title: c-ABL tyrosine kinase modulates p53-dependent p21 induction and ensuing cell fate decision in response to DNA damage.
abstract: The c-ABL non-receptor tyrosine kinase and the p53 tumor suppressor protein are pivotal modulators of cellular responses to DNA damage. However, a comprehensive understanding of the role of c-ABL kinase in p53-dependent transcription of p21(CIP1/WAF1) and ensuing cell fate decision is still obscure. Here, we demonstrate that c-ABL tyrosine kinase regulates p53-dependent induction of p21. As a result, it modulates cell fate decision by p53 in response to DNA damage differently according to the extent of DNA damage. When human cancer cells were treated with DNA damaging agent, adriamycin (0.08 μg/ml), p21 was induced following p53 induction. Owing largely to p21, a substantial fraction of cells treated with adriamycin were blocked at the G2 phase of the cell cycle and most cells eventually became senescent. When these cells were simultaneously treated with a c-ABL kinase inhibitor, STI571, or a c-ABL-specific siRNA along with adriamycin, the p53-dependent p21 induction was dramatically diminished, even though p53 is substantially induced. Accordingly, G2-arrest, and cellular senescence largely dependent on p21 were substantially abrogated. On the contrary, when cells were treated with a relatively high dose of adriamycin (0.4 μg/ml) cells became apoptotic, and the simultaneous presence of a c-ABL kinase inhibitor STI571 augmented the extent of apoptosis. We speculate this is due to abrogation of p53-dependent p21 induction, which leads to elimination of anti-apoptotic function of p21. In summary, c-ABL appears to promote senescence or inhibit apoptosis, depending on the extent of DNA damage. These findings suggest that the combined use of ABL kinase inhibitor and DNA damaging drug in chemotherapy against tumors retaining wild type p53 should be carefully designed.
authors.affiliation: Center for Interdisciplinary Research, Tohoku University, Sendai 980-8578, Japan; Department of Project Programs, Tohoku University, Sendai 980-8575, Japan; Department of Molecular Immunology, Institute of Development, Aging, and Cancer, Tohoku University, Sendai 980-8575, Japan; Graduate School of Medicine, Tohoku University, Sendai 980-8575, Japan.
authors.forename: S M Nashir
authors.initials: SM
authors.lastname: Udden
authors.affiliation: Center for Interdisciplinary Research, Tohoku University, Sendai 980-8578, Japan; Department of Project Programs, Tohoku University, Sendai 980-8575, Japan; International Advanced Research and Education Organization, Tohoku University, Sendai 980-8578, Japan.
authors.forename: Yuiko
authors.initials: Y
authors.lastname: Morita-Fujimura
authors.affiliation: Department of Molecular Immunology, Institute of Development, Aging, and Cancer, Tohoku University, Sendai 980-8575, Japan; Graduate School of Medicine, Tohoku University, Sendai 980-8575, Japan.
authors.forename: Masanobu
authors.initials: M
authors.lastname: Satake
authors.affiliation: Center for Interdisciplinary Research, Tohoku University, Sendai 980-8578, Japan; Department of Project Programs, Tohoku University, Sendai 980-8575, Japan. Electronic address: sikawa@idac.tohoku.ac.jp.
authors.forename: Shuntaro
authors.initials: S
authors.lastname: Ikawa
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D001549:Benzamides / Q000494:pharmacology; D045744:Cell Line, Tumor; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000235:genetics / Q000378:metabolism*; D004249:DNA Damage / Q000187:drug effects; D004317:Doxorubicin / Q000633:toxicity; D059565:G2 Phase Cell Cycle Checkpoints / Q000187:drug effects; D006367:HeLa Cells; D006801:Humans; D000068877:Imatinib Mesylate; D010879:Piperazines / Q000494:pharmacology; D016315:Proto-Oncogene Proteins c-abl / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D011743:Pyrimidines / Q000494:pharmacology; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*
chemical_list: D001549:Benzamides; D050759:Cyclin-Dependent Kinase Inhibitor p21; D010879:Piperazines; D011743:Pyrimidines; D034741:RNA, Small Interfering; D016159:Tumor Suppressor Protein p53; D004317:Doxorubicin; D000068877:Imatinib Mesylate; D016315:Proto-Oncogene Proteins c-abl
keywords: ADR; Adriamycin; DDR; DNA damage response; SA-β-gal; STI571; Senescence; WT; adriamycin; c-ABL; p21; p53; senescence-associated-β-galactosidase; wild-type