期刊
THERANOSTICS
卷 11, 期 7, 页码 3452-3471出版社
IVYSPRING INT PUBL
DOI: 10.7150/thno.53572
关键词
SPINOPHILIN; PP1; cancer stem cell; tumorigenesis; stem cell phenotype; pRB; pocket proteins
资金
- HUVR-IBiS Biobank [PT13/0010/0056]
- Ministerio de Ciencia, Innovacion y Universidades (MCIU) Plan Estatal de I+D+I 2018
- Agencia Estatal de Investigacion (AEI) y al Fondo Europeo de Desarrollo Regional (MCIU/AEI/FEDER, UE) [RTI2018-097455-B-I00, RTI2018-096735-B-I00-]
- AEI-MICIU/FEDER [RED2018-102723-T]
- CIBER de Cancer [CB16/12/00275]
- FEDER from Regional Development European Funds (European Union)
- Consejeria de Salud [PI-0397-2017]
- Consejeria of Economia, Conocimiento, Empresas y Universidad of the Junta de Andalucia [P18-RT-2501]
- Fundacion AECC
- Fundacion Eugenio Rodriguez Pascual
SPN-A566V mutation affects the interaction and phosphatase activity of SPN-PP1, influencing cell cycle progression and stem cell characteristics. The co-occurrence of SPN-A566V and mutant p53 enhances tumorigenic and stemness properties in cells.
Rationale: SPINOPHILIN (SPN, PPP1R9B) is an important tumor suppressor involved in the progression and malignancy of different tumors depending on its association with protein phosphatase 1 (PP1) and the ability of the PP1-SPN holoenzyme to dephosphorylate retinoblastoma (pRB). Methods: We performed a mutational analysis of SPN in human tumors, focusing on the region of interaction with PP1 and pRB. We explored the effect of the SPN-A566V mutation in an immortalized non-tumorigenic cell line of epithelial breast tissue, MCF10A, and in two different p53-mutated breast cancer cells lines, T47D and MDA-MB-468. Results: We characterized an oncogenic mutation of SPN found in human tumor samples, SPN-A566V, that affects both the SPN-PP1 interaction and its phosphatase activity. The SPN-A566V mutation does not affect the interaction of the PP1-SPN holoenzyme with pocket proteins pRB, p107 and p130, but it affects its ability to dephosphorylate them during G0/G1 and G1, indicating that the PP1-SPN holoenzyme regulates cell cycle progression. SPN-A566V also promoted stemness, establishing a connection between the cell cycle and stem cell biology via pocket proteins and PP1-SPN regulation. However, only cells with both SPN-A566V and mutant p53 have increased tumorigenic and stemness properties. Conclusions: SPN-A566V, or other equivalent mutations, could be late events that promote tumor progression by increasing the CSC pool and, eventually, the malignant behavior of the tumor.
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