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4 Transcription factors are proteins that help regulate control the expression from BIOLOGY 512380 at American ..
Unfolded protein response - Wikipedia
The human IGF-2R-coding gene is situated onchromosome 6q25–q27 ().Extracellular domain consists of 15 segments, each containing from134 to 191 aa and a small region homologous to the collagen-bindingdomain of fibronectin (). Mousegene of 93 kb in length, includes 48 exons and codes for a proteinwith 2482 aa (). The receptoritself is identical with cation-independent IGF-2/MPR (,).IGF-2R binds IGF-2 ∼500 higher than IGF-1 (). IGF-2R is a multifunctional proteinand plays a principal role in sorting and transport of lysosomalenzymes from sites of their synthesis to appropriate cellularcompartments and in control of proteins containingmannose-6-phosphate. The receptor is of potential significance formaturation and clearance of growth factors and it mediatesIGF-2-activated signal transduction through a G-protein-coupledmechanism (,). In studies on mice IGF-2R wasdemonstrated to be paternally imprinted, and to be crucial forregulating normal fetal growth, circulating IGF-2, and heartdevelopment ().
IGF-1 binds with IGF-1R to stimulate cellularproliferation or inhibit apoptosis through different pathways,increasing the risk of carcinogenesis (–)(). IGF-1R/IGF axis maypositively control cell cycle progression in many phases, but themajor direct effect is probably exerted at the G1-S interface, andthis is mediated through the phosphatidylinositol3-kinase/serine/threonine-specific protein kinase (PI-3K/Akt)and/or extracellular signal-regulated kinase (ERK) pathways(). IGF-1 exerts a mitogeniceffect influencing stimulation of cyclin D1 and of someproto-oncogenes () expression. Moreover, it actsanti-apoptotically and modulates body immune response by control ofcytokine production (e.g. IL-3 and IL-14) (). It was also demonstrated that shortpeptides of IGF-1 precursors may promote growth of normal andmalignant cells in bronchial epithelium (). IGF-1 controls expression of over 50genes linked to mitogenesis and cell differentiation. However, itexerts mitogenic activity mainly through stimulation of DNAsynthesis and of cyclin D1 expression ().
Protein folding in the endoplasmic reticulum Protein synthesis
Schematic representation of theGH-IGF axis in normal physiology (A) and the proposed model for howit is affected by HCV-associated liver injury (B). (A) In postnatalperiod liver remains to be the main source of circulating IGF-1 andthe protein is produced mainly under effect of growth hormone (GH)and its receptor (GHR) on liver cells (17). IGF-1 produced in liver exertsmainly endocrine activity while IGF-1 synthesised by other tissuesacts in a para- and/or autocrine way (20). IGFs affect a cell specificallybinding three various surface receptors: IGF-1R, IGF-2R and IR. Inmost of activities of IGF-1 and IGF-2, IGF-1R plays the main roleof a mediator (23). (B) InHCV-infected patients, GH insufficiency (GH*) and persistent GHresistance (GHR*) of hepatocytes and low IGF-1 levels weredocumented (139). Other studiesdemonstrated an increased IGF-1R mRNA and a decreased IGF-1 proteinsynthesis in patients with chronic hepatitis C (144). HCV replication was associatedwith overexpression of IGF-2 in the cirrhotic livers (145). Studies on HCV-related HCCsdocumented a decreased IGF-1 expression, an increasedexpression of IGF-2 in 20–50% of HCCs (84,85,146), IGF BP3 downregulation andallelic losses of IGF 2R (84).The increased synthesis of IGF-2 (mRNA and protein) was associatedwith an increased cellular proliferation in HCCs (146). Compared with a non-cirrhoticliver, all cirrhotic specimens showed reduced expression ofIGF-2R/M6PR protein. It was suggested that downregulation ofhepatocellular IGF-2R/M6PR and upregulation of IGF-2 might be earlyevents in hepatocarcinogenesis (131). HCV core protein was shown toincrease endogenous expression of IGF-2 in HepG2 cell line(149).
Hepatocellluar carcinoma is the third leading causeof cancer-related death worldwide (,).The suggested roles of both IGFs and IGF-1R in development of HCCreflect, first of all, observations indicating strong mitogeniceffects of the factors in conditions (,,).Different types of cultured cells produce IGF-1 mRNA () and insulin receptor substrate 1(IRS-1) (). IRS-1 undergoesoverexpression in human HCC (,).The dominating pathways activated by IGF-1 in hepatocytes andhepatoma cell lines involve the PI3K/Akt (,)and signal transducer and activator family protein (STAT) signalingpathways (). IGF-1 has beenimplicated in NF-κB-mediated transcriptional regulation ofinflammatory cytokines and endothelial cell adhesions receptorssuch as intracellular adhesion molecule-1 (ICAM-1) (). Studies on HepG2 and HuH-7 cellsdemonstrated that the cells synthetised and secreted also IGF-2 andinhibition of the protein production resulted in a reduced cellularproliferation (). Recentstudies on HCV-related HCC demonstrated overexpression of gene (resulting from reactivation of fetal promotersP3 and P4), IGF BP3 down-regulation, decreased IGF-1 expression andallelic losses of . Administration of IGF-1R-selectiveinhibitors (A12) reduced IGF-1-induced effects and was associatedwith a significant reduction of liver tumour growth () ().
Ribosomes - Protein Synthesis - Cronodon
Two key regulatory proteins of this axis are known:IGF-1 and IGF-2, which manifest ∼50% sequence identical to that ofinsulin (). They are includedin the insulin-related family together with relaxin while genes ofthe family members were located on distinct genomic fragments(chromosome 2 and 11p-q13) ().To date, 6 types of the IGF BPs have been well characterised (IGFBP1–6), plus two subsequent ones, less well recognised (IGF BP-7and 8) (–). The basic functions of IGF BPsinclude modulation of IGF-1 and IGF-2 bioactivity, mainly throughinteractions with receptors of the factors and with insulinreceptor (IR). Moreover, IGF BPs extend half-life of IGFs in blood,store them in selected tissue compartments and inhibit activity ofIGFs by lowering accessibility of their receptors. They may actindependently of the receptors, inducing mitogenesis and cellmigration (). They participatein the interactions with other growth factors (e.g. TGF-β)(). The most commonlymanifested circulating form of IGF BP, is IGF BP-3, which bindsover 95% of IGFs. The protein as a dimer forms a complex with theacid-labile protein (ALS) subunit (). IGF BP-2, -3 and -5 contain anuclear localisation signal and may influence on activity oftranscription. The IGF BP-3 itself may act also as an inhibitor ofcell growth (,). Free IGF-1 has a half-life of ∼8 minin serum. This can be increased to ∼30 min if bound to IGF BP-3 andto ∼15 h in the ternary complex with IGF BP-3 and ALS ().
Cell Signaling and Neuroscience
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