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

Author(s):Show less -

de Luna Vitorino, Francisca Nathalia ^[1] ; Montoni, Fabio ^[1] ; Moreno, Jaqueline Neves ^[1] ; de Souza, Bruno Ferreira ^[1] ; Lopes, Mariana de Camargo ^[1] ; Cordeiro, Barbara ^[1] ; Fonseca, Cecilia Sella ^{[2, 1]} ; Gilmore, Joshua M. ^[3] ; Sardiu, Mihaela I. ^[3] ; Reis, Marcelo Silva ^[1] ; Florens, Laurence A. ^[3] ; Washburn, Michael P. ^{[3, 4]} ; Armelin, Hugo Aguirre ^[1] ; Chagas da Cunha, Julia Pinheiro ^[1]

Affiliation

^[1] Inst Butantan, Ctr Toxins Immune Response & Cell Signaling CeTIC, Lab Especial Ciclo Celular, BR-05503900 Sao Paulo, SP - Brazil

^[2] Univ Sao Paulo, Inst Quim, Dept Bioquim, BR-05508000 Sao Paulo, SP - Brazil

^[3] Stowers Inst Med Res, Kansas City, MO 64110 - USA

^[4] Univ Kansas, Dept Pathol & Lab Med, Med Ctr, Kansas City, KS 66045 - USA

• Document type: Journal article
• Source: PROTEOMICS; v. 18, n. 17 SEP 2018.
• Web of Science Citations: 0

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. (AU)

• FAPESP's process: 11/22619-7 - Nuclei and chromatin alterations through cell cycle and senescence in mammalian cells
• Grantee: Julia Pinheiro Chagas da Cunha
• Support Opportunities: Research Grants - Young Investigators Grants
• FAPESP's process: 13/07467-1 - CeTICS - Center of Toxins, Immune-Response and Cell Signaling
• Grantee: Hugo Aguirre Armelin
• Support Opportunities: Research Grants - Research, Innovation and Dissemination Centers - RIDC