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Proteomics. 2018 Sep;18(17):e1800203. doi: 10.1002/pmic.201800203. Epub 2018 Aug 14.

FGF2 Antiproliferative Stimulation Induces Proteomic Dynamic Changes and High Expression of FOSB and JUNB in K-Ras-Driven Mouse Tumor Cells.

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Laboratório Especial de Ciclo Celular - Center of Toxins, Immune-Response and Cell Signaling - CeTICS, Instituto Butantan, São Paulo, SP, 05503-900, Brazil.
Departamento de Bioquímica, Instituto de Química, Universidade de São Paulo, São Paulo, SP, 05508-000, Brazil.
Stowers Institute for Medical Research, Kansas City, MO, 64110, USA.
Department of Pathology and Laboratory Medicine, University of Kansas Medical Center, Kansas City, KS, 66045, USA.


Fibroblast growth factor 2 (FGF2) is a well-known cell proliferation promoter; however, it can also induce cell cycle arrest. To gain insight into the molecular mechanisms of this antiproliferative effect, for the first time, the early systemic proteomic differences induced by this growth factor in a K-Ras-driven mouse tumor cell line using a quantitative proteomics approach are investigated. More than 2900 proteins are quantified, indicating that terms associated with metabolism, RNA processing, replication, and transcription are enriched among proteins differentially expressed upon FGF2 stimulation. Proteomic trend dynamics indicate that, for proteins mainly associated with DNA replication and carbohydrate metabolism, an FGF2 stimulus delays their abundance changes, whereas FGF2 stimulation accelerates other metabolic programs. Transcription regulatory network analysis indicates master regulators of FGF2 stimulation, including two critical transcription factors, FOSB and JUNB. Their expression dynamics, both in the Y1 cell line (a murine model of adenocarcinoma cells) and in two other human cell lines (SK-N-MC and UM-UC-3) also susceptible to FGF2 antiproliferative effects, are investigated. Both protein expression levels depend on fibroblast growth factor receptor (FGFR) and src signaling. JUNB and FOSB knockdown do not rescue cells from the growth arrest induced by FGF2; however, FOSB knockdown rescue cells from DNA replication delay, indicating that FOSB expression underlies one of the FGF2 antiproliferative effects, namely, S-phase progression delay.


DNA replication; FGF2; FOSB; JUNB; antiproliferative; proteomics; src


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