دورية أكاديمية
The tyrosine kinase v-Src causes mitotic slippage by phosphorylating an inhibitory tyrosine residue of Cdk1.
العنوان: | The tyrosine kinase v-Src causes mitotic slippage by phosphorylating an inhibitory tyrosine residue of Cdk1. |
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المؤلفون: | Horiuchi M; From the Department of Biochemistry and Molecular Biology, Kyoto Pharmaceutical University, Kyoto 607-8414., Kuga T; From the Department of Biochemistry and Molecular Biology, Kyoto Pharmaceutical University, Kyoto 607-8414., Saito Y; From the Department of Biochemistry and Molecular Biology, Kyoto Pharmaceutical University, Kyoto 607-8414., Nagano M; the Laboratory of Proteome Research, National Institutes of Biomedical Innovation, Health and Nutrition, Osaka 567-0085, and., Adachi J; the Laboratory of Proteome Research, National Institutes of Biomedical Innovation, Health and Nutrition, Osaka 567-0085, and., Tomonaga T; the Laboratory of Proteome Research, National Institutes of Biomedical Innovation, Health and Nutrition, Osaka 567-0085, and., Yamaguchi N; the Laboratory of Molecular Cell Biology, Graduate School of Pharmaceutical Sciences, Chiba University, Chiba 260-8675, Japan., Nakayama Y; From the Department of Biochemistry and Molecular Biology, Kyoto Pharmaceutical University, Kyoto 607-8414, nakayama@mb.kyoto-phu.ac.jp. |
المصدر: | The Journal of biological chemistry [J Biol Chem] 2018 Oct 05; Vol. 293 (40), pp. 15524-15537. Date of Electronic Publication: 2018 Aug 22. |
نوع المنشور: | Journal Article; Research Support, Non-U.S. Gov't |
اللغة: | English |
بيانات الدورية: | Publisher: Elsevier Inc. on behalf of American Society for Biochemistry and Molecular Biology Country of Publication: United States NLM ID: 2985121R Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1083-351X (Electronic) Linking ISSN: 00219258 NLM ISO Abbreviation: J Biol Chem Subsets: MEDLINE |
أسماء مطبوعة: | Publication: 2021- : [New York, NY] : Elsevier Inc. on behalf of American Society for Biochemistry and Molecular Biology Original Publication: Baltimore, MD : American Society for Biochemistry and Molecular Biology |
مواضيع طبية MeSH: | Antineoplastic Agents, Phytogenic/*pharmacology , CDC2 Protein Kinase/*genetics , Microtubules/*drug effects , Mitosis/*drug effects , Oncogene Protein pp60(v-src)/*genetics , Paclitaxel/*pharmacology, CDC2 Protein Kinase/antagonists & inhibitors ; CDC2 Protein Kinase/metabolism ; Cell Proliferation/drug effects ; HeLa Cells ; Humans ; Microtubules/metabolism ; Microtubules/ultrastructure ; Oncogene Protein pp60(v-src)/antagonists & inhibitors ; Oncogene Protein pp60(v-src)/metabolism ; Phosphoproteins/genetics ; Phosphoproteins/metabolism ; Phosphorylation ; Polyploidy ; Protein Kinase Inhibitors/pharmacology ; Pyrimidines/pharmacology ; RNA, Small Interfering/genetics ; RNA, Small Interfering/metabolism ; Time-Lapse Imaging |
مستخلص: | The nonreceptor tyrosine kinase v-Src is an oncogene first identified in Rous sarcoma virus. The oncogenic effects of v-Src have been intensively studied; however, its effects on chromosomal integrity are not fully understood. Here, using HeLa S3/v-Src cells having inducible v-Src expression, we found that v-Src causes mitotic slippage in addition to cytokinesis failure, even when the spindle assembly checkpoint is not satisfied because of the presence of microtubule-targeting agents. v-Src's effect on mitotic slippage was also observed in cells after a knockdown of C-terminal Src kinase (Csk), a protein-tyrosine kinase that inhibits Src-family kinases and was partially inhibited by PP2, an Src-family kinase inhibitor. Proteomic analysis and in vitro kinase assay revealed that v-Src phosphorylates cyclin-dependent kinase 1 (Cdk1) at Tyr-15. This phosphorylation attenuated Cdk1 kinase activity, resulting in a decrease in the phosphorylation of Cdk1 substrates. Furthermore, v-Src-induced mitotic slippage reduced the sensitivity of the cells to microtubule-targeting agents, and cells that survived the microtubule-targeting agents exhibited polyploidy. These results suggest that v-Src causes mitotic slippage by attenuating Cdk1 kinase activity via direct phosphorylation of Cdk1 at Tyr-15. On the basis of these findings, we propose a model for v-Src-induced oncogenesis, in which v-Src-promoted mitotic slippage due to Cdk1 phosphorylation generates genetic diversity via abnormal cell division of polyploid cells and also increases the tolerance of cancer cells to microtubule-targeting agents. (© 2018 Horiuchi et al.) |
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فهرسة مساهمة: | Keywords: Cdk1; Src; cancer; cell cycle; cyclin-dependent kinase (CDK); microtubule-targeting agent; mitosis; mitotic slippage; pTyr-15; phosphorylation; spindle checkpoint; tyrosine kinase; v-Src |
المشرفين على المادة: | 0 (AG 1879) 0 (Antineoplastic Agents, Phytogenic) 0 (Phosphoproteins) 0 (Protein Kinase Inhibitors) 0 (Pyrimidines) 0 (RNA, Small Interfering) EC 2.7.10.2 (Oncogene Protein pp60(v-src)) EC 2.7.11.22 (CDC2 Protein Kinase) EC 2.7.11.22 (CDK1 protein, human) P88XT4IS4D (Paclitaxel) |
تواريخ الأحداث: | Date Created: 20180824 Date Completed: 20190304 Latest Revision: 20210205 |
رمز التحديث: | 20231215 |
مُعرف محوري في PubMed: | PMC6177586 |
DOI: | 10.1074/jbc.RA118.002784 |
PMID: | 30135207 |
قاعدة البيانات: | MEDLINE |
تدمد: | 1083-351X |
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DOI: | 10.1074/jbc.RA118.002784 |