Disease relevance of GCHFR

• Baculoviruses possess two different classes of genes with anti-apoptptic activity: p35 and iap [1].
• P35, an activator of CDK5 that is indicative of its activity, is expressed in a panel of human and rat prostate cancer cell lines, and is also expressed in 87.5% of the human metastatic prostate cancers we examined [2].
• Identification and functional characterization of AMVp33, a novel homolog of the baculovirus caspase inhibitor p35 found in Amsacta moorei entomopoxvirus [3].
• Gene transfer of the pancaspase inhibitor P35 reduces myocardial infarct size and improves cardiac function [4].
• The early protein P35 from the baculovirus Autographa californica nucleopolyhedrovirus is a direct inhibitor of caspases and can block apoptosis in a wide variety of systems [5].

Psychiatry related information on GCHFR

• However, stress-induced locomotor activity was significantly increased in the Caesarean birth plus anoxia at P35, while after puberty (at P56), saline injection, D-amphetamine and stress-induced locomotion were significantly enhanced in the Caesarean birth plus anoxia compared to its control groups [6].
• Since apoE is important in the pathogenesis of Alzheimer's disease (AD), we tested whether apoE treatment of neurons affected molecules important to phosphorylation of tau, such as GSK 3beta, P35, and CDK5, and the phosphorylation of tau itself [7].

High impact information on GCHFR

• The viral antiapoptotic gene P35 mitigated polyglutamine-induced degeneration in vivo [8].
• A nestin scaffold links Cdk5/p35 signaling to oxidant-induced cell death [9].
• To gain insight into developmental events influenced by a premature exposure to high oxygen levels and identify proteins engaged in neurodegenerative and reparative processes, we analyzed mouse brain proteome changes at P7, P14 and P35 caused by an exposure to hyperoxia at P6 [10].
• Differential inhibitory effects of CrmA, P35, IAP and three mammalian IAP homologues on apoptosis in NIH3T3 cells following various death stimuli [11].
• In nuclear import assays, p35 was actively transported into the nuclei of digitonin-permeabilized HeLa cells and cortical neurons by cytoplasmic carrier-mediated mechanisms [12].

Chemical compound and disease context of GCHFR

• Members of the baculovirus p35 gene family encode proteins that specifically inhibit caspases, cysteine proteases that are involved in apoptosis [3].

Biological context of GCHFR

• The yeast 2-hybrid system was used to identify protein domains involved in the oligomerization of human guanosine 5'-triphosphate (GTP) Cyclohydrolase I (GCH1) and the interaction of GCH1 with its regulatory partner, GCH1 feedback regulatory protein (GFRP) [13].
• Incubation of HUVEC with interferon-gamma (100 U/ml) showed an increase of GTPCH I mRNA and a significant downregulation of GFRP mRNA after 24 hours (p = 0.03) [14].
• In this review, we discuss the inhibition of apoptosis by baculoviruses, concentrating mainly on the nature and mechanism of action of the two classes of baculovirus genes, p35 and iap, which are able to control apoptosis in a diversity ofeukaryotes [1].
• Here, we examined the nuclear import properties of p35 [12].
• Further, glucose enhances p35 gene expression, promoting the formation of active p35/CDK5 complexes that regulate the expression of the insulin gene [15].

Anatomical context of GCHFR

• GFRP expression was also suppressed in human umbilical vein endothelial cells treated with 1 microg/ml LPS, as well as in rat tissues 7 h post intraperitoneal injection of 10 mg/kg LPS [16].
• METHODS AND RESULTS: Using RT-PCR and northern blot technique, coexpression of GFRP and GTPCH I could be demonstrated in a number of different tissues such as endothelial cells and peripheral blood cells [14].
• To identify caspase targets in monocytes undergoing macrophagic differentiation, we used the human monocytic leukemic cell line U937, whose macrophagic differentiation induced by exposure to 12-O-tetradecanoylphorbol 13-acetate (TPA) can be prevented by expression of the baculovirus caspase-inhibitory protein p35 [17].
• Changes in tetrahydrobiopterin levels in endothelial cells and adult cardiomyocytes induced by LPS and hydrogen peroxide--a role for GFRP [18]?
• Our results identified indeed a functioning GFRP/GTPCHI axis in epidermal keratinocytes and melanocytes in the cytosol, adding the missing link for 6BH(4) de novo synthesis which in turn controls cofactor supply for catecholamine and serotonin biosynthesis as well as melanogenesis in the human epidermis [19].

Associations of GCHFR with chemical compounds

• Recombinant human GFRP stimulated recombinant human GTP cyclohydrolase I in the presence of phenylalanine and mediated feedback inhibition by tetrahydrobiopterin [16].
• These results demonstrate that LPS down-regulates expression of GFRP, thus rendering pteridine synthesis independent of metabolic control by phenylalanine [16].
• P35 has recently been shown to be capable of inhibiting the ICE/ced-3 family of cysteine proteases, a family of enzymes which are implicated in cell death and which exhibit specificity for cleavage at aspartate residues [1].
• This conclusion is further supported by depletion of biopterin in cells transiently transfected with GFRP [18].
• These ligands, BH4 and phenylalanine, induce complex formation between one molecule of GTP cyclohydrolase I and two molecules of GFRP [20].

Other interactions of GCHFR

• GTP cyclohydrolase I feedback regulatory protein (GFRP) is a 9.7-kDa protein regulating GTP cyclohydrolase I activity in dependence of tetrahydrobiopterin and phenylalanine concentrations, thus enabling stimulation of tetrahydrobiopterin biosynthesis by phenylalanine to ensure its efficient metabolism by phenylalanine hydroxylase [16].

Analytical, diagnostic and therapeutic context of GCHFR

• Immunostimulation alters protein expression of GTPCH I and GFRP in a way that favors BH(4) synthesis [14].
• Preparation and crystallization of the stimulatory and inhibitory complexes of GTP cyclohydrolase I and its feedback regulatory protein GFRP [21].
• Caesarean section birth with or without an additional period of anoxia was performed in Sprague-Dawley rats and their behaviors were studied at P35 and P56, respectively [6].
• We also found that both IL-12 p35 and IL-23 p19 mRNA are expressed rapidly in the liver after ischemia/reperfusion [22].
• The P35-GST protein was used as antigen to detect 125 sera samples by double-sandwich ELISA [23].

References