Disease relevance of VGF

• The VGF gene encodes a secretory protein that is expressed in a cell type-restricted pattern in neuroendocrine cells and is up-regulated by nerve growth factor (NGF) in the rat pheochromocytoma PC12 cell line [1].
• Upsetting the balance: VGF and the regulation of body weight [2].
• In conclusion, we present here the identification in the CNS of a previously uncharacterized VGF-derived peptide and prove that its chronic i.c.v. infusion effected an increase in EE and limited the early phase of diet-induced obesity [3].
• Our data demonstrate that a TK- and VGF- mutant vaccinia virus is significantly attenuated in resting cells in vitro and demonstrates tumor-specific replication in vivo [4].
• There was no toxicity from vvDD-GFP because nude mice receiving 10(8) pfu of IP vvDD-GFP lived >100 days, whereas mice receiving WT, VGF-, or TK- virus had median survivals of only 6, 17, and 29 days, respectively [4].

High impact information on VGF

• Although VGF mRNA is synthesized widely, by neurons in the brain, spinal cord, and peripheral nervous system, its expression is particularly abundant in the hypothalamus [5].
• VGF (non-acronymic) was identified approximately 15 years ago as a nerve growth factor (NGF)-regulated transcript in rat PC12 pheochromocytoma cells [5].
• The predicted VGF sequence is rich in paired basic amino acid residues that are potential sites for proteolytic processing, and VGF undergoes regulated release from dense core secretory vesicles [5].
• Recent analysis of VGF knockout mice indeed demonstrates that VGF plays a critical role in the control of energy homeostasis [5].
• TLQP-21, a VGF-derived peptide, increases energy expenditure and prevents the early phase of diet-induced obesity [3].

Biological context of VGF

• Transient transfection analysis demonstrates that 2.3 kb of the 5'-flanking sequence acts as a tissue-specific promoter, efficiently used only by neuronal cells that express endogenous VGF [1].
• Molecular cloning and characterization of the human VGF promoter region [1].
• In addition to a TATA box and a CCAAT box located at canonical distances from the transcription start site, the human VGF promoter contains several consensus sequences for different transcription factors, including a cyclic AMP response element and an AP-1 element, several GC boxes, and sequences homologous to other neuronal promoters [1].
• The single-copy human VGF gene was isolated from a genomic library [6].
• In contrast to the wild-type virus, a VGF- mutant virus did not induce tyrosine phosphorylation of PLC-gamma 1 [7].

Anatomical context of VGF

• Negative cis-acting elements that repress promoter activity in cell lines that do not normally express VGF are located between nucleotides -2,305 and -573 and between -458 and -204 [1].
• RESULTS: Supernatant from CR-19-infected cells (VGF+) and from truncated vSC20PDGF infected cells caused mild and marked proliferation of 3T3 cells, respectively, whereas supernatant from full-length vSC20PDGF virally infected cells did not [8].
• The neuroendocrine protein VGF is sorted into dense-core granules and is secreted apically by polarized rat thyroid epithelial cells [9].
• Photoperiodic regulation of histamine H3 receptor and VGF messenger ribonucleic acid in the arcuate nucleus of the Siberian hamster [10].
• Using immunocytochemistry, we have localised the corresponding VGF protein product in various neuronal groups, including primary sensory and enteric neurons, and in endocrine cells of the adrenal medulla, adenohypophysis and gut [11].

Associations of VGF with chemical compounds

• Phosphopeptide analysis indicated that the phosphorylation of the PLC-gamma 1 by VGF includes tyrosine residues identical to those phosphorylated by EGF [7].
• Nerve growth factor rapidly regulates VGF gene transcription through cycloheximide sensitive and insensitive pathways [12].
• Twelve candidates were identified using mass-spectrometric techniques as fragments of the possibly neuroprotective neuroendocrine protein VGF and another one as the complement factor C3 descendent C3f [13].
• These findings suggest that the induction of VGF by NGF is distinct from that by bFGF in terms of sensitivities to MTA and staurosporine [14].

Regulatory relationships of VGF

• We show mRNA for the histamine H3 receptor is down-regulated and VGF is up-regulated in the dmpARC in hamsters switched from long- to short-day photoperiod [10].
• In addition to the morphological change, VIP induced expression of VGF protein, a neuron-specific protein associated with neuronal differentiation [15].

Other interactions of VGF

• Thus TGF-alpha and VGF failed to functionally compete for the EGF receptor in the murine spleen cell system [16].
• However, VGF did not cross-react in a radioimmunoassay specific for small and large forms of TGF-alpha and exhibited minimal cross-reactivity with antisera to EGF [17].
• Our results suggest that the unglycosylated form of VGF is an EGF antagonist to selected cells and that the production of unglycosylated form of VGF by the cytolytic vaccinia virus may serve as a mechanism whereby inhibition of growth and metabolism of selected host cells may be used to facilitate the propagation of the virus infection [18].
• Moreover, human chromogranin B, a protein of the regulated pathway, co-localizes in the same granules with VGF [9].
• Four of them were further purified by strong anionic exchange chromatography (SAX) and identified by MS analysis as cystatin C, two beta-2-microglobulin isoforms, an unknown 7.7 kDa polypeptide, and a 4.8 kDa VGF polypeptide [19].

Analytical, diagnostic and therapeutic context of VGF

• Here, a VGF peptide designated TLQP-21 was identified in rat brain extracts by means of immunoprecipitation, microcapillary liquid chromatography-tandem MS, and database searching algorithms [3].
• By immunoelectron microscopy, we have demonstrated that VGF localizes in dense-core granules [9].
• By confocal microscopy, we have found that in transient transfection, all mutant proteins are sorted into granules and co-localize with the full-length VGF [9].
• Site-directed mutagenesis was used to identify the KRKRKK(488) motif as the target within VGF sequence which leads to the production of VGF20 [20].
• 3. On the basis of in situ hybridization and immunohistochemical studies, the in vivo tissue-specific expression of VGF during differentiation and in the adult will be summarized [21].

References