Mechanism of attenuation of angiotensin-II-induced protein degradation by insulin-like growth factor-I (IGF-I)

Insulin-like growth factor-I (IGF-I) has been shown to attenuate protein degradation in murine myotubes induced by angiotensin II through downregulation of the ubiquitin-proteasome pathway, although the mechanism is not known. Angiotensin II is known to upregulate this pathway through a cellular signalling mechanism involving release of arachidonic acid, activation of protein kinase Calpha (PKCalpha), degradation of inhibitor-kappaB (I-kappaB) and nuclear migration of nuclear factor-kappaB (NF-kappaB), and all of these events were attenuated by IGF-I (13.2 nM). Induction of the ubiquitin-proteasome pathway has been linked to activation of the RNA-activated protein kinase (PKR), since an inhibitor of PKR attenuated proteasome expression and activity in response to angiotensin II and prevented the decrease in the myofibrillar protein myosin. Angiotensin II induced phosphorylation of PKR and of the eukaryotic initiation factor-2 (eIF2) on the alpha-subunit, and this was attenuated by IGF-I, by induction of the expression of protein phosphatase 1, which dephosphorylates PKR. Release of arachidonic acid and activation of PKCalpha by angiotensin II were attenuated by an inhibitor of PKR and IGF-I, and the effect was reversed by Salubrinal (15 muM), an inhibitor of eIF2alpha dephosphorylation, as was activation of PKCalpha. In addition myotubes transfected with a dominant-negative PKR (PKRDelta6) showed no release of arachidonate in response to Ang II, and no activation of PKCalpha. These results suggest that phosphorylation of PKR by angiotensin II was responsible for the activation of the PLA(2)/PKC pathway leading to activation of NF-kappaB and that IGF-I attenuates protein degradation due to an inhibitory effect on activation of PKR.     

Insulin-like growth factor-I (IGF-I) protects cultured equine Leydig cells from undergoing apoptosis

Leydig cells located in the interstitial space of the testicular parenchyma produce testosterone which plays a critical role in the maintenance and restoration of spermatogenesis in many species, including horses. For normal spermatogenesis, maintaining Leydig cells is critical to provide an optimal and constant level of testosterone. Recently, an anti-apoptotic effect of IGF-I in testicular cells in rats has been reported, but a similar effect of IGF-I on equine Leydig cells remains to be elucidated. If IGF-I also protects stallion testicular cells from undergoing apoptosis, then IGF-I may have potential as a treatment regime to prevent testicular degeneration. The present study was designed to evaluate the anti-apoptotic effect of IGF-I on cultured equine Leydig cells. Testes were collected from 5 post-pubertal stallions (2-4 years old) during routine castrations. A highly purified preparation of equine Leydig cells was obtained from a discontinuous Percoll gradient. Purity of equine Leydig cells was assessed using histochemical 3β-HSD staining. Equine Leydig cells and selected doses of recombinant human IGF-1 (rhIGF-I; Parlow A.F., National Hormone and Peptide Program, Harbor-UCLA Medical Center) were added to wells of 24 or 96 well culture plates in triplicate and cultured for 24 or 48 h under 95% air:5% CO(2) at 34°C. After 24 or 48 h incubation, apoptotic rate was assessed using a Cell Death Detection ELISA kit. Significantly lower apoptotic rates were observed in equine Leydig cells cultured with 5, 10, or 50ng/ml of rhIGF-I compared with control cells cultured without rhIGF-I for 24h. Exposure to 1, 5, 10 or 50 ng/ml of rhIGF-I significantly decreased apoptotic rate in equine Leydig cells cultured for 48 h. After 48 h incubation, cells were labeled with Annexin V and propodium iodine to determine the populations of healthy, apoptotic, and necrotic cells by counting stained cells using a Nikon Eclipse inverted fluorescence microscope. As a percentage of the total cells counted, significantly lower numbers of apoptotic cells were observed in cells treated with 10 (9%) or 50 ng/ml (10%) of rhIGF-I compared with cells cultured without rhIGF-I (control, 22%). In this study, the results from the two assays indicated that rhIGF-I protected equine Leydig cells from undergoing apoptosis during cell culture for 24h or 48 h. In conclusion, IGF-I may be an important paracrine/autocrine factor in protecting equine Leydig cells from undergoing apoptosis.     

Insulin-like growth factor I (IGF-I) receptors and IGF-I action in oligodendrocytes from rat brains.

Oligodendrocyte progenitor cells were prepared by mechanical dissociation of 1-day-old rat brain cultures. These cells undergo proliferation and differentiation into oligodendrocytes as demonstrated by the expression of proliferation and differentiation-related specific antigens. We have used this unique culture system to characterize insulin-like growth factor I (IGF-I) receptors and their action in the central nervous system (CNS). 125I-IGF-I specifically binds to these cultures with high affinity. Competition-inhibition data suggest that IGF-I is most potent in competing for 125I-IGF-I binding, followed by IGF-II and insulin. Scatchard analyses of the binding data indicate a curvilinear plot with a Kd for high affinity of 0.2 nM, and a Bmax of 247 fmol/mg, and a Kd for low affinity of 3.2 nM and Bmax of 1213 fmol/mg protein. Covalent cross-linking followed by SDS-PAGE analysis demonstrated a radioactive band of Mr 135,000 which corresponds to the alpha subunit of the IGF-I receptor. Solution hybridization/RNase protection assay produced a single protected band corresponding to IGF-I receptor messenger RNA, further confirming the presence of these receptors. Incubation of progenitor cells with IGF-I resulted in a time- and concentration-dependent increase in [3H]thymidine incorporation and cell numbers. This effect appears to be mediated by IGF-I receptors since IGF-II and insulin were proportionately less potent. In addition to its effect on proliferation, IGF-I also increased the number of 4E7- and GC-antigen positive cells. These observations indicate that oligodendrocytes in primary culture express specific IGF-I receptors and that the interaction of IGF-I with these receptors results in the proliferation as well as differentiation of oligodendrocytes.     

Insulin-like growth factor-I (IGF-I) and IGF binding protein-5 in Schwann cell differentiation

Schwann cells (SCs) are the myelin producing cells of the peripheral nervous system. During development, SCs cease proliferation and differentiate into either a myelin-forming or non-myelin forming mature phenotype. We are interested in the role of insulin-like growth factor-I (IGF-I) in SC development. We have shown previously SCs proliferate in response to IGF-I in vitro. In the current study, we investigated the role of IGF-I in SC differentiation. SC differentiation was determined by morphological criteria and expression of myelin proteins. Addition of 1 mM 8-bromo cyclic AMP (cAMP) or growth on Matrigel matrix decreased proliferation and induced differentiation of SCs. IGF-I enhanced both cAMP and Matrigel matrix-induced SC differentiation, as assessed by both morphological criteria and myelin gene expression. Cultured SCs also express IGF binding protein-5 (IGFBP-5), which can modulate the actions of IGF-I. We examined the expression of IGFBP-5 during SC differentiation. Both cAMP and Matrigel matrix treatment enhanced IGFBP-5 protein expression and cAMP increased IGFBP-5 gene expression five fold. These findings suggest IGF-I potentiates SC differentiation. The concomitant up-regulation of IGFBP-5 may play a role in targeting IGF-I to SCs and thus increase local IGF-I bioavailability. J. Cell. Physiol. 171:161–167, 1997. © 1997 Wiley-Liss, Inc.     

Characterization of pituitary IGF-I receptors: modulation of prolactin and growth hormone

There have been no studies in any vertebrate that have localized insulin-like growth factor (IGF)-I receptors in prolactin (PRL) cells or that have correlated pituitary binding to the potency of IGF-I in regulating both PRL and growth hormone (GH) secretion. We show that IGF-I binds with high affinity and specificity to the pituitary gland of hybrid striped bass (Morone saxatilis x M. chrysops). IGF-I and IGF-II were equipotent in inhibiting saturable (125)I-IGF-I binding, whereas insulin was ineffective. IGF-I binds with similar affinity to the rostral pars distalis (>95% PRL cells) as the whole pituitary gland and immunohistochemistry colocalizes IGF-I receptors and PRL in this same region. Des(1-3)IGF-I, a truncated analog of IGF-I that binds with high affinity to IGF-I receptors but weakly to IGF-I binding proteins (IGFBPs), showed a similar inhibition of saturable (125)I-IGF-I binding, but it was more potent than IGF-I in stimulating PRL and inhibiting GH release. These results are the first to localize IGF-I receptors to PRL cells, correlate IGF-I binding to its efficacy in regulating GH and PRL secretion, as well as demonstrate that IGFBPs may play a significant role in modulating the disparate actions of IGF-I on PRL and GH secretion.     

Insulin-like growth factor-I mediates osteoclast-like cell formation stimulated by parathyroid hormone

There have been several lines of evidence that parathyroid hormone (PTH) stimulates production of insulinlike growth factor I (IGF-I) in bone and that IGF-I stimulates osteoclast formation. Thus, the present study was performed to clarify the possible role of IGF-I in PTH-stimulated osteoclastlike cell formation and the role of PTH-responsive dual signal transduction systems (cyclic [c] AMP-dependent protein kinase [PKA] and calcium/protein kinase C [PKC]) in its mechanism. Treatment with anti-IGF-I antibody (1–10 μg/ml) partially but significantly blocked hPTH-(1-34)-stimulated osteoclastlike cell formation in unfractionated mouse bone cell cultures, although it did not affect osteoclastlike cell formation stimulated by 1,25-dihydroxyvitamin D₃. Rp-cAMPS (10^-4 M), a direct PKA inhibitor, as well as two types of PKC inhibitors, H-7 (10 μM) and staurosporine (3 nM), and dantrolene (10^-5 M), an inhibitor of calcium mobilization from intracellular calcium stores, all significantly blocked PTH-stimulated osteoclastlike cell formation. Anti-IGF-I antibody (3 μg/ml) significantly blocked osteoclastlike cell formation stimulated by 10^-4 M dbcAMP, 10^-4 M Sp-cAMPS, a direct PKA activator, and 10^-5 M forskolin in mouse bone cell cultures. Dibutyryl cAMP, forskolin, and hPTH-(1-34) significantly stimulated mRNA expression of both IGF-I and IGF-binding protein 5 (IGFBP-5) in these cultures, but neither 10^-7 M PMA, a PKC activator, nor 10^-7 M A23187 did. Moreover, anti-IGF-I antibody significantly blocked osteoclastlike cell formation stimulated by the conditioned medium from MC3T3-E1 cells pretreated with 10^-8 PTH-(1-34), which induced IGF-I and IGFBP-5 mRNA expression in these cells. In conclusion, the present study indicates that IGF-I mediates osteoclastlike cell formation stimulated by PTH and that the PKA pathway is involved in its mechanism. However, IGF-I does not seem to be the sole effector molecule to be active in this system. J. Cell. Physiol. 172:55–62, 1997. © 1997 Wiley-Liss, Inc.     

Insulin-like growth factor-I (IGF-I) induces epidermal growth factor receptor transactivation and cell proliferation through reactive oxygen species

Insulin-like growth factor-I (IGF-I) plays an important role in proliferation of vascular smooth muscle cells (VSMCs). However, the mechanism that IGF-I induces VSMCs proliferation is not completely understood. In this study, we determined (a) whether and how IGF-I induces transactivation of epidermal growth factor receptor (EGFR) in primary rat aortic VSMCs, (b) the contribution of EGFR to IGF-I-stimulated activation of extracellular signal-regulated kinase (ERK) and cell proliferation, and (c) the role of reactive oxygen species (ROS) in the cellular function. We showed that IGF-I induced phosphorylation of EGFR and ERK1/2 in VSMCs. AG1478, an EGFR inhibitor, inhibited IGF-I-induced phoshorylation of EGFR and ERK1/2. IGF-I stimulated ROS production and Src activation. Antioxidants inhibited IGF-I-induced ROS generation and activation of EGFR, ERK, and Src. Src kinase inhibitor PP1 and Src siRNA blocked IGF-I-induced activation of EGFR and ERK1/2. Inhibition of IGF-I-stimulated EGFR activation inhibited IGF-I-induced VSMC proliferation. These results suggest that (1) IGF-I induces EGFR activation through production of ROS and ROS-mediated Src activation in VSMCs, and (2) EGFR transactivation is required for IGF-I-induced VSMC proliferation.     

Interaction of secreted insulin-like growth factor-I (IGF-I) with cell surface receptors is the dominant mechanism of IGF-I's autocrine actions.

In a prior report we presented evidence that insulin-like growth factor-I (IGF-I) can act in an autocrine fashion by demonstrating that FRTL-5 cells transfected with hIGF-IA fusion genes express and secrete biologically active IGF-I that renders the stimulation of DNA synthesis in FRTL-5 cells independent of their requirement for exogenous IGFs or insulin. To determine if IGF-I's autocrine actions require secretion or can be mediated by interactions with intracellular receptors, we have created a new line of FRTL-5 cells that express a mutant IGF-IA precursor containing the endoplasmic reticulum retention amino acid sequence, Lys-Asp-Glu-Leu (KDEL), at its carboxyl terminus. The mutant IGF-IA/KDEL precursor expressed by stably transfected FRTL-5 cells was shown to be retained intracellularly and to have biological activity comparable with mature IGF-I, as judged by the activity of partially purified IGF-IA/KDEL in wild type FRTL-5 cells. Expression of IGF-IA/KDEL in FRTL-5 cells, however, neither augmented TSH-stimulated DNA synthesis nor stimulated IGF-binding protein-5 expression, as does IGF-IA expression in transfected FRTL-5 cells and the addition of exogenous IGF-I to wild type FRTL-5 cells. IGF-IA/KDEL expression, however, desensitized FRTL-5 cells to the actions of exogenous IGF-I despite having only minimal effects on cell surface type I receptor number, suggesting that intracellular IGF-I is capable of significant biological actions. The failure of IGF-IA/KDEL to replicate the actions of secreted IGF-I, taken together with the findings that a monoclonal antibody against IGF-I blocked IGF-I's actions in IGF-I-secreting transfected FRTL-5 cells, provides evidence that IGF-I secretion and interaction with cell surface type I IGF receptors is the dominant mechanism of IGF-I's autocrine actions.     

Differential roles of the insulin and insulin-like growth factor-I (IGF-I) receptors in response to insulin and IGF-I

Insulin and insulin-like growth factor-I (IGF-I) receptors are highly homologous tyrosine kinase receptors that share many common steps in their signaling pathways and have ligands that can bind to either receptor with differing affinities. To define precisely the signaling specific to the insulin receptor (IR) or the IGF-I receptor, we have generated brown preadipocyte cell lines that lack either receptor (insulin receptor knockout (IRKO) or insulin-like growth factor receptor knockout (IGFRKO)). Control preadipocytes expressed fewer insulin receptors than IGF-I receptors (20,000 versus 60,000), but during differentiation, insulin receptor levels increased so that mature adipocytes expressed slightly more insulin receptors than IGF-I receptors (120,000 versus 100,000). In these cells, insulin stimulated IR homodimer phosphorylation, whereas IGF-I activated both IGF-I receptor homodimers and hybrid receptors. Insulin-stimulated IRS-1 phosphorylation was significantly impaired in IRKO cells but was surprisingly elevated in IGFRKO cells. IRS-2 phosphorylation was unchanged in either cell line upon insulin stimulation. IGF-I-dependent phosphorylation of IRS-1 and IRS-2 was ablated in IGFRKO cells but not in IRKO cells. In control cells, both insulin and IGF-I produced a dose-dependent increase in phosphorylated Akt and MAPK, although IGF-I elicited a stronger response at an equivalent dose. In IRKO cells, the insulin-dependent increase in phospho-Akt was completely abolished at the lowest dose and reached only 20% of the control stimulation at 10 nm. Most interestingly, the response to IGF-I was also impaired at low doses, suggesting that IR is required for both insulin- and IGF-I-dependent phosphorylation of Akt. Most surprisingly, insulin- or IGF-I-dependent phosphorylation of MAPK was unaltered in either receptor-deficient cell line. Taken together, these results indicate that the insulin and IGF-I receptors contribute distinct signals to common downstream components in response to both insulin and IGF-I.     

Insulin-like growth factor-I (IGF-I) stimulates protein synthesis and collagen gene expression in monolayer and lattice cultures of fibroblasts.

Fibroblasts cultivated in three-dimensional tissue-like matrices are characterized by a slowed metabolism and a decrease of protein synthesis, unless they are submitted to physical tensions. We checked the effects of insulin like growth factor-I (IGF-I), known as a potent stimulator of mitogenesis and protein synthesis for many cell types, in various models of cultures: confluent monolayers, collagen lattices, non-retracting or retracting fibrin lattices. IGF-I (1-100 ng.ml-1) had no effect on cell divisions in lattice cultures. It was able to stimulate collagen lattice retraction when the medium was supplemented with low concentrations of serum. IGF-I at 10 or 100 ng.ml-1 stimulated collagen and non-collagen syntheses in all culture systems, but stimulation of collagen synthesis only began at the highest concentration (100 ng.ml-1) in retracted lattices. Northern blot and dot-blot analyses of mRNAs extracted from monolayer cultures of fibroblasts showed that IGF-I stimulated pro alpha 1(I) collagen synthesis at the pretranslational level. Cycloheximide (7.5 micrograms.ml-1) completely inhibited pro alpha 1(I) collagen gene expression induced by IGF-I. These results show that IGF-I is a potent stimulus for protein synthesis and collagen gene expression in monolayers and tridimensional cultures of fibroblasts, but that it exerts no mitogenic activity in tridimensional lattices. Synergistic associations of IGF-I with other growth factors will have to be found in order to reverse the quiescent status of fibroblasts in lattices.     

Effects of human insulin-like growth factor-I on release of growth hormone by rainbow trout (Oncorhynchus mykiss) pituitary cells.

A recombinant human IGF-I (rhIGF-I) was applied to primary cultures of rainbow trout pituitary cells. In wells containing 3 x 10(4) and 6 x 10(4) cells/well, rhIGF-I inhibited basal GH release both in short (6 h) and long (12 and 24 h) exposures. The decline in GH release was dose-dependent over the range of 0.01 and 100 mM. The combination of rhIGF-I and low concentrations of synthetic somatostatin (SRIF) enhanced the inhibitory effect of rhIGF-I in an additive manner. Any appreciable effect of rhIGF-I on PRL release was not evidenced. To our knowledge, this report demonstrates for the first time the participation of IGFs on the inhibitory component of fish GH regulation.     

Insulin-like growth factor-I feedback regulation of growth hormone and luteinizing hormone secretion in the pig: evidence for a pituitary site of action

Three experiments (EXP) were conducted to determine the role of insulin-like growth factor-I (IGF-I) in the control of growth hormone (GH) and LH secretion. In EXP I, prepuberal gilts, 65 ± 6 kg body weight and 140 days of age received intracerebroventricular (ICV) injections of saline (n = 4), 25 μg (n = 4) or 75 μg (n = 4) IGF-I and jugular blood samples were collected. In EXP II, anterior pituitary cells in culture collected from 150-day-old prepuberal gilts (n = 6) were challenged with 0.1, 10 or 1000 nM [Ala15]-h growth hormone-releasing hormone-(1-29)NH2 (GHRH), or 0.01, 0.1, 1, 10, 30 nM IGF-I individually or in combinations with 1000 nM GHRH. Secreted GH was measured at 4 and 24 h after treatment. In EXP III, anterior pituitary cells in culture collected from 150-day-old barrows (n = 5) were challenged with 10, 100 or 1000 nM gonadotropin-releasing hormone (GnRH) or 0.01, 0.1, 1, 10, 30 nM IGF-I individually or in combinations with 100 nM GnRH. Secreted LH was measured at 4 h after treatment. In EXP I, serum GH and LH concentrations were unaffected by ICV IGF-I treatment. In EXP II, relative to control all doses of GHRH increased (P < 0.01) GH secretion. Only 1, 10, 30 nM IGF-I enhanced (P < 0.02) basal GH secretion at 4 h, whereas by 24 h all doses except for 30 nM IGF-I suppressed (P < 0.02) basal GH secretion compared to control wells. All doses of IGF-I in combination with 1000 nM GHRH increased (P < 0.04) the GH response to GHRH compared to GHRH alone at 4 h, whereas by 24 h all doses of IGF-I suppressed (P < 0.04) the GH response to GHRH. In EXP III, all doses of IGF-I increased (P < 0.01) basal LH levels while the LH response to GnRH was unaffected by IGF-I (P > 0.1). In conclusion, under these experimental conditions the results suggest that the pituitary is the putative site for IGF-I modulation of GH and LH secretion. Further examination of the role of IGF-I on GH and LH secretion is needed to understand the inhibitory and stimulatory action of IGF-I on GH and LH secretion.     

Stimulation of the development of bovine embryos by insulin and insulin-like growth factor-I (IGF-I) is mediated through the IGF-I receptor

To study the effects of insulin and insulin-like growth factor-I (IGF-I) on the development of bovine embryos, fertilized bovine embryos in vitro were cultured in a chemically defined, protein-free medium: modified synthetic oviduct fluid (mSOF) supplemented with 1 mg/ml polyvinyl alcohol. Dose-response studies showed that insulin (0.5 to 10 microg/ml) and IGF-I (2 to 200 ng/ml) stimulated the development of bovine embryos to the morula stage 5 d after in vitro fertilization. The addition of 0.5 microg/ml insulin or 2 ng/ml IGF-I to the mSOF had beneficial effects on embryonic development to the morula stage in the presence of amino acids, but insulin and IGF-I did not affect the development of bovine embryos to the morula stage in the absence of amino acids. The antiIGF-I receptor antibody (alphaIR-3) completely blocked the stimulation of development to the morula stage by insulin and IGF-I. These findings suggest that the stimulation of embryonic development by insulin and IGF-I is mediated through the IGF-I receptor.     

Thyroid hormone modulates insulin-like growth factor-I(IGF-I) and IGF-binding protein-3, without mediation by growth hormone, in patients with autoimmune thyroid diseases.

The expression and synthesis of insulin-like growth factor-1 (IGF-I) and IGF-binding protein-3 (IGFBP-3) are regulated by various hormones and nutritional conditions. We evaluated the effects of thyroid hormones on serum levels of IGF-I and IGFBP-3 levels in patients with autoimmune thyroid diseases including 54 patients with Graves' disease and 17 patients with Hashimoto's thyroiditis, and in 32 healthy age-matched control subjects. Patients were subdivided into hyperthyroid, euthyroid and hypothyroid groups that were untreated, or were treated with methylmercaptoimidazole (MMI) or L-thyroxine (L-T4). Serum levels of growth hormone (GH), IGF-I and IGFBP-3 were determined by radioimmunoassay. Serum GH levels did not differ significantly between the hyperthyroid and the age-matched euthyroid patients with Graves' disease. The serum levels of IGF-I and IGFBP-3 showed a significant positive correlation in the patients (R=0.616, P<0.001). The levels of both IGF-I and IFGBP-3 were significantly higher in the hyperthyroid patients with Graves' disease or in those with Hashimoto's thyroiditis induced by excess L-T4 administration than in control subjects. Patients with hypothyroid Graves' disease induced by the excess administration of MMI showed significantly lower IGFBP-3 levels as compared to those in healthy controls (P<0.05). Levels of IGFBP-3, but not IGF-I levels, showed a significant positive correlation with the levels of free T4 and free T3. In Graves' disease, levels of TPOAb, but not of TRAb, showed a significant positive correlation with IGFBP-3. We conclude that in patients with autoimmune thyroid diseases, thyroid hormone modulates the synthesis and/or the secretion of IGF-I and IGFBP-3, and this function is not mediated by GH.     

Insulin-like growth factor-I (IGF-I) receptor activation rescues UV-damaged cells through a p38 signaling pathway. Potential role of the IGF-I receptor in DNA repair

The activated insulin-like growth factor-I receptor (IGF-IR) is implicated in mitogenesis, transformation, and anti-apoptosis. To investigate the role of the IGF-IR in protection from UV-mimetic-induced DNA damage, 4-nitroquinoline N-oxide (4-NQO) was used. In this study we show that the activation of the IGF-IR is capable of rescuing NWTb3 cells overexpressing normal IGF-IRs from 4-NQO-induced DNA damage as demonstrated by cellular proliferation assays. This action was specific for the IGF-IR since cells expressing dominant negative IGF-IRs were not rescued from 4-NQO UV-mimetic treatment. DNA damage induced by 4-NQO in NWTb3 cells was significantly decreased after IGF-IR activation as measured by comet assay. IGF-I was also able to overcome the cell cycle arrest, observed after 4-NQO treatment, thereby enhancing the ability of NWTb3 cells to enter S phase. Interestingly, the p38 mitogen-activated protein kinase pathway was shown to represent the main signaling pathway involved in the IGF-IR-mediated rescue of UV-like damaged cells. The ability of the IGF-IR to induce DNA repair was also demonstrated by infecting NWTb3 cells with UV-irradiated adenovirus. Activation of the IGF-IR resulted in enhanced beta-galactosidase reporter gene activity demonstrating repair of the damaged DNA. This study indicates a direct role of the IGF system in the rescue of damaged cells via DNA repair.