Direct Regulation of rRNA Transcription by Fibroblast Growth Factor 2

Abstract

Fibroblast growth factor 2 (FGF-2), which is highly expressed in developing tissues and malignant cells, regulates cell growth, differentiation, and migration. Five isoforms (18 to ∼34 kDa) of FGF-2 are derived from alternative initiation codons of a single mRNA. The 18-kDa FGF-2 isoform is released from cells by a nonclassical secretory pathway and regulates gene expression by binding to cell surface receptors. This isoform also localizes to the nucleolus, raising the possibility that it may directly regulate ribosome biogenesis, a rate-limiting process in cell growth. Although several growth factors have been shown to accumulate in the nucleolus, their function and mechanism of action remain unclear. Here we show that 18-kDa FGF-2 interacts with upstream binding factor (UBF), an architectural transcription factor essential for rRNA transcription. The maximal activation of rRNA transcription in vitro by 18-kDa FGF-2 requires UBF. The 18-kDa FGF-2 localizes to rRNA genes and is necessary for the full activation of pre-rRNA synthesis in vivo. Our results demonstrate that 18-kDa FGF-2 directly regulates rRNA transcription.

ACKNOWLEDGMENTS

We thank Wenquan Wang (University of Alabama) for assistance in statistical analysis of data, Sonia Navarro (University of Southern California) for technical assistance, Jimmy Calaycay and Julie Rushbrook for the mass spectrometry analysis at the Protein Structure Laboratory at SUNY Downstate, Sui Huang for providing pEGFP-C1-UBF, and Vincent Garofalo (SUNY Downstate) for assistance with digital images.

This work was supported by an award (0151261T) from the American Heart Association to William J. Chirico.