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Mutation of SPINOPHILIN (PPP1R9B) found in human tumors promotes the tumorigenic and stemness properties of cells
- Source :
- Theranostics, Digital.CSIC. Repositorio Institucional del CSIC, instname
- Publication Year :
- 2021
- Publisher :
- Ivyspring International Publisher, 2021.
-
Abstract
- [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).<br />[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.<br />[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.<br />[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.<br />This work was supported by grants from the Ministerio de Ciencia, Innovación y Universidades (MCIU) Plan Estatal de I+D+I 2018, a la Agencia Estatal de Investigación (AEI) y al Fondo Europeo de Desarrollo Regional (MCIU/AEI/FEDER, UE): RTI2018-097455-B-I00 and RTI2018-096735-B-I00 grant from AEI-MICIU/FEDER (RED2018-102723-T); from CIBER de Cáncer (CB16/12/00275), co-funded by FEDER from Regional Development European Funds (European Union); from Consejeria de Salud (PI-0397-2017) and Consejeria of Economía, Conocimiento, Empresas y Universidad of the Junta de Andalucia (P18-RT-2501). Special thanks are also due to the Fundacion AECC and Fundacion Eugenio Rodriguez Pascual for supporting this work.
- Subjects :
- 0301 basic medicine
Anatomy::Cells::Cells, Cultured::Cell Line::Cell Line, Tumor [Medical Subject Headings]
Proteína de retinoblastoma
Carcinogenesis
Mutant
Medicine (miscellaneous)
Anatomy::Cells::Stem Cells::Neoplastic Stem Cells [Medical Subject Headings]
medicine.disease_cause
environment and public health
Retinoblastoma Protein
Organisms::Eukaryota::Animals::Chordata::Vertebrates::Mammals::Primates::Haplorhini::Catarrhini::Hominidae::Humans [Medical Subject Headings]
Mice
0302 clinical medicine
Breast cancer
pRB
Anatomy::Cells::Cells, Cultured::Cell Line [Medical Subject Headings]
stem cell phenotype
Chemicals and Drugs::Amino Acids, Peptides, and Proteins::Proteins::Nerve Tissue Proteins [Medical Subject Headings]
Protein Phosphatase 1
Organisms::Eukaryota::Animals [Medical Subject Headings]
Proteína fosfatasa 1
Analytical, Diagnostic and Therapeutic Techniques and Equipment::Investigative Techniques::Evaluation Studies as Topic::Drug Evaluation, Preclinical::Drug Screening Assays, Antitumor::Xenograft Model Antitumor Assays [Medical Subject Headings]
Phosphorylation
Phenomena and Processes::Metabolic Phenomena::Metabolism::Phosphorylation [Medical Subject Headings]
Pharmacology, Toxicology and Pharmaceutics (miscellaneous)
Phenomena and Processes::Cell Physiological Phenomena::Cell Physiological Processes::Cell Cycle [Medical Subject Headings]
Cell Line, Transformed
Mutation
Chemicals and Drugs::Macromolecular Substances::Polymers::Biopolymers::Microfilament Proteins [Medical Subject Headings]
Retinoblastoma
Línea celular
Microfilament Proteins
Proteína 1 de unión a retinoblastoma
Cell cycle
Diseases::Neoplasms::Neoplastic Processes::Carcinogenesis [Medical Subject Headings]
PP1
Phenomena and Processes::Cell Physiological Phenomena::Cell Physiological Processes::Cell Cycle::Cell Cycle Checkpoints::G1 Phase Cell Cycle Checkpoints [Medical Subject Headings]
Chemicals and Drugs::Amino Acids, Peptides, and Proteins::Proteins::Neoplasm Proteins::Tumor Suppressor Proteins::Tumor Suppressor Protein p53 [Medical Subject Headings]
Gene Expression Regulation, Neoplastic
Anatomy::Cells::Cells, Cultured::Cell Line::Cell Line, Transformed [Medical Subject Headings]
Diseases::Neoplasms::Neoplasms by Site::Eye Neoplasms::Retinal Neoplasms [Medical Subject Headings]
SPINOPHILIN
030220 oncology & carcinogenesis
Neoplasias de la mama
Neoplastic Stem Cells
Cell lines
Female
biological phenomena, cell phenomena, and immunity
Research Paper
Signal Transduction
Carcinogénesis
cancer stem cell
animal structures
Phenomena and Processes::Genetic Phenomena::Genetic Variation::Mutation [Medical Subject Headings]
Stem cell phenotype
Mice, Nude
Breast Neoplasms
Nerve Tissue Proteins
macromolecular substances
Biology
Resting Phase, Cell Cycle
Chemicals and Drugs::Amino Acids, Peptides, and Proteins::Proteins::Neoplasm Proteins::Tumor Suppressor Proteins::Retinoblastoma Protein [Medical Subject Headings]
Dephosphorylation
Chemicals and Drugs::Enzymes and Coenzymes::Enzymes::Hydrolases::Esterases::Phosphoric Monoester Hydrolases::Phosphoprotein Phosphatases::Protein Phosphatase 1 [Medical Subject Headings]
03 medical and health sciences
Cancer stem cell
Cell Line, Tumor
medicine
Animals
Humans
Diseases::Neoplasms::Neoplasms by Site::Breast Neoplasms [Medical Subject Headings]
Células madre neoplásicas
Organisms::Eukaryota::Animals::Chordata::Vertebrates::Mammals::Rodentia::Muridae::Murinae::Mice [Medical Subject Headings]
Phenomena and Processes::Cell Physiological Phenomena::Cell Physiological Processes::Signal Transduction [Medical Subject Headings]
Organisms::Eukaryota::Animals::Chordata::Vertebrates::Mammals::Rodentia::Muridae::Murinae::Mice::Mice, Mutant Strains::Mice, Nude [Medical Subject Headings]
pocket proteins
medicine.disease
G1 Phase Cell Cycle Checkpoints
Xenograft Model Antitumor Assays
Phenomena and Processes::Genetic Phenomena::Genetic Processes::Gene Expression Regulation::Gene Expression Regulation, Neoplastic [Medical Subject Headings]
enzymes and coenzymes (carbohydrates)
tumorigenesis
030104 developmental biology
Check Tags::Female [Medical Subject Headings]
Tumor progression
Cell culture
Retinoblastoma protein
Tumorigenesis
Cancer research
Tumor Suppressor Protein p53
Pocket proteins
Chemicals and Drugs::Enzymes and Coenzymes::Enzymes::Holoenzymes [Medical Subject Headings]
Subjects
Details
- Language :
- English
- ISSN :
- 18387640
- Volume :
- 11
- Issue :
- 7
- Database :
- OpenAIRE
- Journal :
- Theranostics
- Accession number :
- edsair.doi.dedup.....dc94057a330544993a83e9fc556b68b2