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Cancer Res. 2016 Nov 1;76(21):6311-6319. Epub 2016 Sep 7.

Posttranscriptional Upregulation of p53 by Reactive Oxygen Species in Chronic Lymphocytic Leukemia.

Samuel J1,2,3,4, Jayne S3,4,5, Chen Y1,2,3,4, Majid A6, Wignall A1,2,3,4, Wormull T1,2,3,4, Najeeb H4,5,7, Luo JL4, Jones GD4,5, Macip S8,2,3,4, Dyer MJ3,4,5.

Author information

1
Department of Molecular and Cell Biology, University of Leicester, Leicester, United Kingdom.
2
Mechanisms of Cancer and Ageing Lab, University of Leicester, Leicester, United Kingdom.
3
Ernest and Helen Scott Haematological Research Institute, University of Leicester, Leicester, United Kingdom.
4
CRUK Leicester Centre, University of Leicester, Leicester, United Kingdom.
5
Department of Cancer Studies, University of Leicester, Leicester, United Kingdom.
6
MRC Toxicology Unit, Leicester, United Kingdom.
7
Department of Clinical Biochemistry, College of Medicine, University of Duhok, Kurdistan Regional Government, Iraq.
8
Department of Molecular and Cell Biology, University of Leicester, Leicester, United Kingdom. sm460@le.ac.uk.

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.

PMID:
27634759
DOI:
10.1158/0008-5472.CAN-16-0843
[Indexed for MEDLINE]
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