The small GTPases Ras, Rac, and Cdc42 transcriptionally regulate expression of human fibroblast growth factor 1

Area of Science:

• Molecular Biology
• Cell Signaling

Background:

• Fibroblast growth factor 1 (FGF1) is encoded by a single gene with four distinct promoters (1A, 1B, 1C, 1D).
• These promoters direct alternatively spliced transcript variants, leading to differential regulation in a cell-specific manner.
• Understanding the biological function of multiple promoter usage is crucial for comprehending gene regulation.

Purpose of the Study:

• To investigate the transcriptional regulation of FGF1 promoters by signaling pathways.
• To delineate the role of Ras superfamily GTPases in controlling FGF1 gene expression.
• To explore the involvement of FGF1 in cell proliferation, survival, and division.

Main Methods:

• Analysis of FGF1 promoter activity in response to defined signaling pathways.
• Identification of transcription factor binding sites (Ets, CArG) within FGF1 promoters.
• Assessment of FGF1 and FGF2 promoter activation by Ras, Rac1, Cdc42, and Ets2.
• Quantification of intracellular FGF1 levels during cell division.

Main Results:

• Promoters 1C and 1D of FGF1 are specifically associated with Ras superfamily GTPase signaling cascades.
• The serum-response element in promoter 1D is regulated by distinct signaling cascades targeting Ets and CArG motifs.
• Ras and Rac1 activate both FGF1 and FGF2 promoters, while Ets2 synergistically activates FGF1 in a Ras/Rac1-dependent manner.
• High intracellular FGF1 levels were observed in cells undergoing cytokinesis.

Conclusions:

• FGF1 gene expression is intricately regulated by distinct promoters responding to specific signaling pathways.
• Ras, Rac1, and Ets2 play significant roles in the transcriptional activation of FGF1.
• FGF1 is implicated in fundamental cellular processes including cell division, spreading, migration, and proliferation.