic investigations revealed that under the conditions studied, p53 was phosphorylated on residues associated with p53 activation and increased half-life. However, p53 protein induced in this manner could transcriptionally activate only a subset of target genes. The addition of a DNA-damaging agent further upregulated p53 protein levels, which led to apoptosis. p53 induction relied on the increase in intracellular reactive oxygen species observed after CD154 and IL4 stimulation. We propose that chronic oxidative stress is a characteristic of the microenvironment in B-cell "proliferation centers" in CLL that are capable of elevating the basal expression of p53, but to levels below the threshold needed to induce arrest or apoptosis. Our findings suggest that reactivation of the full transcriptional activities of p53 in proliferating CLL cells may offer a possible therapeutic strategy. Cancer Res; 76(21); 6311-9. ©2016 AACR.
authors.affiliation: Department of Molecular and Cell Biology, University of Leicester, Leicester, United Kingdom.|Mechanisms of Cancer and Ageing Lab, University of Leicester, Leicester, United Kingdom.|Ernest and Helen Scott Haematological Research Institute, University of Leicester, Leicester, United Kingdom.|CRUK Leicester Centre, University of Leicester, Leicester, United Kingdom.
authors.forename: Jesvin
authors.initials: J
authors.lastname: Samuel
authors.affiliation: Ernest and Helen Scott Haematological Research Institute, University of Leicester, Leicester, United Kingdom.|CRUK Leicester Centre, University of Leicester, Leicester, United Kingdom.|Department of Cancer Studies, University of Leicester, Leicester, United Kingdom.
authors.forename: Sandrine
authors.initials: S
authors.lastname: Jayne
authors.affiliation: Department of Molecular and Cell Biology, University of Leicester, Leicester, United Kingdom.|Mechanisms of Cancer and Ageing Lab, University of Leicester, Leicester, United Kingdom.|Ernest and Helen Scott Haematological Research Institute, University of Leicester, Leicester, United Kingdom.|CRUK Leicester Centre, University of Leicester, Leicester, United Kingdom.
authors.forename: Yixiang
authors.initials: Y
authors.lastname: Chen
authors.affiliation: MRC Toxicology Unit, Leicester, United Kingdom.
authors.forename: Aneela
authors.initials: A
authors.lastname: Majid
authors.affiliation: Department of Molecular and Cell Biology, University of Leicester, Leicester, United Kingdom.|Mechanisms of Cancer and Ageing Lab, University of Leicester, Leicester, United Kingdom.|Ernest and Helen Scott Haematological Research Institute, University of Leicester, Leicester, United Kingdom.|CRUK Leicester Centre, University of Leicester, Leicester, United Kingdom.
authors.forename: Alice
authors.initials: A
authors.lastname: Wignall
authors.affiliation: Department of Molecular and Cell Biology, University of Leicester, Leicester, United Kingdom.|Mechanisms of Cancer and Ageing Lab, University of Leicester, Leicester, United Kingdom.|Ernest and Helen Scott Haematological Research Institute, University of Leicester, Leicester, United Kingdom.|CRUK Leicester Centre, University of Leicester, Leicester, United Kingdom.
authors.forename: Timothy
authors.initials: T
authors.lastname: Wormull
authors.affiliation: CRUK Leicester Centre, University of Leicester, Leicester, United Kingdom.|Department of Cancer Studies, University of Leicester, Leicester, United Kingdom.|Department of Clinical Biochemistry, College of Medicine, University of Duhok, Kurdistan Regional Government, Iraq.
authors.forename: Hishyar
authors.initials: H
authors.lastname: Najeeb
authors.affiliation: CRUK Leicester Centre, University of Leicester, Leicester, United Kingdom.
authors.forename: Jin-Li
authors.initials: JL
authors.lastname: Luo
authors.affiliation: CRUK Leicester Centre, University of Leicester, Leicester, United Kingdom.|Department of Cancer Studies, University of Leicester, Leicester, United Kingdom.
authors.forename: George D D
authors.initials: GD
authors.lastname: Jones
authors.affiliation: Department of Molecular and Cell Biology, University of Leicester, Leicester, United Kingdom. sm460@le.ac.uk.|Mechanisms of Cancer and Ageing Lab, University of Leicester, Leicester, United Kingdom.|Ernest and Helen Scott Haematological Research Institute, University of Leicester, Leicester, United Kingdom.|CRUK Leicester Centre, University of Leicester, Leicester, United Kingdom.
authors.forename: Salvador
authors.initials: S
authors.lastname: Macip
authors.affiliation: Ernest and Helen Scott Haematological Research Institute, University of Leicester, Leicester, United Kingdom.|CRUK Leicester Centre, University of Leicester, Leicester, United Kingdom.|Department of Cancer Studies, University of Leicester, Leicester, United Kingdom.
authors.forename: Martin J S
authors.initials: MJ
authors.lastname: Dyer
mesh_terms: D023201:CD40 Ligand / Q000494:pharmacology; D006801:Humans; D015847:Interleukin-4 / Q000494:pharmacology; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000378:metabolism* / Q000473:pathology; D017382:Reactive Oxygen Species / Q000378:metabolism*; D015533:Transcriptional Activation; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000502:physiology*; D015854:Up-Regulation
chemical_list: D017382:Reactive Oxygen Species; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D023201:CD40 Ligand; D015847:Interleukin-4