Accessibility to DNA in carcinoma chromatin is promoted by nanomolar okadaic acid: effect on AT-rich DNA binding proteins.
Differential accessibility to DNA in tumor cell chromatin is important to growth, differentiation apoptosis, and the targeting of DNA modifying drugs. We now show that endonuclease accessibility to DNA in the nuclei of A431 human carcinoma cells is increased within 90 min by nontoxic nanomolar levels of okadaic acid, known to inhibit protein phosphatase 2A. This genomic hypersensitivity was partly enhanced by joint treatment with epidermal growth factor and okadaic acid but did not appear without the latter. Nuclei with greater DNA susceptibility showed a decrease in M(r) 80,000 DNA binding protein doublet specific for dAT-rich sequences concurrent with the "apparent" hyperphosphorylation of a M(r) 70,000 nuclear matrix protein. We propose that some of the tumor-promoting effects of okadaic acid may be partly associated with its ability to promote genomic susceptibility.
Rieber
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MS
I.V.I.C., Caracas, Venezuela.
Rieber
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D000225:Adenine / Q000378:metabolism*; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism; D002843:Chromatin / Q000187:drug effects / Q000502:physiology*; D004273:DNA, Neoplasm / Q000187:drug effects / Q000378:metabolism* / Q000528:radiation effects; D004268:DNA-Binding Proteins / Q000187:drug effects* / Q000378:metabolism; D004586:Electrophoresis; D004720:Endonucleases / Q000378:metabolism; D004815:Epidermal Growth Factor / Q000494:pharmacology; D004988:Ethers, Cyclic / Q000494:pharmacology*; D006801:Humans; D007700:Kinetics; D008970:Molecular Weight; D009687:Nuclear Proteins / Q000187:drug effects / Q000378:metabolism / Q000528:radiation effects; D019319:Okadaic Acid; D010766:Phosphorylation / Q000187:drug effects; D013936:Thymidine / Q000378:metabolism*; D014407:Tumor Cells, Cultured; D014466:Ultraviolet Rays
D002843:Chromatin; D004273:DNA, Neoplasm; D004268:DNA-Binding Proteins; D004988:Ethers, Cyclic; D009687:Nuclear Proteins; D019319:Okadaic Acid; D004815:Epidermal Growth Factor; D004720:Endonucleases; D000225:Adenine; D013936:Thymidine