Regulation of non‐classical FGF1 release and FGF‐dependent cell transformation by CBF1‐mediated notch signaling

Abstract

FGF1, a widely expressed proangiogenic factor involved in tissue repair and carcinogenesis, is released from cells through a nonclassical pathway independent of endoplasmic reticulum and Golgi. Although several proteins participating in FGF1 export were identified, genetic mechanisms regulating this process remained obscure. We found that FGF1 export and expression are regulated through Notch signaling mediated by transcription factor CBF1and its partner MAML. The expression of a dominant negative (dn) form of CBF1 in 3T3 cells induces transcription of FGF1 and sphingosine kinase 1 (SphK1), which is a component of FGF1 export pathway. dnCBF1 expression stimulates the stress-independent release of transduced FGF1 from NIH 3T3 cells and endogenous FGF1 from A375 melanoma cells. NIH 3T3 cells transfected with dnCBF1 form colonies in soft agar and produce rapidly growing highly angiogenic tumors in nude mice. The transformed phenotype of dnCBF1 transfected cells is efficiently blocked by dn forms of FGF receptor 1 and S100A13, which is a component of FGF1 export pathway. FGF1 export and acceleration of cell growth induced by dnCBF1 depend on SphK1. Similar to dnCBF1, dnMAML transfection induces FGF1 expression and release, and accelerates cell proliferation. The latter effect is strongly decreased in FGF1 null cells. We suggest that the regulation of FGF1 expression and release by CBF1-mediated Notch signaling can play an important role in tumor formation.

Notch Signaling Activation Is Associated with Patient Mortality and Increased FGF1-Mediated Invasion in Squamous Cell Carcinoma of the Oral Cavity

“…Although FGF1 is not a classical target of Notch transcription, ours is not the first evidence of a regulatory relationship between Notch and FGF signaling. In several previous studies, the constitutive activation of canonical (CBF1 dependent) Notch-mediated transcription was found to suppress FGF1 expression, while inhibition of CBF1 and its coactivator MAML induced FGF1 expression and transport into the extracellular compartment (31)(32)(33). Surprisingly, we observed evidence of the opposite, as in vitro Notch activation increased FGF1 transcript levels and produced an FGF1-dependent invasive phenotype.…”

HIV envelope protein gp120-induced apoptosis in lung microvascular endothelial cells by concerted upregulation of EMAP II and its receptor, CXCR3

“…The mechanism of EMAP II membrane binding and release is unknown. It is possible this mechanism is similar to the alternative release of FGF1, whereby several proteins including S100A13 and synaptotagmin 1, form a membrane-associated protein complex that mediates the flip-flop from intracellular to extracellular membrane localization (12,17,22). The apparently delayed release of surface bound EMAP II may be a result of such a mechanism with yet unknown binding partners.…”

Notch Signaling Modulates Hypoxia-Induced Neuroendocrine Differentiation of Human Prostate Cancer Cells

“…One likely candidate is the prototype member of the Fibroblast Growth Factor family, FGF-1. Indeed FGF-1 is a well-known mitogenic stimulus for prostate cancer cells (47) and its secretion has been linked to a down regulation of N1 receptor activity (48). …”