Myristoylated alanine-rich C-kinase substrate effector domain phosphorylation regulates the growth and radiation sensitization of glioblastoma.
Int J Oncol
; 54(6): 2039-2053, 2019 Jun.
Article
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| MEDLINE
| ID: mdl-30942445
ABSTRACT
Glioblastoma harbors frequent alterations in receptor tyrosine kinases, phosphatidylinositol3 kinase (PI3K) and phosphatase and tensin homolog (PTEN) that dysregulate phospholipid signaling driven tumor proliferation and therapeutic resistance. Myristoylated alaninerich Ckinase substrate (MARCKS) is a 32 kDa intrinsically unstructured protein containing a polybasic (+13) effector domain (ED), which regulates its electrostatic sequestration of phospholipid phosphatidylinositol (4,5)bisphosphate (PIP2), and its binding to phosphatidylserine, calcium/calmodulin, filamentous actin, while also serving as a nuclear localization sequence. MARCKS ED is phosphorylated by protein kinase C (PKC) and Rhoassociated protein kinase (ROCK) kinases; however, the impact of MARCKS on glioblastoma growth and radiation sensitivity remains undetermined. In the present study, using a tetracyclineinducible system in PTENnull U87 cells, we demonstrate that MARCKS overexpression suppresses growth and enhances radiation sensitivity in vivo. A new image cytometer, Xcyto10, was utilized to quantify differences in MARCKS ED phosphorylation on localization and its association with filamentous actin. The overexpression of the nonphosphorylatable ED mutant exerted growthsuppressive and radiationsensitizing effects, while the pseudophosphorylated ED mutant exhibited an enhanced colony formation and clonogenic survival ability. The identification of MARCKS proteinprotein interactions using coimmunoprecipitation coupled with tandem mass spectrometry revealed novel MARCKSassociated proteins, including importinß and ku70. On the whole, the findings of this study suggest that the determination of the MARCKS ED phosphorylation status is essential to understanding the impact of MARCKS on cancer progression.
Texto completo:
1
Banco de datos:
MEDLINE
Asunto principal:
Tolerancia a Radiación
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Neoplasias Encefálicas
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Glioblastoma
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Dominios Proteicos
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Sustrato de la Proteína Quinasa C Rico en Alanina Miristoilada
Tipo de estudio:
Prognostic_studies
Límite:
Animals
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Female
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Humans
Idioma:
En
Revista:
Int J Oncol
Asunto de la revista:
NEOPLASIAS
Año:
2019
Tipo del documento:
Article
País de afiliación:
Estados Unidos