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|Title:||Post-transcriptional upregulation of p53 by reactive oxygen species in chronic lymphocytic leukemia|
Jones, George D. D.
Dyer, Martin J. S.
|Publisher:||American Association for Cancer Research|
|Citation:||Cancer Research, 2016, 76 (21), pp. 6311-6319|
|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.|
|Rights:||Copyright © American Association for Cancer Research, 2016. This version of the article is distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License (http://creativecommons.org/licenses/by-nc-nd/4.0/ ), which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.|
|Description:||The file associated with this record is embargoed until 12 months after the date of publication. The final published version may be available through the links above. Following the embargo period the above license applies.|
|Appears in Collections:||Published Articles, Dept. of Biochemistry|
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|0008-5472.CAN-16-0843.full.pdf||Post-review (final submitted author manuscript)||7.03 MB||Adobe PDF||View/Open|
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