胰岛素样生长因子与乳腺癌

胰岛素样生长因子 ( Insulin- like growth factors,IGFs)家族最初是由 Salman和 Daughaday于 195 7年发现的 ,因其在基因结构上与胰岛素原具有高度同源性 ,具有类似胰岛素的作用而得名。 IGFs系统是一个庞大的家族 ,包括 IGF- 和 IGF- 两类生长因子 ;两类受体有 型胰岛素样生长因子受体 ( IGF- R)和 型胰岛素样生长因子受体 ( IGF- R) ,以及胰岛素样生长因子结合蛋白 ( IGFBPs)。IGF- 和 IGF- 分别通过同细胞膜上的相关受体 ( IGF- R,IGF- R)结合 ,引发相继的生物学效应。在循环中 ,它们通常是同它们的特异性结合…     

胰岛素样生长因子-1与骨关节炎研究进展

胰岛素样生长因子(IGFs)是一类进化上十分保守的复杂多肽系统,由胰岛素样生长因子(IGF)-1,IGF-2、IGF-1受体(IGF-1R)、IGF-2受体(IGF-2R)及6种胰岛素样生长因子结合蛋白(IGFBPs)共同组成.IGF-1是IGFs系统中的主要因子之一,可由多种组织细胞合成,通过内分泌、旁分泌或自分泌方式作用于靶器官,调节糖原和蛋白质的合成与分解,参与个体的新陈代谢、细胞增殖、分化及凋亡过程,对机体多个系统的损伤及修复也具有十分重要的作用.骨关节炎(OA)是以软骨退变为主要病理表现的骨骼运动系统疾病,目前研究认为尽管OA的病因病机不十分清楚,但是IGF-1在OA发病过程中所起到的作用越来越引起人们重视.本文就IGF-1对OA影响的研究作一综述.     

肝癌和癌旁肝组织中IGF-I,IGF-I受体mRNA的表达

目的 探讨胰岛素样生长因子I(IGF-I)及其受体(IGF-I R)在肝细胞癌变过程中的作用及意义.方法 采用DNA-RNA原位杂交方法观察肝癌(n=30)和癌旁肝组织中IGF-I,IGF-I受体mRNA的表达.结果 在肝癌和癌旁肝组织中IGF-I的表达率分别为40.0%和50.0%,IGF-I受体的表达率分别为46.7%和53.3%;IGF-I,IGF-I受体在分化较差的癌细胞和不典型增生肝细胞中表达最为明显. 结论 IGF-I和IGF-I受体可能在肝细胞癌变过程中发挥重要作用.     

肝癌和癌旁肝组织中IGF-Ⅰ,IGF受体mRNA的表达

目的 探讨胰岛素样生长因子I(IGF-I)及其受体(IGF-I R)在肝细胞癌变过程中的作用及意义.方法 采用DNA-RNA原位杂交方法观察肝癌(n=30)和癌旁肝组织中IGF-I,IGF-I受体mRNA的表达.结果 在肝癌和癌旁肝组织中IGF-I的表达率分别为40.0%和50.0%,IGF-I受体的表达率分别为46.7%和53.3%;IGF-I,IGF-I受体在分化较差的癌细胞和不典型增生肝细胞中表达最为明显. 结论 IGF-I和IGF-I受体可能在肝细胞癌变过程中发挥重要作用.     

胰岛素样生长因子和胰岛素样生长因子结合蛋白在人类胎儿生长中的作用

尽管人类胎儿生长的激素作用机制还不清楚 ,但研究表明 ,胰岛素样生长因子 (IGFs)和胰岛素样生长因子结合蛋白 (IGFBPs)起了重要作用。其中胰岛素样生长因子 1(IGF 1)和胰岛素样生长因子结合蛋白 (IGFBP) 3的水平与胎儿的身长和体重呈正相关 ,而IGFBP 1的水平与胎儿的身长和体重呈负相关     

IGFs家族与肝癌

胰岛素样生长因子(Insulin-like growth factor IGFs)是机体生长发育的调节性多肽,该家族包括IGF-I、IGF-Ⅱ两个基本成员。     

生长激素、催乳素和IGF-I对大鼠INS-1细胞中IGFBP-3基因表达的调控

激素和生长因子一直是胰岛生长发育的重大研究课题。目前 ,尚未发现任何一种激素或生长因子是胰岛细胞生长和分化的决定性因素 ,但不论在体还是离体 ,生长激素 (GH)及其相关的激素 ,如催乳素 (PRL)、胎催乳激素 (PL) ,对胰腺 β细胞具有促进细胞增生和胰岛素分泌的作用 [1 ]。 Swenne等 [2 ]已证明 ,人生长激素(h GH)能促进正常β细胞的增生 ,而在肝细胞中 ,GH通过其受体促使肝细胞分泌 IGF- 1。 IGF- I对细胞的增生作用主要通过自分泌和旁分泌两种途径。IGFs根据不同的靶器官与相应的特异性蛋白结合 (IGFBPs) ,来调节自身的生物…     

胰岛素样生长因子和胰岛素样生长因子结合蛋白在人类胎儿生长中的作用

尽管人类胎儿生长的激素作用机制还不清楚，但研究表明，胰岛素样生长因子（IGFs)和胰岛素样生长因子结合蛋白（IGFBPs)起了重要作用。其中胰岛素样生长因子－1（IGF－1）和胰岛素样生长因子结合蛋白（IGFBP）－3的水平与胎儿的身长和体重呈正相关，而IGFBP－1的水平与胎儿的身长和体重呈负相关。     

胰岛素样生长因子与脑缺血

胰岛素样生长因子(IGF)包括IGF-Ⅰ、IGF-Ⅱ及Des-IGF-Ⅰ，由70个氨基酸组成。50%的氨基酸序列与胰岛素前体一样，含有A、B、C、D四个结构阈，是一类多肽类生长因子，存在于多种组织中，也存在于脑组织，是一类重要的调节神经生长及修复的生物活性物质。近年研究发现，IGFs及其受体及IGFs结合蛋白参与脑缺血损伤的病理过程，脑缺血后IGFs及其受体在脑皮层及纹状体系统表达增加，是一类重要的神经生长因子，参与脑缺血后内源性的神经保护机制，是潜在的脑缺血缺氧的神经保护剂。     

胰岛素样生长因子-Ⅰ与老年男性的癌症死亡率

在美国,癌症已成为越来越严重的公共健康问题,估计2007年有144万新病例发生,并有56万人死于癌症.预计癌症不久将取代心脏病成为头号死因.考虑到癌症与年龄有关以及人口的老龄化,未来数十年中这一问题的严重性将大大增加.在搜寻癌症发生的危险因素时,人们的注意力日益集中于胰岛素样牛长因子(IGFs,包括IGF-I)的作用.IGFs是与胰岛素结构相似、能刺激生长的多肽,对各种组织的生长和发育均有影响.     

Regulatory Actions of Insulin-like Growth Factor-binding Proteins.

The six insulin-like growth factor-binding proteins (IGFBPs) are important regulators of insulin-like growth factor (IGF) action. Circulating high molecular weight complexes that contain IGF and IGFBP-3 restrict IGF bioavailability, and excess IGFBPs inhibit IGF action by forming biologically inactive complexes. IGFs can be released from these complexes by proteolysis. Potentiation of IGF activity might occur under specific circumstances, and involves the slow dissociation of IGFs from IGFBP complexes localized in the pericellular space, whose affinity has been reduced by dephosphorylation or association with the cell surface or extracellular matrix. Several IGFBPs or IGFBP fragments also have activities that do not involve IGFs or IGF receptors. The mechanisms by which IGFBPs regulate IGF action and exert their independent actions will be examined.     

Bone metabolism in relation to alterations in systemic growth hormone.

Growth hormone (GH) has a major role in the maintenance of bone mass in adults by regulating bone remodeling through a complex interaction of circulating GH, insulin-like growth factors (IGFs), IGF binding protein (IGFBPs), and locally produced IGFs and IGFBPs, acting in an autocrine and paracrine way. In vitro data has greatly increased our understanding of GH and IGFs effects and regulation in bone cells under controlled conditions, and especially the molecular pathways involved. However, the GH-and type I IGF-receptor are present in many tissues and various systemic factors may potentially regulate local expression of IGFs and IGFBPs in the intact organism. The use of genetically altered mice has changed this and had a major impact on defining the role of IGFs in skeletal homeostasis, and especially the role of systemic IGF-I in the development and maintenance of the adult skeleton.The focus of this review is to describe recent work on the effect of GH/IGF on remodeling in the adult skeleton emphasizing on data obtained in patient populations (i.e. acromegaly, GH deficiency, postmenopausal osteoporosis) and experimental models (i.e. animals with genetically altered expression of different GH and IGF family members) characterized by different systemic levels of these proteins. The role of IGF-I as a coupling agent between resorption and bone formation through effects on osteoprotegerin (OPG) and receptor activator of NFkappaB ligand (RANKL) are also discussed.     

IGFs and IGFBPs: role in health and disease

The insulin-like growth factors (IGFs), IGF-binding proteins (IGFBPs), and IGFBP proteases are the main regulators of somatic growth and cellular proliferation. IGFs are involved in growth pre-natally and post-natally. Dysregulation of the IGF axis can lead to growth disorders such as growth hormone deficiency and acromegaly. Pre-natally, this dysregulation can lead to IUGR or macrosomia. IGFs also have an important mitogenic action and play a role in tumorigenesis and cancer. These actions are regulated by co-interactions with IGFBPs, especially IGFBP-3. In addition to somatic growth and mitogenic activity, IGFs have hypoglycaemic and insulin sensitizing actions, and their dysregulation is involved in diabetes and its complications.In this chapter, we examine the role of IGFs and IGFBPs in growth, tumorigenesis and diabetes, and discuss treatment modalities for each disease involving the GH-IGF-IGFBP axis, including discussion of current in vitro and in vivo investigations in this field.     

Serum growth hormone binding protein (GHBP) and insulin-like growth factor binding protein (IGFBP)]

Insulin--like growth factors bind to specific binding proteins (IGFBPs) in serum and tissues. At present, six different IGFBPs have been characterized. Recent studies suggest that IGFBPs act as a reservoir for IGFs but also modulate the bioavailability of IGFs. Binding protein for growth hormone (GH) in serum has been recognized recently. Interestingly, the high affinity GH binding protein (GHBP) is identical with the extracellular domain of GH receptor and is absent in patients with Laron-type dwarfism, suggesting that serum GHBP might serve as a marker for the GH receptor in tissue. In this short review, updated information on serum GHBP and IGFBP is presented.     

Specifying the cellular responses to IGF signals: roles of IGF-binding proteins

Regulation of peptide growth factor/hormone activities by secreted hormone-binding proteins has emerged as a common theme in cell-cell signaling. Among the best-studied examples are members of the IGF-binding protein (IGFBP) gene family. These secreted proteins bind the IGF ligands with equal or even greater affinities than do the IGF receptors, and therefore are placed in a critical regulatory position between IGFs and their cell surface receptors. The circulating IGF/IGFBP complexes prolong the half-lives of IGFs and buffer the potential hypoglycemic effects of IGFs. Locally expressed IGFBPs provide a means of localizing IGFs in specific cells and can alter the IGF biological activity. While some members of the IGFBP gene family have been consistently shown to inhibit IGF actions by preventing them from gaining access to the IGF receptors, others potentiate IGF actions by facilitating the ligand-receptor interaction. Furthermore, recent studies indicate that some IGFBPs can regulate several cellular processes through ligand-independent mechanisms. This review will focus on the roles of IGFBPs in vascular smooth muscle cells. A conceptual model of the molecular mechanisms by which IGFBPs act to determine the specific physiological outcomes of IGF stimulation is proposed and discussed.     

Insights from insulin-like growth factor binding protein transgenic mice

The existence of abundant high affinity binding proteins for the IGFs, the IGF binding proteins (IGFBPs), was first demonstrated more than 40 yr ago in the very early days of somatomedin research. With the development of molecular techniques and transgenic and knockout mouse models, the nature, complexity, and redundancy of the IGFBPs have now started to be elucidated. Indeed the functional role of the circulating IGFs and the originally proposed endocrine somatomedin hypothesis have recently been questioned. The limited reports to date indicate that IGFBP knockout mice have few phenotypic manifestations. In contrast, overexpression of IGFBPs in transgenic mice is associated with manifestations that provide some insight into the physiological role of the binding proteins. The predominant effect of generalized or tissue-specific overexpression of the IGFBPs has been growth inhibition as would be anticipated from inhibition of the actions of IGF-I and -II. In addition, impaired glucose homeostasis and reduced fecundity have been observed in both IGFBP-1- and IGFBP-3-overexpressing transgenic mice. This review examines the data reported to date for transgenic mouse models that overexpress IGFBPs. In addition, data from transgenic mice that overexpress the acid-labile subunit, an important component of the ternary complex, have also been reviewed.     

The role of the insulin-like growth factors and their binding proteins in glucose homeostasis

The insulin like growth factors (IGF-I and -II) are structurally and functionally related to insulin. While insulin is a key regulator of glucose homeostasis over the short term, emerging evidence suggests that the IGFs are involved in the longer term glucose homeostasis, possibly by modulating insulin sensitivity. Unlike insulin, the IGFs are present in most biological fluids as complexes with high affinity binding proteins, the insulin-like growth factor binding proteins (IGFBPs). The IGFBPs regulate the bioavailability of the IGFs. Of the six IGFBPs identified there is evidence from studies in transgenic mice that both IGFBP-1 and IGFBP-3 may have a role in glucose regulation.     

The role of the insulin-like growth factor system in colorectal cancer: review of current knowledge

Background The insulin-like growth factor system, which includes insulin-like growth factors (IGF-I and IGF-II), IGF receptors (IGF-IR and IGF-IIR) and IGF binding proteins (IGFBPs), plays an important role in epithelial growth, anti-apoptosis and mitogenesis. There is a growing body of evidence showing that IGFs control growth and proliferation of several types of cancer. This review introduces the latest information on the biology of the IGF system and its pathophysiological role in the development of colorectal cancer.Discussion The growth promoting effects of IGF-I and IGF-II on cancer cells are mediated through the IGF-IR, which is a tyrosine kinase and cancer cells with a strong tendency to metastasise have a higher expression of the IGF-IR. Most of the IGFs in circulation are bound to the IGFBPs, which regulate the bioavailability of the IGFs. All IGFBPs inhibit IGF action by high affinity binding, while some of them also potentiate the effects of IGFs. Colon cancer cells produce specific proteases that degrade the IGFBP so that the IGF will be free to act on the cancer cell in an autocrine manner. Therefore, the IGFBPs play a crucial role in the development of the cancer.Conclusion The current knowledge about the link between IGFs and colon cancer is mainly based on in vitro investigations. Further in vivo study is needed to understand the exact role of the IGF system, especially its binding proteins, so that they can be manipulated for the prevention and treatment of colorectal cancer.     

Insulin-like growth factor binding protein production in bovine retinal endothelial cells

Retinopathy is the most frequent microangiopathic complication in diabetes. Many circulating hormones and locally produced mitogenic factors have been involved. Bovine retinal endothelial cells (BRECs) were cultured to investigate if insulin, insulin-like growth factors (IGFs), IGF binding proteins (IGFBPs), and a chronic high-glucose condition could control endothelial cell growth. Specific IGF-I receptors with two binding sites with high (K_d 0.03 nmol/L) and low (K_d 1.3 nmol/L) affinity were found when analyzing families of displacement curves between IGF-I versus IGF-I and IGF-I versus insulin. However, IGFs failed to be mitogenic factors in these cells. This could be explained by an inhibitory effect due to the presence of specific IGFBPs with a molecular weight between 24 and 43 kd. Using Western blot and immunoblot analysis, Northern blot study, and specific radioimmunoassay (RIA), these IGFBPs have been identified as IGFBP-3, -2, -5, and -4. Insulin, which does not bind to IGFBPs, was a potent mitogenic factor in these cells at a high concentration (10 nmol/L), suggesting a cross-reaction to IGF-I receptor. These IGFBPs, except the 24-kd form (IGFBP-4), were modulated by both IGF-I and IGF-II, with a maximum effect at 100 and 10 nmol/L, respectively. This regulation on IGFBPs was IGF-I receptor—independent. In fact, (1) IGFBP mRNA levels were not modified after stimulation with 100 nmol/L IGF-I, (2) 100 nmol/L IGF plus an equimolar concentration of αIR3 did not affect IGFBP production, (3) Des(1–3)IGF-I had no effect on IGFBP modulation, whereas at 10 nmol/L it enhanced BREC thymidine cell incorporation, and (4) 100 nmol/L insulin, which at this concentration can cross-react with the IGF-I receptor, did not modify the IGFBP pattern. Chronic exposure (4 weeks) of BRECs to 25 mmol/L glucose had no effect on cell growth. However, after 3 weeks, we observed a decreased IGFBP detection, and addition of 100 nmol/L IGF-I did not change IGFBP levels and did not modify cell growth. Conversely, BRECs grown in regular medium for 4 weeks showed increased IGFBP production. In conclusion, we showed that conditions mimicking hyperinsulinemia, rather than high levels of IGFs, could regulate BREC growth and that the IGF-I analog, Des(1–3), even with reduced affinity for IGFBPs but in part capable of binding to IGFBP-3, significantly stimulated BRECs growth only at 10 nmol/L. IGF actions are modulated by locally produced endothelial IGFBPs, and in turn, these endothelial IGFBPs are regulated, via an IGF-I receptor—independent mechanism, by the presence of IGFs. The autoregulatory IGF system together with the direct glucose modulation of IGFBPs could contribute in diabetic subjects to the retinal endothelial cell growth and metabolism through local changes in IGF bioavailability.