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A Tumor-Promoting Phorbol Ester Causes a Large Increase in APOBEC3A Expression and a Moderate Increase in APOBEC3B Expression in a Normal Human Keratinocyte Cell Line without Increasing Genomic Uracils.
- Source :
-
Molecular and cellular biology [Mol Cell Biol] 2018 Dec 11; Vol. 39 (1). Date of Electronic Publication: 2018 Dec 11 (Print Publication: 2019). - Publication Year :
- 2018
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Abstract
- Phorbol 12-myristate 13-acetate (PMA) promotes skin cancer in rodents. The mutations found in murine tumors are similar to those found in human skin cancers, and PMA promotes proliferation of human skin cells. PMA treatment of human keratinocytes increases the synthesis of APOBEC3A, an enzyme that converts cytosines in single-stranded DNA to uracil, and mutations in a variety of human cancers are attributed to APOBEC3A or APOBEC3B expression. We tested here the possibility that induction of APOBEC3A by PMA causes genomic accumulation of uracils that may lead to such mutations. When a human keratinocyte cell line was treated with PMA, both APOBEC3A and APOBEC3B gene expression increased, anti-APOBEC3A/APOBEC3B antibody bound a protein(s) in the nucleus, and nuclear extracts displayed cytosine deamination activity. Surprisingly, there was little increase in genomic uracils in PMA-treated wild-type or uracil repair-defective cells. In contrast, cells transfected with a plasmid expressing APOBEC3A acquired more genomic uracils. Unexpectedly, PMA treatment, but not APOBEC3A plasmid transfection, caused a cessation in cell growth. Hence, a reduction in single-stranded DNA at replication forks may explain the inability of PMA-induced APOBEC3A/APOBEC3B to increase genomic uracils. These results suggest that the proinflammatory PMA is unlikely to promote extensive APOBEC3A/APOBEC3B-mediated cytosine deaminations in human keratinocytes.<br /> (Copyright © 2018 American Society for Microbiology.)
- Subjects :
- Carcinogens metabolism
Cell Line
Cell Transformation, Neoplastic genetics
Cytosine metabolism
DNA, Single-Stranded drug effects
Genomics
Humans
Keratinocytes metabolism
Mutagenesis drug effects
Neoplasms genetics
Cytidine Deaminase drug effects
Minor Histocompatibility Antigens drug effects
Phorbol Esters pharmacology
Proteins drug effects
Uracil metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1098-5549
- Volume :
- 39
- Issue :
- 1
- Database :
- MEDLINE
- Journal :
- Molecular and cellular biology
- Publication Type :
- Academic Journal
- Accession number :
- 30348839
- Full Text :
- https://doi.org/10.1128/MCB.00238-18