FGF2 (fibroblast growth factor 2 (basic))

Note	Human FGF2 is located on chromosome 4 in the region of 4q25-4q27 on the forward DNA strand, opposite to the NUDT6 gene locus. FGF2 and NUDT6 overlap at their 3' ends.
	Figure A. The schematic representation of the human FGF2 and NUDT6 (FGF-AS) gene transcript overlap (colored boxes, coding region; connecting vertical lines, complementary regions between transcripts). Adapted from: MacFarlane LA, et al., 2010. Molecular Endocrinology 24. Figure B. The schematic representation of the human FGF2 gene and its RNA transcript (yellow rectangles, coding regions; UTR, untranslated region; ATG, translation start codon; TGA, translation stop codon; A1, polyadenylation site 1).
Description	Human FGF2 gene is 70990 bp in length, composed of a 5'UTR, 3 exons, 2 introns and an extremely long 3'UTR. The 5' and 3'UTR contain a variety of regulatory elements that regulate FGF2 expression in response to growth factors, cell density, neurotransmitters, hormones and second messenger pathways. The FGF2 core promoter maps from -1800 to +314 (relative to the transcription start site +1, up-stream -), which is 44 kb upstream of the NUDT6 promoter. The promoter lacks the typical consensus CATT and TATA box motifs. The distal -512/-854 region contains a single negative regulatory domain (-521/-854), a cell density dependent element (-512/-650) with STAT transcription factor binding sites, a growth factor responsive element (-512/-554) with STAT transcription factors binding sites, a protein kinase C (PKC)/cyclic adenosine monophosphate (cAMP) responsive element (-556/-624), and a dyad symmetry element (-597/-643). The proximal -511/+314 region maintains low promoter basal transcription activity and contains specific transcription factor binding sites which include AP-1 at the -243 position, p53 (wild type and mutant) between -20/+50, and Sp1 at positions -166, -139, -83, and -65. The unusually long AU-rich 3'UTR of FGF2 contains multiple regulatory elements that regulate polyadenylation, translation initiation, and RNA stability. A unique translation enhancer located in the 3'UTR just upstream of the most distal polyadenylation site (+5404/+6775) is involved in selecting the active polyadenylation site and modulating the use of alternative translation initiation sites. A destabilizing element (referred to as DEST) located between the first and second polyadenylation sites (+1019/+3326) alters mRNA stability. Additionally, two regions of the FGF2 3'UTR (+1183/+1765 and +6160/+6215) are fully complementary to the 3'end of the NUDT6 transcript, which enables mRNAs to form a sense-antisense pair. The formation of a sense-antisense pair has been implicated in the regulation of FGF2 mRNA stability.
Transcription	The full length 6774 bp FGF2 transcript contains the 3 exons and the 3'untranslated region, which contains at least 6 alternative polyadenylation sites. Alternative use of polyadenylation sites yields a variety of transcripts that have the same coding region but different length 3'UTR and contained regulatory elements. Consequently, transcript stability varies with the length of the 3'UTR, the shortest transcript is the most stable and the longest is the least stable.
Pseudogene	NA.

Note	Human FGF2 encodes 5 biologically active isoforms that differ in molecular weight, subcellular localization and function.
	Schematic representing human FGF2 isoform expression by alternative translation initiation (CUG, alternative leucine translation initiation codon; AUG, classical methionine translation initiation codon; IRES, internal ribosome entry sire; kDa, kilo Dalton; LMW, low molecular weight; HMW, high molecular weight; NLS, nuclear localization sequence; GR, Glutamic acid - Arginine; HIV, human immunodeficiency virus).
Description	The 6774-nt human FGF2 mRNA can have translation initiated at one of five in-frame codons indicated to generate five different molecular weight isoforms by cap-dependent or IRES dependent translation. All isoforms contain a carboxyl-terminal bipartite NLS. The HMW isoforms (34, 24, 22.5 and 22 kDa), initiated from CUG codons (86, 319, 346, 361), also contain an amino-terminal Glutamic acid - Arginine repeat domain that acts as an NLS. The 34 kDa isoform contains an additional NLS similar in structure to that of the human immunodeficiency virus (HIV) Rev protein.
Expression	FGF2 is expressed in a developmental and tissue specific manner. Differentiating populations of cells also have shifting levels of FGF2 protein content. Cell phenotype and environment can affect the length of the FGF2 mRNA and isoform expression by post-transcriptional regulation of polyadenylation. Primary cell types almost exclusively use the distal polyadenylation site to generate the full length 6775-nt FGF2 mRNA encompassing the full 3'UTR and all regulatory elements, whereas transformed and stressed cells favor the use of the most proximal polyadenylation site to generate transcripts with a much shorter 3'UTR lacking critical regulatory elements. In contrast to primary cells that predominantly express the LMW FGF2, the shorter FGF2 mRNA transcripts in stressed and transformed cells translate from the upstream CUG initiation codons to generate HMW FGF2 isoforms. FGF2 protein expression has been classified into two distinct patterns. The first, characterized by high levels of the AUG-initiated LMW isoform accompanied by low/undetectable levels of CUG-initiated HMW isoforms, is observed in normal cells such as skin fibroblasts, retinal pigment epithelial cells and aortic endothelial cells. In contrast, the second pattern, defined by high levels of HMW isoforms and low/undetectable levels of LMW, is seen in transformed cells including uterus carcinoma (HeLa cells), liver adenocarcinoma (SK-Hep-1 cells), pancreatic carcinoma (MIA PaCa-2 cells), epidermoid carcinoma (A-431 cells), breast adenocarcinoma (MCF-7 cells) and colon adenocarcinoma (HT-29). Fluctuations in FGF2 protein expression and localization occur in response to cell density, cell cycle and differentiation. Low density cell cultures have significantly higher LMW FGF2 expression which is predominantly nuclear, compared to high density cultures that express low levels of cytosolic FGF2. This variation can be attributed to differences in proliferation among the populations, as FGF2 is expressed in a cell cycle dependent manner. Increased proliferation in low density populations correlates with elevated FGF2 levels during the G0-G1 transition of the cell cycle and nuclear accumulation of FGF2.
Localisation	Subcellular localization and expression of FGF2 isoforms is determined by cell types, environment, level of differentiation, cell cycle phase and cell density. FGF2 isoform subcellular localization is essential for specific biological functions. Although all FGF2 isoforms can be found in the nucleus, cytoplasm and extracellular space at one time or another, they exhibit preferential localization. The LMW18 kDa FGF2 is primarily found in the cytoplasm. However, LMW FGF2 can be secreted and subsequently internalized to the cytoplasm and translocated to the nucleus. FGF2 lacks a conventional amino terminal signal sequence and therefore is secreted via a non-classical secretory pathway. The HMW FGF2 isoforms are predominantly located in the nucleus but are able to shuttle back to the cytoplasm. HMW FGF2 isoforms can be released from cells through vesicle shedding at the plasma membrane and as a result of cell injury or death that compromises cell membrane integrity. However, it is unclear to what extent HMW FGF2 isoforms exist extracellularly in vivo. Changes in isoform distribution can occur in response to cAMP and PKC signaling, cell density, cellular stress and post-translational modification.
Function	FGF2 is a pleiotropic signaling molecule involved in many biological processes including angiogenesis, embryonic development (brain, limb, lung, heart, muscle, bone, blood, eye and skin) and wound healing. Despite complex involvement in any aspects of embryogenesis FGF2 knockout mice are viable, functioning and do not display any apparent neurological deficit. FGF2 deficient mice have impaired brain development, blood pressure regulation, wound repair and bone formation. LMW FGF2 stimulates cell growth, proliferation, migration and differentiation via FGFR signaling and ligand receptor complex internalization. The FGF2 mitogenic response is controlled by direct and indirect regulation of nuclear kinase and transcription factor activity essential for ribosome biogenesis during cell proliferation and growth. Translokin, a cytoplasmic protein of relative molecular mass 55 kDa, interacts specifically with the 18 kDa form of FGF-2 and mediates its translocation to the nucleus. Nuclear LMW FGF2 binds the transcription factor UBF to directly regulate ribosomal RNA (rRNA) transcription. Nuclear LMW FGF2 also binds and modulates the nuclear kinases CK2 and ribosomal S6 kinase 2 (RSK2) responsible for nucleolin and histone phosphorylation, respectively, which are essential for ribosome biogenesis and cell cycle progression. LMW FGF2 indirectly influences rRNA transcription through receptor-mediated ERK dependent phosphorylation of the transcription initiation factor TIF-1A, which is essential for RNA polymerase 1 transcription. LMW FGF2 stimulates a mitogenic response in most cell types. However the particular signaling pathway activated appears to be dependent on cell type and the specific FGFR. Receptor-mediated ERK activation also stimulates cell migration and differentiation. However, other signaling pathways such as PI3K and MAPK have also been implicated in regulation of these processes. LMW FGF2 stimulated migration, growth and differentiation responses mediate angiogenesis, wound repair, embryonic development and maintenance of vascular tone. The affects of HMW are dependent on isoform, expression level and cell type. The majority of HMW FGF2 functions require nuclear localization. The HMW nuclear forms of FGF-2 have been reported to interact with a 55 kDa nuclear protein, FIF (FGF-2-interacting-factor), which interacts specifically with FGF-2 but not with FGF-1, FGF-3, or FGF-6. Some of the biological effects of FGF-2 may be mediated by interaction with FIF, which has anti-apoptotic activity. Nuclear 34 kDa HMW FGF2 acts as a survival factor, sustaining cell growth in low-serum conditions. However, in normal conditions the effects of HMW FGF2 on proliferation vary with cell type and expression level. High levels of HMW FGF2 induce proliferation in a variety of cells including aortic endothelial, fibroblasts, glioma, pancreatic tumor and liver adenocarcinoma cells. Low levels of HMW FGF2 inhibit cell proliferation in glioma and fibroblast cells. These effects have been attributed in part to the ability of HMW FGF2 to control mitosis by inhibiting phosphorylation of the translation initiation factor 4E-BP1, which is critical for translation associated with cell cycle progression. In contrast, low levels of HMW FGF2 favor proliferation in cardiomyocytes and embryonic kidney cells while high levels inhibit proliferation and promote cell death by inducing chromatin compaction and cytosolic release of cytochrome C. Furthermore, HMW FGF2 up-regulates the growth inhibiting nuclear protein 1 (Nupr1) which is related to the High Mobility Group (HMG) of proteins that function in chromatin remodeling and transcription factor recruitment. HMW FGF2 has also been implicated in apoptosis, cell adhesion, migration and differentiation. HMW FGF2 can suppress apoptosis, which could be in part attributable to its ability to bind to the prosurvival factor API5. However, FGF2 has also been shown to induce apoptosis. This effect has been associated with the observation that FGF2 overexpression reduces the antiapoptotic protein BCL-2 to promote apoptosis. HMW FGF2 up-regulates cell adhesion molecules and stabilizes focal adhesion complexes in a variety of tissue, which may explain the ability of HMW FGF2 to suppress migration. Additionally, migration suppression could be associated with the level of cellular differentiation. HMW FGF2 has been shown to induce high level differentiation.
Homology	FGF2 is a member of a large family of structurally related heparin-binding proteins (the FGFs) involved in the regulation of cell proliferation, growth and differentiation.

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