IGF-I receptor expression is negatively regulated by growth factors (IGF-I and TGF-β1) and IGF-binding proteins (IGFBP-3 and IGFBP-5)

Estudos in vitro e em animais sugerem que os membros do sistema insulin-like growth factors (IGFs), incluindo IGF-I, IGF-II, receptores de IGF-I e IGF-II (IGF-IR e IGF-IIR), e as IGF-binding proteins (IGFBPs) podem ter um importante envolvimento no desenvolvimento e na progressão de neoplasias. Mais especificamente, as IGFs promovem a progressão do ciclo celular e inibem a apoptose tanto por ação direta com outros fatores de crescimento como por ação indireta interagindo com outros sistemas moleculares intracelulares envolvidos na promoção e/ou progressão do câncer. Além disso, inúmeros estudos epidemiológicos têm sugerido que concentrações elevadas das IGFs, independente das alterações nas IGFBPs, podem estar associadas a um aumento no risco de desenvolver determinadas neoplasias. Esta revisão tem como objetivo apresentar o envolvimento do sistema IGF na regulação tumoral, os principais estudos epidemiológicos realizados e o risco de desenvolvimento de neoplasia em pacientes (com ou sem história pessoal de neoplasia prévia) que receberam hormônio de crescimento (rhGH). É importante salientar que o uso clínico de rhGH, nas indicações aprovadas internacionalmente, é seguro e não existem evidências, até o momento, da associação com o desenvolvimento de neoplasias.

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Circulating insulin-like growth factors (IGFs), IGF-binding proteins (IGFBPs) and tissue mRNA levels of IGFBP-2 and IGFBP-4 in the ovine fetus

Journal of Endocrinology ◽

10.1677/joe.0.1450545 ◽

1995 ◽

Vol 145 (3) ◽

pp. 545-557 ◽

Cited By ~ 40

Author(s):

J M Carr ◽

J A Owens ◽

P A Grant ◽

P E Walton ◽

P C Owens ◽

...

Keyword(s):

Binding Proteins ◽

Mrna Level ◽

Common Factor ◽

Late Gestation ◽

Mrna Levels ◽

Igf Binding Proteins ◽

Fetal Sheep ◽

Igf I ◽

Igf Binding ◽

Igfbp 3

Abstract The IGF-binding proteins (IGFBPs) are a family of at least six structurally related proteins, which bind the IGFs and modulate their actions, including the regulation of preand postnatal growth. In this study we have examined the relationship between circulating and tissue mRNA levels of IGFBPs and related this to circulating IGFs in the fetal sheep over the gestational period when rapid growth and development occurs. Circulating IGFBP-2, as measured by Western ligand blot (WLB), increases between early and mid gestation, remains high, then declines throughout late gestation (P=0·0002). Circulating IGFBP-3 increases throughout gestation, as measured by WLB or RIA (P=0·04 and P=0·0001 respectively), as does circulating IGFBP-4 (P=0·004). These ontogenic changes in circulating IGFBPs-2 and -4 are paralleled by changes in liver mRNA for these proteins and, for IGFBP-2, by those in kidney IGFBP-2 mRNA also. This suggests that liver and kidney may be the primary contributors to circulating IGFBP-2 and the liver to circulating IGFBP-4. IGFBP-2 mRNA is present in the heart and lung in early gestation but barely detectable in these tissues after approximately 60 days gestation. IGFBP-4 mRNA is also present in the heart in early but not late gestation, but is abundant in the lung throughout gestation. These results demonstrate tissue specific and developmental regulation of IGFBPs-2 and -4 at the mRNA level. To assess any role the circulating IGFs may play in mediating these changes in IGFBPs, or vice versa, both plasma IGF-I and IGF-II were measured by RIA. Circulating IGF-I increases as gestation progresses (P=0·0001), while circulating IGF-II increases between early and mid gestation, remains high (P=0·01), then declines. Circulating IGF-I is positively correlated with fetal weight (r=0·66, P=0·03), circulating IGFBP-3 (r=0·54, P=0·01) and IGFBP-4 (r=0·52, P=0·01). Circulating IGF-II positively correlates with circulating IGFBP-2 (r=0·48, P=0·02) throughout gestation and at 1 day postnatally. These relationships are consistent with circulating IGF-I influencing IGFBPs-3 and -4, and similarly, IGF-II determining IGFBP-2, or vice versa. Alternatively, these correlations may reflect coordinate regulation of IGF and IGFBP by a common factor. Journal of Endocrinology (1995) 145, 545–557

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Ontogeny of Insulin-like Growth Factors (IGF-I and IGF-II) and IGF-Binding Proteins in the Chicken Following Hatching

General and Comparative Endocrinology ◽

10.1006/gcen.1997.6898 ◽

1997 ◽

Vol 107 (1) ◽

pp. 109-117 ◽

Cited By ~ 10

Author(s):

Steven V. Radecki ◽

Marie C. Capdevielle ◽

Frances C. Buonomo ◽

Colin G. Scanes

Keyword(s):

Growth Factors ◽

Binding Proteins ◽

Igf Binding Proteins ◽

Igf I ◽

Igf Binding ◽

Insulin Like Growth Factors

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Differential effects of GH stimulation on fasting and prandial metabolism and plasma IGFs and IGF-binding proteins in lean and obese sheep

Journal of Endocrinology ◽

10.1677/joe.0.1540329 ◽

1997 ◽

Vol 154 (2) ◽

pp. 329-346 ◽

Cited By ~ 11

Author(s):

J P McCann ◽

S C Loo ◽

D L Aalseth ◽

T Abribat

Keyword(s):

Binding Proteins ◽

Binding Capacity ◽

Plasma Concentrations ◽

Whole Body ◽

Daily Injection ◽

Gh Treatment ◽

Igf Binding Proteins ◽

Igf I ◽

Igf Binding ◽

Igfbp 3

Abstract The effect of body condition per se on plasma IGFs and IGF-binding proteins (IGFBPs) and the whole-body metabolic responses to recombinant DNA-derived bovine GH (rbGH) in both the fed and the fasted state were determined in lean and dietary obese sheep (n=6/group). Sheep at zero-energy balance and equilibrium body weight were injected s.c. for 12 days with 100 μg/kg rbGH immediately before their morning feeding. Before GH treatment, fasting plasma concentrations of insulin (17·0 ± 1·9 vs 7·5 ± 0·7 μU/ml), IGF-I (345 ± 25 vs 248 ± 10 ng/ml), glucose (52·6 ± 1·1 vs 48·3 ± 0·7 mg/dl), and free fatty acid (FFA) (355 ± 45 vs 229 ± 24 nmol/ml) were greater (P<0·05) and those of GH (1·1 ± 0·2 vs 2·6 ± 0·3 ng/ml) were lower (P<0·05) in obese than in lean sheep. Fasting concentrations of IGF-II and glucagon were not affected (P>0·05) by obesity. GH concentrations were increased equivalently by 6–9 ng/ml in lean and obese sheep during GH treatment. GH caused an immediate and a marked fivefold increase in the fasting insulin level in obese sheep but only minimally affected insulin concentration in lean sheep. The increment in fasting glucose during GH treatment was greater (P<0·05) in obese (8–12 mg/dl) than in lean (2–5 mg/dl) sheep. Frequent measurements in the first 8 h after feeding and injection of excipient (day 0) or the first (day 1), sixth (day 6) and twelfth (day 12) daily injection of GH showed that prandial metabolism in both groups of sheep was affected minimally by GH. However, GH treatment on day 1 (not days 6 or 12) acutely attenuated the feeding-induced suppression of plasma FFA in both groups of sheep and this effect was significantly greater in obese than in lean sheep. Although obese sheep were hyposomatotropic, the basal and GH-induced increases in plasma IGF-I concentrations were greater (P<0·05) in obese than in lean sheep. Plasma IGF-II was unaffected by obesity and was not increased by GH stimulation. Western ligand blotting showed that IGFBP-3 accounted for approximately 50–60% of the plasma IGF-I binding capacity in sheep respectively both before and during GH treatment. Basal plasma levels of IGFBP-2 were lower (P<0·05) and those of IGFBP-3 greater (P<0·05) in obese compared with lean sheep. GH increased the level of IGFBP-3 equally in lean and obese sheep, but suppressed the expression of IGFBP-2 more (P<0·05) in lean than in obese sheep. We concluded that the diabetogenic-like actions of GH in sheep were exaggerated markedly by obesity, and were expressed more during the fasted than the fed states. The effects of GH stimulation on the endocrine pancreas may be selective for β-cells and preferentially enhanced by obesity. GH regulation of IGF-I and the IGFBPs differs in lean and obese sheep. Journal of Endocrinology (1997) 154, 329–346

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Synthesis of the acid-labile subunit of the growth-hormone-dependent insulin-like-growth-factor-binding protein complex by rat hepatocytes in culture

Biochemical Journal ◽

10.1042/bj2750441 ◽

1991 ◽

Vol 275 (2) ◽

pp. 441-446 ◽

Cited By ~ 20

Author(s):

C D Scott ◽

R C Baxter

Keyword(s):

Growth Hormone ◽

Binding Proteins ◽

Rat Hepatocytes ◽

Alpha Subunit ◽

Igf Binding Proteins ◽

Rat Serum ◽

Igf I ◽

Igf Binding ◽

Acid Labile ◽

Igfbp 3

Insulin-like growth factors (IGFs) circulate predominantly in a growth-hormone-dependent ternary complex of 125-150 kDa. This study investigates the production of the alpha-subunit of this complex, an acid-labile glycoprotein without intrinsic IGF-binding activity, which binds to the IGF-binding protein IGFBP-3 in the presence of IGFs. Medium conditioned by primary cultures of rat hepatocytes produced alpha-subunit with similar complex-forming activity to purified rat serum alpha-subunit. Bovine growth hormone stimulated hepatocyte production of both IGF-I and alpha-subunit. IGF-I tracer bound to pure rat IGFBP-3 was converted from approx. 60 kDa to 150 kDa by serum alpha-subunit, whole rat serum or rat hepatocyte culture medium; this converting activity was destroyed by transient acidification. In contrast, IGF-I bound to hepatocyte-medium IGF-binding proteins could not be converted into a high-molecular-mass from by purified rat serum alpha-subunit. Rat serum and hepatocyte-medium alpha-subunit appeared identical by electrophoretic analysis, since reaction of either with cross-linked IGF-I.IGFBP-3 tracer resulted in bands of molecular mass 130 kDa and 160 kDa, probably representing intact and partially deglycosylated complexes. However, IGF-binding proteins in rat serum and hepatocyte medium were different, in that affinity labelling of medium binding proteins, depleted of endogenous IGFs, showed no evidence of the 50-60 kDa cluster of bands characteristic of rat serum IGFBP-3. We conclude that rat hepatocytes in primary culture produce alpha-subunit similar to that in rat serum; however, alpha-subunit is unable to form ternary complexes with hepatocyte IGF-binding proteins, since cultured hepatocytes do not secrete IGFBP-3.

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Acute response of IGF-I and IGF binding proteins induced by thermal injury

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.2000.278.6.e1087 ◽

2000 ◽

Vol 278 (6) ◽

pp. E1087-E1096 ◽

Cited By ~ 25

Author(s):

Charles H. Lang ◽

Xiaoli Liu ◽

Gerald J. Nystrom ◽

Robert A. Frost

Keyword(s):

Plasma Concentration ◽

Binding Proteins ◽

Thermal Injury ◽

Igf Binding Proteins ◽

Igf System ◽

Significant Difference ◽

Mrna Transcripts ◽

Igf I ◽

Igf Binding ◽

Igfbp 3

Previous studies demonstrate that thermal injury decreases circulating levels of insulin growth factor I (IGF-I) and alters the plasma concentration of several IGF binding proteins (IGFBP), but the mechanisms for these alterations have not been elucidated. In the current study, a 30% total body surface area full-thickness scald burn was produced in anesthetized rats, and animals were studied 24 h later. The plasma concentration of both total and free IGF-I was decreased (38 and 65%, respectively) in burn rats compared with values from time-matched control animals. Thermal injury decreased the IGF-I peptide content in liver ∼40%, as well as in fast-twitch skeletal muscle (56–69%) and heart (28%). In contrast, IGF-I content in kidney was elevated by 36% in burn rats. Northern blot analysis of liver indicated that burn decreased the expression of small (1.7- and 0.9- to 1.2-kb) IGF-I mRNA transcripts but increased the expression of the 7.5-kb transcript. In contrast, there was a coordinate decrease in all IGF-I mRNA transcripts in muscle and kidney of ∼30%. For liver, muscle, and kidney, there was no significant difference in the expression of growth hormone receptor mRNA between control and burn rats. Thermal injury increased plasma IGFBP-1 levels, and this change was associated with increased IGFBP-1 mRNA in both liver and kidney. IGFBP-3 levels in plasma were concomitantly decreased by burn injury. This change was associated with a reduction in IGFBP-3 mRNA in liver but an increased expression of IGFBP-3 in kidney and muscle. Thermal injury also decreased the concentration of the acid-labile subunit (ALS) in plasma and ALS mRNA expression in liver. Finally, hepatic expression of IGFBP-related peptide-1 was increased twofold in liver but was unchanged in kidney or muscle of burn rats. These results characterize burn-induced changes in various components of the IGF system in select tissues and thereby provide potential mechanisms for alterations in the circulating IGF system and for changes in tissue metabolism.

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