Search results

The peroxisome proliferator activated receptors (PPARs) are ligandactivated transcription factors within the nuclear receptor superfamily, which play important roles in adipogenesis, glucose homeostasis andinflammation. Three different isotypes can be distinguished; alpha, beta and gamma. PPARg, is mainly expressed in adipose tissue and to lesser extent in colon, the immune system and the retina. Whereas PPARg operates in the catabolism of fatty acids in the liver, PPARg influences the storage of fatty acids in the adipose tissue and plays a role in adipocyte differentiation. PPARg binds to DNA as a heterodimer with retinoid X receptor (RXR), activating expression of target genes after binding ligand.

Excess adiposity is the most important risk in the development of insulin resistance and type 2 diabetes mellitus (T2DM). Adipose tissue produces several proteins (adipocytokines) such as leptin, adiponectin, resistin, tumor necrosis factor-?, and IL-6, that modulate insulin sensitivity and appear to play an important role in the pathogenesis of insulin resistance, diabetes, dyslipidemia, inflammation, and atherosclerosis. However, the mechanisms by which fat tissue induces insulin resistance and the role of adipocytokines in the pathogenesis of T2DM have not been well established. Visfatin, also known as pre-B cell colony-enhancing factor (PBEF), is a cytokine that is highly expressed in visceral fat and was originally isolated as a secreted factor that synergizes with IL-7 and stem cell factors to promote the growth of B cell precursors. Visfatin homologs have been identified in carp, invertebrate mollusks, and bacteria, as well as in vertebrates, including humans and the mouse. It has been postulated to play a role in innate immunity.
Visfatin exerts insulin-mimetic effects that are dose-dependent and quantitatively similar to those of insulin in stimulating muscle and adipocyte glucose transport, and in inhibiting hepatocyte glucose production. Intravenous injection of recombinant visfatin in mice decreased plasma glucose in a dose-dependent fashion. In keeping with its insulin-mimetic effects, visfatin was as effective as insulin in reducing hyperglycemia in insulin-deficient diabetic mice. Visfatin was also found to be bound to and activate insulin receptor, causing receptor phosphorylation and the activation of downstream signaling molecules. However, visfatin and insulin did not compete for binding to the insulin receptor, indicating that the two proteins were recognized by different regions of the receptor. Thus, visfatin might play a role in glucose homeostasis and dysregulation in biosynthesis or signal transduction, and might contribute to the pathogenesis of diabetes.

GH is a member of the somatotropin/prolactin family of hormones which play an important role in growth control. The gene, along with four other related genes, is located at the growth hormone locus on chromosome 17 where they are interspersed in the same transcriptional orientation; an arrangement which is thought to have evolved by a series of gene duplications. The five genes share a remarkably high degree of sequence identity. Alternative splicing generates additional isoforms of each of the five growth hormones, leading to further diversity and potential for specialization. This particular family member is expressed in the pituitary but not in placental tissue as is the case for the other four genes in the growth hormone locus. Mutations in or deletions of the gene lead to growth hormone deficiency and short stature.

TNFSF12 is a cytokine that is part of the TNF ligand family. TNFSF12 is a ligand for the FN14/TWEAKR receptor. TNFSF12 has overlapping signaling functions with TNF, but displays a much wider tissue distribution. TNFSF12 induces apoptosis through multiple pathways of cell death in a cell type-specific manner. TNFSF12 promotes proliferation and migration of endothelial cells, and therefore acts as a regulator of angiogenesis. TNFSF12 is expressed in adult heart, pancreas, skeletal muscle, small intestine, spleen and peripheral blood lymphocytes. TWEAK h induces NFkB and chemokine secretion. TNFSF12 exerts an apoptotic activity in HT-29 human adenocarcinoma cells whilst cultured in the presence of IFN-?. TNFSF12 promotes proliferation and migration of endothelial cells.

CD30 Ligand (TNFSF8) is a cytokine which is a member of the tumor necrosis factor (TNF) ligand family. The TNFSF8 cytokine is a ligand for TNFRSF8/CD30, which is a cell surface antigen and a marker for Hodgkin lymphoma and related hematologic malignancies. The employment of the TNFSF8 cytokine expressed on B cell surface has an inhibitory role in modulating Ig class switch. TNFSF8 enhances cell proliferation of some lymphoma cell lines, while inducing cell death and reducing cell proliferation of other lymphoma cell lines. The pleiotropic biological activities of the TNFSF8 cytokine on different CD30+ lymphoma cell lines has a pathophysiologic role in Hodgkin's and some non-Hodgkin's lymphomas.

Bcl2 modifying factor, is a member of the Bcl2 protein family of apoptosis mediators. Bcl2 modifying factor is widely expressed in many tissues.
Bcl2 modifying factor contains a single Bcl2 homology domain 3 (BH3), and binds Bcl2 proteins and functions as an apoptotic activator. Also, Bcl2 modifying factor is important for histone deacetylase (HDAC) inhibitors which alters the balance between acetylation and deacetylation, significantly increasing histone acetylation, while strongly inducing apoptosis in a variety of cancer cell types. Bcl2 modifying factor supports Bim in regulating cell death processes in response to many stimuli. A synergistic role for bim and Bcl2 modifying factor in an apoptotic pathway leading to the clearance of Neisseria gonorrhoeae -infected cells.

Osteoprotegerin acts as decoy receptor for rankl and thereby neutralizes its function in osteoclastogenesis. OPG inhibits the activation of osteoclasts and promotes osteoclast apoptosis in vitro. Bone homeostasis seems to depend on the local rankl/opg ratio. Osteoprotegerin may also play a role in preventing arterial calcification. May act as decoy receptor for trail and protect against apoptosis. Trail binding blocks the inhibition of osteoclastogenesis.

Thrombopoietin is a glycoprotein hormone produced mainly by the liver and the kidney which regulates the production of platelets by the bone marrow. TPO stimulates the production as well as differentiation of megakaryocytes, the bone marrow cells which fragment into large numbers of platelets.

Galectin-3 mediates with the alpha-3, beta-1 integrin the stimulation by cspg4 of endothelial cells migration. Galectin-3 plays an necessary part during the acquisition of vasculogenic mimicry and angiogenic properties associated with melanoma progression. LGALS3 overexpression is highly expressed in early stages of papillary carcinoma, and its expression intensity declines during tumor progression. Serum levels of LGALS3 are high in patients with thyroid malignancy but there is considerable overlap in serum LGALS3 concentrations between those with benign and malignant nodular thyroid disease. LGLAS3 takes part as an immune regulator to inhibit T-cell immune responses and promote tumor growth, as a result providing a new mechanism for tumor immune tolerance.

Periostin is a disulfide linked 90 kDa, 811 amino acid protein originally isolated as a osteoblast-specific factor that functions as a cell adhesion molecule for preosteoblasts and is thought to be involved in osteoblast recruitment, attachment and spreading. Additionally, periostin expression has previously been shown to be significantly increased by both transforming growth factor beta-1(TGFbeta1) and bone morphogenetic protein (BMP-2). OSF-2 has a typical signal sequence, followed by a cysteine-rich domain, a fourfold repeated domain and a C-terminal domain. The fourfold repeated domain of OSF-2 shows homology with the insect protein fasciclin
Periostin mRNA is expressed in the developing mouse embryonic and fetal heart, and that it is localized to the endocardial cushions that ultimately divide the primitive heart tube into a four-chambered heart.

PEDF is a noninhibitory serpin with neurotrophic, anti-angiogenic, and anti-tumorigenic properties. PEDF is a 50,000 dalton glycoprotein created and secreted in many tissues all the way through the body. A key component of the anti-angiogenic action of PEDF is the induction of apoptosis in proliferating endothelial cells. Additionally, PEDF is capable to inhibit the activity of angiogenic factors such as VEGF and FGF-2. The neuro-protective effects of PEDF are achieved through suppression of neuronal apoptosis induced by peroxide, glutamate, or other neurotoxins. The recognition of a lipase-linked cell membrane receptor for PEDF (PEDF-R) that binds to PEDF with high affinity should facilitate further elucidation of the underlying mechanisms of this pluripotent serpin. To date, PEDF-R is the only signaling receptor known to be used by a serpin family member. The unique range of PEDF activities associate it as a potential therapeutic agent for the treatment of vasculature related neurodegenerative diseases such as age-related macular degeneration (AMD) and proliferative diabetic retinopathy (PDR). PEDF in addition has the potential to be functional in the treatment of various angiogenesis-related diseases including a number of cancers.

TFPI is a protease inhibitor which controls the tissue factor (TF)-dependent pathway of blood coagulation. The coagulation process starts with the creation of a factor VIIa-TF complex, that proteolytically triggers additional proteases (factors IX and X) and eventually results in a fibrin clot. TFPI inhibits the activated factor X and VIIa-TF proteases in an autoregulatory loop. TFPI is glycosylated and predominantly located in the vascular endothelium and plasma in both free forms and complexed with plasma lipoproteins. A number of alternatively spliced transcript variants of this gene have are known, however the full-length nature of several of these variants were not yet established.

Profilin1 (PFN1) is a ubiquitous actin monomer-binding protein which is a member of the profilin family. PFN1 significantly boosts skin wound healing in-vitro and in-vivo which may be mediated by purinergic receptors. PFN1 is also active in endothelial cell migration and vessel sprouting. PFN1 is thought to control actin polymerization in response to extracellular signals. PFN1 binds to actin and affects the formation of the cytoskeleton. In addition, PFN1 has an important role in the regulation of epithelial cell-cell adhesion. At high concentrations, profilin averts the polymerization of actin, while at low concentrations it enhances the polymerization. PFN1 gene deletion is linked to Miller-Dieker syndrome.

GH is a member of the somatotropin/prolactin family of hormones which play an important role in growth control. The gene, along with four other related genes, is located at the growth hormone locus on chromosome 17 where they are interspersed in the same transcriptional orientation; an arrangement which is thought to have evolved by a series of gene duplications. The five genes share a remarkably high degree of sequence identity. Alternative splicing generates additional isoforms of each of the five growth hormones, leading to further diversity and potential for specialization. This particular family member is expressed in the pituitary but not in placental tissue as is the case for the other four genes in the growth hormone locus. Mutations in or deletions of the gene lead to growth hormone deficiency and short stature.

Phosphoglycerate kinase 1, also referred to PGK1, is an X-linked enzyme whichfunctions in the glycolytic pathway.The gene encoding the erythrocyte enzyme PGK1 & it seems that PGK-1 plays a role as a polymerase alpha cofactor protein (primer recognition protein) as a glyxolytic enzyme role. The PGK1 catalyzes the reversible conversion of 1, 3-diphosphoglycerate to 3-phosphoglycerate during glycolysis, generating one molecule of ATP.

The Melanoma Inhibitory protein (MIA) was identified as an inhibitor of in vitro growth of malignant melanoma cells. The protein contains a SH3 domain.
MIA acts as a potent tumor cell growth inhibitor for malignant melanoma cells and some other neuroectodermal tumors, including gliomas, in an autocrine fashion. In a study of human melanoma cell lines with different metastatic capacity MIA mRNA expression appeared to be inversely correlated with pigmentation. MIA has been shown to represent a very sensitive and specific serum marker for systemic malignant melanoma that might be useful for staging of primary melanomas, detection of progression from localized to metastatic disease during follow-up, and monitoring therapy of advanced melanomas.

Growth hormone receptor, also known as GHR is part of the cytokine receptor family. GHR binds 2 receptor molecules and in this manner induces signal transduction through receptor dimerization. Furthermore, at high concentrations, growth hormone performs as an antagonist since there is a large difference in affinities at the respective binding sites. The antagonist action can be enhanced further by reducing binding in the low affinity binding site.

proBDNF (the precursor form of Brain-derived neurotrophic factor) interacts preferentially with p75NTR (the pan-neurotrophin receptor p75) and vps10p domain-containing receptor sortilin and induces neuronal apoptosis, while the mature BDNF selectively binds with great affinity to the TrkB kinase receptor and promotes the survival, growth and differentiation of neurons. Since proneurotrophins and mature neurotrophins bring forth opposite biological effects, proBDNF cleavage in the neuronal system is regulated in a specific and cell-context dependent manner. proBDNF has an important role in negative regulation of neurotrophic actions in the brain.

Inhibins are dimeric peptide hormones produced by female ovarian granulose cells and male Sertoli cells as well as a variety of other tissues. Inhibins have two isoforms, A and B, with the same alpha subunit but different beta subunits. Inhibin A is a dimer of alpha and beta A subunits, inhibin B is a dimer of alpha and beta B subunits.
Inhibins are thought to inhibit the production of follicle-stimulating hormone (FSH) by the pituitary gland. In addition, Inhibins are also thought to play a role in the control of gametogenesis, and embryonic and fetal development.

FSTL1 protein resembles follistatin, an activin-binding protein. FSTL1 is an autoantigen associated with rheumatoid arthritis and it holds an FS section, a follistatin-like sequence having 10 conserved cysteine residues.

EIF1AX is an important eukaryotic translation initiation factor. EIF1AX is essential for the binding of the 43S complex (a 40S subunit, eIF2/GTP/Met-tRNAi and eIF3) to the 5'' end of capped RNA. EIF1AP1 is needed for maximal rate of protein biosynthesis. EIF1AX increases ribosome dissociation into subunits and stabilizes the binding of the initiator Met-tRNA (I) to 40 S ribosomal subunits.

GHBP is a transmembrane receptor for growth hormone. Binding of growth hormone to the receptor leads to receptor dimerization and the activation of an intra- and intercellular signal transduction pathway leading to growth. A common alternate allele of this gene, called GHRd3, lacks exon three and has been well-characterized. Mutations in this gene have been associated with Laron syndrome, also known as the growth hormone insensitivity syndrome (GHIS), a disorder characterized by short stature. Other splice variants, including one encoding a soluble form of the protein (GHRtr), have been observed but have not been thoroughly characterized.