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DNA Cell Biol. 2007 Dec;26(12):811-26.

Integrative nuclear signaling in cell development--a role for FGF receptor-1.

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Molecular and Structural Neurobiology and Gene Therapy Program, State University of New York, Buffalo, New York 14214, USA.


Ontogeny requires the coordinated regulation of multigene programs by a plethora of extracellular and intracellular signals, thereby allowing cells to transition between different states, including proliferation and differentiation. Disruption of this regulation can result in oncogenic transformation in which cells are "arrested" in the proliferative state. This article summarizes our current understanding of a novel "Integrative Nuclear Fibroblast Growth Factor Receptor-1 (FGFR1) Signaling" (INFS) pathway, which influences differentiation of neural progenitor cells and the associated gene activities. Activation of cell surface neurotransmitter, hormonal, or growth factor receptors stimulates the release of FGFR1 from cytoplasmic membranes into the cytosol. This process is enabled by the atypical transmembrane domain of FGFR1 and is facilitated by the interaction with pp90 ribosomal S6 kinase-1. Cytosolic FGFR1 is transported into the nucleus by importin beta and activates transcription in cooperation with CBP (cyclic AMP Responsive Element-Binding Protein) by augmenting RNA polymerase II activity and histone acetylation. To explain the developmental function of FGFR1, a "feed-forward-and-gate" signaling mechanism is presented in which the INFS pathway "feeds forward" the developmental signals to the common and essential transcriptional coactivator, CBP. The coupled activation of CBP (by INFS) and transcription factors (by specific signaling pathways) enables the coordinated regulation of multigene programs by developmental cues. In some cancer cells, in which INFS is inactive, the reconstitution of nuclear FGFR1 signaling may be used to reestablish this coordinated regulation thereby inhibiting tumor cell proliferation and inducing differentiation.

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