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1、胰岛素样生长因子（Insulin-like growth factor）Insulin-like growth factorBasic conceptShanghai Ya Xi (International) snow America authorized biomedical technology services center marketing P DepartmentInsulin-like growth factors (IGFs) is a class of multifunctional cell proliferation regulating factors. It pla
2、ys an important role in cell differentiation, proliferation and individual growth and development. This paper reviews the general situation of IGFs and its relationship with growth and development.History of IGFSGrowth hormone and Daughaday on 1957 Salmon (growth hormone, referred to as GH) in the p
3、rocess of giving first found in hypophysectomized rats after GH serum can stimulate S into cultured cartilage, but directly into the liquid culture of GH has no effect, so that GH itself can directly stimulate the growth of cartilage, but through a SF role, this factor became known as growth regulat
4、or. 1963 Froesh found in the serum insulin like effect on muscle and fat cells are only a small part of the insulin antiserum inhibited the remaining soluble insulin like activity was not inhibited in acidified ethanol, and named NSILAS which is inhibited by insulin like activity (nonsuppressible in
5、sulin-like activity). In 1972, Pieron and Temin purified a cytokine from bovine serum that stimulated cell division, called proliferation stimulating activity. After the above three experiments were completed, it was found that the above three substances had an inhibitory insulin-like activity and a
6、 growth stimulatory effect. With the development of molecular biology, 1978 people purified two kinds of NSILA (I, II) and found its structure and proinsulin were named as similar, insulin-like growth factor I and II (IGF I, II) to emphasize their homology with insulin structure. It was also confirm
7、ed that the sulfation factor and the proliferation stimulating activity were members of the same polypeptide family as IGF.Composition, physical and chemical properties of IGFs systemThe IGFs family is composed of two low molecular polypeptides (IGF-, I, IGF- II), two specific receptors and six bind
8、ing proteins. IGF- I is a single nucleotide protein with 70 amino acids, the molecular weight of 7649Da, heat resistance, while IGF- II is a single stranded weak acid protein with 67 amino acids, with a molecular weight of 7471Da and stable for 0.1%SDS. Both 70% are homologous, approximately 50% of
9、the structure and function of human proinsulin. The biological function of IGFs is achieved by binding to receptors on specific target cell surfaces. At present, two kinds of IGF receptors with different structures are found: IGF- I receptor and IGF- II receptor (mannose -6 phosphate receptor), also
10、 known as type I receptor, type II receptor. The former structure and insulin receptor (Insulin receptor Ir) is similar to that of 2 beta 2 glycoprotein four dimer consisting of alpha and beta two subunit alpha, alpha subunit is a ligand binding site, beta subunit with intrinsic tyrosine kinase acti
11、vity and tyrosinase activity. IGF and insulin (Insulin, Ins) on IGF receptor affinity of the order of Ir is Ins IGF- I IGF- II; on IGF- receptor: IGF- I IGF- II Ins; on IGF- II receptor: IGF- IGF- I and Ins II, with no cross reaction.Unlike other growth factors, IGFs is associated with a specific bi
12、nding protein (Binding, Proteins, BPs) in serum, in extracellular fluid and in cell cultures, and in the form of inactive complexes. So far, 6 IGFBP1, 2, 3, 4, 5 and 6 have been found, and their characteristic structures constitute a correlation. The secretory protein families are low molecular pept
13、ides, similar in structure to 50%. They are high affinity with two IGF without binding to insulin. In the blood and tissue fluid, the IGFBP3 content is highest, and more than 80% of the IGF in the cycle is combined with IGFBP3 to form the 150kDa three molecular complex (an unstable acid subunit, a b
14、inding subunit and IGF peptide). IGFBP2,5,6 has a higher affinity with IGF- II, and IGFBP1, 3, and 4 are similar in affinity to IGF- I and IGF- ii. IGFBP has the function of prolonging the circulating level of IGF half-life and stabilizing IGF serum concentration. Normally, the affinity of IGF with
15、its binding protein is greater than or approximately equal to its receptor binding. In addition, the low expression of the high affinity receptor leads to a balance between a small amount of free IGF and a large number of IGF/IGFBP complexes. At present, there are at least three mechanisms involved
16、in the activation of IGF:(1) parallel movement. In specific cases, such as growth, development, or damage to the organism, high affinity receptors are abundantly expressed, competing for IGF and separating it from binding proteins;(2) chemical modification of IGF or IGFBP, such as phosphorylation, t
17、o reduce the affinity of the complexes and dissociate them;(3) binding protein hydrolase specific water samples IGFBP to release the IGF.IGFs and growth and developmentIGF- I and IGF- II have similar structures and in vitro activity, but their biological effects are not the same. The biological func
18、tions of IGFs are not limited to mitogenic stimuli, but they can also induce differentiation or promote the expression of differentiated functions. The precise biological effects depend on the state of cell development and the presence of other hormones or growth factors. Especially in different tis
19、sues and different growth stages, there is a considerable difference in the function and level of IGF- I and IGF- ii. IGF- I, dependent on GH, can promote proliferation of many cells in vitro and promote protein and DNA synthesis. Many tissues and cells in the body can autocrine and paracrine IGF- I
20、. IGF- II, known as the major growth factor before birth, does not require growth hormone regulation and is expressed in a variety of tissues and organs.Studies have shown that in early pregnancy, trophoblast cells invade the endometrium is strictly controlled by the micro environment; progesterone
21、regulating endometrium and decidua and villus development and promote embryo implantation are mediated by IGFs, the mechanism was to increase the adhesion of the extracellular matrix, invasion and migration of human trophoblast cells to stimulate, promote early embryo cultivation. In vitro experimen
22、t of Kniss and IGFs could promote early pregnancy decidua and villi on transport of glucose and amino acids, in a dose-dependent manner, suggesting that the fetal circulation before the embryo mainly from the surrounding environment and nutrition, through the role of IGFs. At the same time, a large
23、number of studies have shown that during embryonic development, the level of IGF- II mRNA is much higher than that of IGF- I and mRNA, and has higher expression in embryonic tissues. With the increase of differentiation degree, the expression of it decreases. The expression of mRNA and IGF-I is affe
24、cted by many factors, a large increase in liver, heart and kidney after birth than before birth; and significantly decreased in muscle, stomach and testis after birth than before birth; only IGF- in the brain and lung of mRNA showed a wavy change. Clinical studies have shown that the concentration o
25、f IGF- I in maternal circulation increases during pregnancy, and that fetal IGF- I is approximately 15 weeks pregnant. The levels of IGF-, I and IGFBP1 in umbilical artery and umbilical vein were similar. There was no significant difference between the two groups, indicating that the secretion of IG
26、F- I in the mother and fetus was independent, and that IGF- I might not pass through the placenta. Some scholars detected the concentration of cord blood IGF- I, and the results showed that intrauterine fetal growth retardation, IGF- in cord blood was lower than that in gestational age group by abou
27、t 40%, while that of gestational age IGF- was 8% to 10% higher than that in gestational age group. IGFBP1 increased significantly in preterm infants and small in gestational age infants, and negatively correlated with birth weight. There are serum levels and neonatal IGF- I reported the birth weight
28、 and length were positively correlated, and as the main growth factor before the birth of IGF- II and the neonatal birth height and weight have no obvious correlation, and decreased rapidly after birth. Arsio IGF- concentration was measured in umbilical cord blood of 131 gestational age between 19 a
29、nd 40 weeks of gestation by umbilical vascular puncture. The results showed that IGF- I was positively correlated with gestational age. In conclusion, the mechanism of IGFss action on the fetus is not very clear, but its role in fetal growth and development has been widely recognized. This is also c
30、onfirmed by genetic studies. Growth inhibition was first observed at 10.5 days after the mutation of IGF- I and IGF- II genes, and the weight of newborn rats at birth was only 30% of the normal weight of wild species. Another report: IGF- I and IGF- II deficient mice or IGF- II R and IGF- I R have d
31、efects in animal performance not only dwarf more serious, only 45% wild mice, these small animal have obvious muscle hypoplasia, the number of fiber cells in skeletal muscle and reduce serious skin hypoplasia. Births often die of respiratory failure. In conclusion, the expression of each of the IGF
32、and IGF receptors is essential for normal embryo and fetal growth, and indicates that the two are absent and very few other components are up and down. Daughaday pointed out in 1988 that postnatal human plasma IGF- I and IGF- II concentration is inversely related to possible mechanisms for the compe
33、tition between IGF-BP3 (1); (2) both inhibit the secretion of GH, and the GH of IGF- I IGF- II positive regulation; through the secretion of GH play a role of indirect inhibition of IGF-I. It can be assumed that it is precisely because of the interaction between IGF- I and IGF- II that the bodys res
34、ponse is balanced. The process of growth and development of IGF- I was regulated by GH and other growth factors. The expression level of IGF- I increased after birth was related to GH, and the tissue with decreased expression was related to specific factors. A large number of studies on the IGF- I a
35、nd -GH axis have recently suggested that GH stimulates liver secretion of IGF- I, and IGF- I, in turn, inhibits GH. The complex of IGF and binding proteins in the cycle constitutes the major repository of IGF- I in circulation, and GH regulates its cycle levels. In the past, somatic cell theory sugg
36、ested that most of GHs action was mediated by cyclic IGF- I during the linear growth of the organism,But recently, GH has been found to stimulate the production of IGF- I, a autocrine or paracrine action of IGF- I, which is important for normal growth in rodents, liver, and other tissues. Molecular
37、biology studies were conducted using animal experiments to examine malnutrition in children due to inadequate caloric and protein intake. The results showed that malnutrition in children caused by growth arrest, the key is the diminutive of IGF- gene transcription level decreased, liver cell IGF- I
38、decreased mRAN level, decrease of plasma IGF- content of clear, too fast. The mechanism of action may be the regulation of GH on the expression of IGF- I gene. Therefore, IGF- I is closely related to the growth and development of children.In addition, Urderwood reported the use of IGFs in the treatm
39、ent of GH insensitive short stature patients, including Larons syndrome and GH deficiency. Larons patients lack GH receptors and do not respond to GH. Such patients have low levels of IGF- I, slow growth, but high levels of circulating GH, which is due to a decrease in GH feedback inhibition by IGF-
40、 I. The GH deficient person mistakenly identified GH as an exotic protein, producing a large number of antibodies that weakened or disappeared the bodys response to GH. One case of Larons boys treated with GH showed no improvement in growth rate, but was treated with IGF- I for 2 years and grew at a
41、 rate of 10cm/ years. In addition, recent studies have shown that GH itself is not directly required for growth, and all the height development described by GH is actually done by IGF- I.The research of IGFs is a hotspot in the field of cell biology, and has been paid more and more attention to. It
42、will probably become an important breakthrough for human beings to explore the mysteries of life. IGF is closely related to human embryo development and individual growth and development. However, the effect of IGF on many system tissues is only in vitro and animal experiments, so there is still muc
43、h work needed to do further research on IGFs.ReferenceWH., Salmon, WD, Daughaday, A, hormonally, controlled, serum, factor, which, stimulates, sulfate, in, corporation, by, cartilage, in, vitro., J, Lab, Clin, Med, 1957,49:825-836.2 Froech ER. Antibody-suppressible and nosuppressible insulin-like ac
44、itivities in human serum and their physiologic significance. An insulin assay with adipose tissue of incneased precision and specificity. J Clin Invest, 1963,42:1816-1834.3 Pierson RW, Jr.The partial purification from calf serum of a fraction with multiplication-stimulating activity for chicken firo
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