Antisense inhibition of Bcr-Abl/c-Abl synthesis promotes telomerase activity and upregulates tankyrase in human leukemia cells.
Clinical studies in chronic myelogenous leukemia demonstrate that the overexpression of Bcr-Abl tyrosine kinase is usually accompanied by relatively low telomerase activity in the chronic phase, which reverts to a high activity in blast crisis. The present study was designed to investigate the cross-talk between both enzymes, using Bcr-Abl-positive K-562 and Bcr-Abl-negative Jurkat cell lines, treated with antisense oligodeoxyribonucleotides (ODNs) against Bcr-Abl/c-Abl mRNA. The decreased amount and enzyme activity of Bcr-Abl/c-Abl provoked telomerase activation in both cell lines. After short-term treatment with anti-Bcr-Abl/c-Abl ODNs (6 days), no variations in hTERT and phospho-hTERT were detected. The decreased amount of Bcr-Abl/c-Abl was accompanied by: alterations in telomeric associated proteins-overexpression of tankyrase and decreased amount of TRF1/Tin2, cell growth arrest of K-562 cells, reaching a plateau after 6 days treatment, and increased proliferating activity of Jurkat cells. No changes in telomere length were detected after short-term treatment. In contrast, after long-term treatment with anti-Bcr-Abl/c-Abl ODNs (36 days), a significant elongation of telomeres and enhancement of hTERT were established, accompanied by an increased proliferating activity of both cell lines. These data provide evidence that the inhibition of Bcr-Abl or c-Abl synthesis keeps a potential to restore or induce cell proliferation through telomere lengthening control and telomerase activation.
Bakalova
Rumiana
R
Single-Molecule Bioanalysis Laboratory, National Institute for Advanced Industrial Science and Technology, AIST-Shikoku, 2217-14 Hayashi-cho, Takamatsu, Kagawa 761-0395, Japan. r.bakalova-zheleva@aist.go.jp
Ohba
Hideki
H
Zhelev
Zhivko
Z
Kubo
Takanori
T
Fujii
Masayuki
M
Ishikawa
Mitsuru
M
Shinohara
Yasuo
Y
Baba
Yoshinobu
Y
D001483:Base Sequence; D001665:Binding Sites / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D004268:DNA-Binding Proteins; D016044:Fusion Proteins, bcr-abl / Q000037:antagonists & inhibitors; D006801:Humans; D019169:Jurkat Cells; D020014:K562 Cells; D008969:Molecular Sequence Data; D020319:Oligodeoxyribonucleotides, Antisense / Q000494:pharmacology*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D016315:Proto-Oncogene Proteins c-abl / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D038501:Tankyrases / Q000096:biosynthesis*; D019098:Telomerase / Q000187:drug effects / Q000378:metabolism*; D015854:Up-Regulation / Q000187:drug effects
D004268:DNA-Binding Proteins; D016044:Fusion Proteins, bcr-abl; D020319:Oligodeoxyribonucleotides, Antisense; D011505:Protein-Tyrosine Kinases; D016315:Proto-Oncogene Proteins c-abl; D038501:Tankyrases; D019098:Telomerase; C418109:TNKS protein, human