DMPK is a New Candidate Mediator of Tumor Suppressor p53-Dependent Cell Death
Tumor suppressor p53 plays an integral role in DNA-damage induced apoptosis, a biological process that protects against tumor progression. Cell shape dramatically changes when cells undergo apoptosis, which is associated with actomyosin contraction; however, it remains entirely elusive how p53 regul...
| Main Authors: | , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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MDPI AG
2019-09-01
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| Series: | Molecules |
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| Online Access: | https://www.mdpi.com/1420-3049/24/17/3175 |
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| author | Katsuhiko Itoh Takahiro Ebata Hiroaki Hirata Takeru Torii Wataru Sugimoto Keigo Onodera Wataru Nakajima Ikuno Uehara Daisuke Okuzaki Shota Yamauchi Yemima Budirahardja Takahito Nishikata Nobuyuki Tanaka Keiko Kawauchi |
| author_facet | Katsuhiko Itoh Takahiro Ebata Hiroaki Hirata Takeru Torii Wataru Sugimoto Keigo Onodera Wataru Nakajima Ikuno Uehara Daisuke Okuzaki Shota Yamauchi Yemima Budirahardja Takahito Nishikata Nobuyuki Tanaka Keiko Kawauchi |
| author_sort | Katsuhiko Itoh |
| collection | DOAJ |
| description | Tumor suppressor p53 plays an integral role in DNA-damage induced apoptosis, a biological process that protects against tumor progression. Cell shape dramatically changes when cells undergo apoptosis, which is associated with actomyosin contraction; however, it remains entirely elusive how p53 regulates actomyosin contraction in response to DNA-damaging agents. To identify a novel p53 regulating gene encoding the modulator of myosin, we conducted DNA microarray analysis. We found that, in response to DNA-damaging agent doxorubicin, expression of myotonic dystrophy protein kinase (DMPK), which is known to upregulate actomyosin contraction, was increased in a p53-dependent manner. The promoter region of DMPK gene contained potential p53-binding sequences and its promoter activity was increased by overexpression of the p53 family protein p73, but, unexpectedly, not of p53. Furthermore, we found that doxorubicin treatment induced p73 expression, which was significantly attenuated by downregulation of p53. These data suggest that p53 induces expression of DMPK through upregulating p73 expression. Overexpression of DMPK promotes contraction of the actomyosin cortex, which leads to formation of membrane blebs, loss of cell adhesion, and concomitant caspase activation. Taken together, our results suggest the existence of p53-p73-DMPK axis which mediates DNA-damage induced actomyosin contraction at the cortex and concomitant cell death. |
| first_indexed | 2024-04-13T00:18:43Z |
| format | Article |
| id | doaj.art-1c0ab0a5ef6b4f21b72089c08212e9b6 |
| institution | Directory Open Access Journal |
| issn | 1420-3049 |
| language | English |
| last_indexed | 2024-04-13T00:18:43Z |
| publishDate | 2019-09-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Molecules |
| spelling | doaj.art-1c0ab0a5ef6b4f21b72089c08212e9b62022-12-22T03:10:51ZengMDPI AGMolecules1420-30492019-09-012417317510.3390/molecules24173175molecules24173175DMPK is a New Candidate Mediator of Tumor Suppressor p53-Dependent Cell DeathKatsuhiko Itoh0Takahiro Ebata1Hiroaki Hirata2Takeru Torii3Wataru Sugimoto4Keigo Onodera5Wataru Nakajima6Ikuno Uehara7Daisuke Okuzaki8Shota Yamauchi9Yemima Budirahardja10Takahito Nishikata11Nobuyuki Tanaka12Keiko Kawauchi13Frontiers of Innovative Research in Science and Technology (FIRST), Konan University, Kobe 650-0047, JapanFrontiers of Innovative Research in Science and Technology (FIRST), Konan University, Kobe 650-0047, JapanMechanobiology Laboratory, Nagoya University Graduate School of Medicine, Nagoya 466-8550, JapanFrontiers of Innovative Research in Science and Technology (FIRST), Konan University, Kobe 650-0047, JapanFrontiers of Innovative Research in Science and Technology (FIRST), Konan University, Kobe 650-0047, JapanDepartment of Molecular Oncology, Institute for Advanced Medical Sciences, Nippon Medical School, Tokyo 113-8602, JapanDepartment of Molecular Oncology, Institute for Advanced Medical Sciences, Nippon Medical School, Tokyo 113-8602, JapanDepartment of Molecular Oncology, Institute for Advanced Medical Sciences, Nippon Medical School, Tokyo 113-8602, JapanGenome information research center, Research institute for microbial diseases, Osaka University, Osaka 565-0871, JapanGraduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo 113-0033, JapanFrontiers of Innovative Research in Science and Technology (FIRST), Konan University, Kobe 650-0047, JapanFrontiers of Innovative Research in Science and Technology (FIRST), Konan University, Kobe 650-0047, JapanDepartment of Molecular Oncology, Institute for Advanced Medical Sciences, Nippon Medical School, Tokyo 113-8602, JapanFrontiers of Innovative Research in Science and Technology (FIRST), Konan University, Kobe 650-0047, JapanTumor suppressor p53 plays an integral role in DNA-damage induced apoptosis, a biological process that protects against tumor progression. Cell shape dramatically changes when cells undergo apoptosis, which is associated with actomyosin contraction; however, it remains entirely elusive how p53 regulates actomyosin contraction in response to DNA-damaging agents. To identify a novel p53 regulating gene encoding the modulator of myosin, we conducted DNA microarray analysis. We found that, in response to DNA-damaging agent doxorubicin, expression of myotonic dystrophy protein kinase (DMPK), which is known to upregulate actomyosin contraction, was increased in a p53-dependent manner. The promoter region of DMPK gene contained potential p53-binding sequences and its promoter activity was increased by overexpression of the p53 family protein p73, but, unexpectedly, not of p53. Furthermore, we found that doxorubicin treatment induced p73 expression, which was significantly attenuated by downregulation of p53. These data suggest that p53 induces expression of DMPK through upregulating p73 expression. Overexpression of DMPK promotes contraction of the actomyosin cortex, which leads to formation of membrane blebs, loss of cell adhesion, and concomitant caspase activation. Taken together, our results suggest the existence of p53-p73-DMPK axis which mediates DNA-damage induced actomyosin contraction at the cortex and concomitant cell death.https://www.mdpi.com/1420-3049/24/17/3175DMPKp53p73actinmyosin |
| spellingShingle | Katsuhiko Itoh Takahiro Ebata Hiroaki Hirata Takeru Torii Wataru Sugimoto Keigo Onodera Wataru Nakajima Ikuno Uehara Daisuke Okuzaki Shota Yamauchi Yemima Budirahardja Takahito Nishikata Nobuyuki Tanaka Keiko Kawauchi DMPK is a New Candidate Mediator of Tumor Suppressor p53-Dependent Cell Death Molecules DMPK p53 p73 actin myosin |
| title | DMPK is a New Candidate Mediator of Tumor Suppressor p53-Dependent Cell Death |
| title_full | DMPK is a New Candidate Mediator of Tumor Suppressor p53-Dependent Cell Death |
| title_fullStr | DMPK is a New Candidate Mediator of Tumor Suppressor p53-Dependent Cell Death |
| title_full_unstemmed | DMPK is a New Candidate Mediator of Tumor Suppressor p53-Dependent Cell Death |
| title_short | DMPK is a New Candidate Mediator of Tumor Suppressor p53-Dependent Cell Death |
| title_sort | dmpk is a new candidate mediator of tumor suppressor p53 dependent cell death |
| topic | DMPK p53 p73 actin myosin |
| url | https://www.mdpi.com/1420-3049/24/17/3175 |
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