DMPK is a New Candidate Mediator of Tumor Suppressor p53-Dependent Cell Death.
Animals
Caspases
/ metabolism
Cell Adhesion
/ drug effects
Cell Death
/ drug effects
Doxorubicin
/ pharmacology
Enzyme Activation
/ drug effects
Fibroblasts
/ drug effects
Humans
MCF-7 Cells
Mice
Myotonin-Protein Kinase
/ genetics
Promoter Regions, Genetic
Tumor Protein p73
/ metabolism
Tumor Suppressor Protein p53
/ metabolism
DMPK
actin
myosin
p53
p73
Journal
Molecules (Basel, Switzerland)
ISSN: 1420-3049
Titre abrégé: Molecules
Pays: Switzerland
ID NLM: 100964009
Informations de publication
Date de publication:
01 Sep 2019
01 Sep 2019
Historique:
received:
08
08
2019
revised:
30
08
2019
accepted:
31
08
2019
entrez:
5
9
2019
pubmed:
5
9
2019
medline:
31
1
2020
Statut:
epublish
Résumé
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.
Identifiants
pubmed: 31480541
pii: molecules24173175
doi: 10.3390/molecules24173175
pmc: PMC6749264
pii:
doi:
Substances chimiques
DMPK protein, mouse
0
Tumor Protein p73
0
Tumor Suppressor Protein p53
0
Doxorubicin
80168379AG
Myotonin-Protein Kinase
EC 2.7.11.1
Caspases
EC 3.4.22.-
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Subventions
Organisme : Japan Society for the Promotion of Science
ID : JPH04054 and JP18K06231
Organisme : The Nakatomi Foundation, the Naito Foundation, and the HIRAO TARO Foundation of Konan University
ID : N.A.
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