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FGF2 Antiproliferative Stimulation Induces Proteomic Dynamic Changes and High Expression of FOSB and JUNB in
Francisca Nathalia de Luna Vitorino1, Fabio Montoni1, Jaqueline Neves Moreno1
1Laboratório Especial de Ciclo Celular - Center of Toxins, Immune-Response and Cell Signaling - CeTICS, Instituto Butantan, São Paulo, SP, 05503-900, Brazil.
Abstract:
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.
Insights
Fibroblast growth factor 2 (FGF2) can halt cell proliferation by altering cellular processes. This study reveals FGF2 impacts metabolism and DNA replication via transcription factors FOSB and JUNB, with FOSB delaying S-phase progression.
Area of Science:
- Molecular Biology
- Proteomics
- Cancer Research
Background:
- Fibroblast growth factor 2 (FGF2) is known to promote cell proliferation but can also induce cell cycle arrest.
- The molecular mechanisms underlying FGF2's antiproliferative effects remain incompletely understood.
- Investigating early proteomic changes offers insight into FGF2-induced growth inhibition.
Purpose of the Study:
- To elucidate the early systemic proteomic differences induced by FGF2 in a K-Ras-driven mouse tumor cell line.
- To identify key molecular players and pathways regulated by FGF2 during cell cycle arrest.
- To investigate the role of transcription factors FOSB and JUNB in FGF2's antiproliferative effects.
Main Methods:
- Quantitative proteomics approach to analyze protein expression changes.
- Analysis of over 2900 proteins in a K-Ras-driven mouse tumor cell line (Y1) upon FGF2 stimulation.
- Transcription regulatory network analysis and gene knockdown experiments in Y1, SK-N-MC, and UM-UC-3 cell lines.
Main Results:
- FGF2 stimulation enriched proteins associated with metabolism, RNA processing, replication, and transcription.
- FGF2 delayed abundance changes for proteins involved in DNA replication and carbohydrate metabolism.
- FOSB and JUNB were identified as master regulators; FOSB knockdown rescued S-phase progression delay but not overall growth arrest.
Conclusions:
- FGF2 induces complex proteomic changes impacting metabolism and cell cycle regulation.
- FOSB plays a critical role in mediating the S-phase progression delay induced by FGF2.
- Understanding these FGF2-driven pathways provides insights into potential therapeutic strategies for FGF2-responsive cancers.
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