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Highlights - 3rd International Congress of the GRS and the IGF Research Society« Back to Volume 23, Issue 2, June 2007 - Table of Contents The 3rd International Congress of the GRS (Growth Hormone Research Society) and the IGF (Insulin-like Growth Factor) Research Society held in Kobe, Japan, November 2006 comprised interesting plenary lectures and poster presentations, and satellite symposia. Some of the highlights are summarized below.. Diabetes Mellitus Kadowaki showed that glucose can promote beta cell hyperplasia through glucokinase and IRS-2. Pancreatic beta cell specific glucokinase heterozygous knock-out mice developed early-onset mild diabetes due to impaired insulin-secretory response to glucose. They failed to show beta cell hyperplasia even on high fat diet. Microarray analysis revealed that the expression of IRS-2 was reduced in these mice. Crossing beta cell specific glucokinase heterozygous knock-out mice with beta cell specific IRS-2 transgenic mice partially prevented diabetes by increasing beta cell mass. Kadowaki also showed the mechanism of the endothelial cell specific IRS-2 knock-out mice (ET-IRS2) skeletal muscle insulin resistance. IRS-1 was mainly distributed in skeletal muscle, whereas IRS-2 was mainly in islet beta cell, liver, and endothelial cells. ET-IRS2 mice had impaired vascular relaxation induced by insulin and IGF-I. They showed hypertension and decreased blood flow in skeletal muscle. These led to impaired insulin delivery in skeletal muscle. Growth Hormone Doping Measurement of the 20K and 22K isoforms of growth hormone (GH) can be used to detect abuse of exogenous 22K GH in athletes. To determine the influence of demographic factors and sporting type, Nelson et al measured the 20K and 22K isoforms in serum samples from 972 elite athletes, representing 4 major ethnic groups. The log 22K/20K ratio was normally distributed and minimally influenced by demographic factors and sporting type (the median 22K/20K ratio was 7.9). Growth Hormone Clinical Katsumata et al reported 2 apparent nonsense mutations in exon 3 of the GH1 gene causing IGHD2 in 2 families. Growth Hormone and Metabolism Kawai et al showed that the GH-STAT5A/5B signaling pathway stimulated adipogenesis through 2 distinct steps: one was the transcriptional activation of C/EBPbeta/delta, leading to the up-regulation of PPARgamma; the other was the direct transcriptional activation of PPARgamma. IGF-I and Cancer Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) have been used to treat non-small cell lung cancer (NSCLC). However, the overall response rate to EGFR TKIs is limited. Lee et al reported new mechanisms mediating resistance to the drugs. Most of NSCLC expressed both EGFR and IGF-1R. Treatment with EGFRTKI, erlotinib, increased the levels of EGFR/IGF-1R heterodimer localized on cell membrane, activated IGF-1R and its downstream signaling mediators, and stimulated mammalian target of rapamycin (mTOR)-mediated de novo protein synthesis of EGFR and surviving in NSCLC cells. Inhibition of IGF-1R activation, suppression of mTOR-mediated protein synthesis, or knock-down of surviving expression abolished resistance to erlotinib and induced apoptosis in NSCLC cells in vitro and in vivo. Lee et al said that once NSCLC acquired the resistance against erlotinib by heterodimerization of EGFR and IGF-1R, the change would be irreversible. Growth Hormone and Cancer Simple forced expression of the human GH (hGH) gene is sufficient for oncogenic transformation of the immortalized human mammary epithelial cells. In contrast, exogenous hGH supports neither tumor formation nor invasion by human mammary epithelial cells. Lobie extracted a subset of 305 genes which were remarkably different in their response to autocrine and exogenous hGH. Among them, he picked up 2 genes, trefoil 1 & 3 (TFF1/3). They were soluble secreted peptides and were regulated by various factors including GH, EGF, IGF-I, FGF, HER2, E2, Tamoxifen, and HOXA1. TFF1/3 mediated the oncogenic effects of autocrine hGH in human mammary carcinoma cells. Barkey et al showed that GH receptor was expressed in human prostate cancer cells and tissue from patients with prostate cancer. They also showed that GH was proapoptotic to LNCaP cells in vitro. Epidemiology of Cancer Laron et al reported that patients with GH-IGF-I axis abnormality were protected from the development of malignancies. In an Israeli cohort, none of the 40 patients with Laron syndrome (males 18, females 22, ages 3–75), none of the 22 patients with GH-IGF-I axis abnormality other than Laron syndrome (males 13, females 9, ages 3–56) had malignancy. On the other hand, 24 out of 99 relatives of the patients with Laron syndrome (males 50, females 49, ages 19–91), 7 out of 83 relatives of the patients with GH-IGF-I axis abnormality other than Laron syndrome (males 43, females 40, ages 5–93) had malignancy. In other cohorts, none of the 129 patients with Laron syndrome (males 59, females 70, ages 6–78), none of the 31 patients with GH-IGF-I axis abnormality other than Laron syndrome (males 19, females 12, ages 2.5–50) had malignancy. On the other hand, 17 out of 151 relatives of the patients with Laron syndrome (males 78, females 73, ages 27–68), 3 out of 5 relatives of the patients with GH-IGF-I axis abnormality other than Laron syndrome (males 3, females 2, ages 40–80) had malignancy. Obesity and Cancer Yakar et al showed that body adiposity increased in ovarectomized females irrespective of the diet administered and that tumor growth correlated positively with body adiposity in their mouse models. IGF-I Signaling Fukushima et al showed that IRS associated protein, Nedd4, is an E3 ubiquitin ligase and enhances IRS-2 mediated signals with its activity. Ren et al studied the molecular basis of hypoxic inhibition of muscle differentiation with murine C2C12 model. Hypoxia treatment activated reporter gene expression in a hypoxia responsive element dependent manner and induced the expression of several endogenous HIF-1 target genes. CoCL2, which stabilizes HIF-1 alpha, prevented myoblast differentiation in a dose-dependent manner. Hypoxia or CoCL2 treatment reduced pAkt and pErk levels, the expression of IGF-II and IGF binding protein (IGFBP)-5. No significant change was detected in the level of IGF-1R and other IGFBPs. The expression of myrAkt, a constitutively active Akt, in C2C12 cells restored muscle differentiation in hypoxia or CoCL2 treated cells. These results indicate that hypoxia inhibits muscle differentiation by reducing the activity of the IGF signaling pathway through a HIF-1-dependent mechanism. IGF-I Physiology Govoni et al crossed Col1alpha2-Cre mice with IGF-I loxP mice to generate Cre+ (IGF-I disrupted) and Cre- (Control), loxP homozygous mice. IGF-I expression measured by real-time RT-PCR was reduced 51% in the legs of Cre+ embryos and 59% in femurs at 12 weeks. No difference in circulating IGF-I was observed between Cre+ and Cre- mice at 12 weeks. Similar to total IGF-I disruption, 40% of the Cre+ mice died at birth. Body weight of Cre+ mice was reduced 37% and 30% at 4 and 12 weeks in both sexes. Rate of gain for body weight was reduced 44% in Cre+ mice between 2 and 4 weeks. Total body and femoral bone mineral content was reduced. Loss of IGF-I in Col1alpha2-expressing cells also led to an 18% reduction in femoral bone size. Muzumdar et al demonstrated expression of IGF-I, IGF-1R, and IGFBP-3 in mediobasal hypothalamus using RT-PCR. They infused small amounts of human IGF-I, IGFBP-3, and NLS-mutant IGFBP-3 or artificial CSF into the third ventricle (ICV) of awake, chronically catheterized rats during physiological insulin clamps. ICV IGF-I significantly improved hepatic insulin action (50% more suppression of hepatic glucose production). ICV IGFBP-3 significantly impaired hepatic insulin action (45% increases in hepatic glucose production). ICV NLS-IGFBP-3 had a reduced effect on hepatic and peripheral insulin action relative to IGFBP-3, indicating both IGF-dependent and IGF-independent activity. IGF-I Clinical Kawashima et al reported a new heterozygous missense mutation at alpha subunit of IGF-1R (R431L). The patient showed intra uterine growth retardation (IUGR) and failed to respond treatment with GH. Circulatory IGF-I and Cancer Yakar S et al demonstrated delayed tumor growth or metastasis in liver specific IGF-I deficient (LID) or iLID (tamoxifen inducible LID) mice. Colon 38 cells, a mouse adenocarcinoma, grew less in the cecum of LID mice. The onset of chemically induced mammary tumor delayed in LID mice. The number of lung metastasis of K7M2 osteosarcoma was reduced in LID mice. On the other hand, Anzo M et al failed to show the reduction of tumor progression in their prostate cancer mouse model with very low circulatory IGF-I. They speculated the compensation of either locally produced IGF-I or elevated systemic GH on the progression of prostate cancer in their model. Nuclear IRS-1 Nuclear localization of IRS-1 contributes to the control of DNA repair. Reiss found that IRS-1 was localized in the nucleus in medulloblastoma cell. IRS-1 was associated with JCV T-antigen (human polyomavirus protein). Serine phosphorylated cytosolic fraction of IRS-1 bound to Rad51, which was the major enzymatic component of homologous recombination DNA repair (HRR). IGF-I triggered dissociation of the IRS-1-Rad51 complex led to nuclear translocation of Rad51, which co-localized with damaged DNA. IGF-I mediated HRR was blocked by JCV T-antigen. In the presence of JCV T-antigen, nuclear IRS-1 interacted with Rad51 at the site of damaged DNA. This nuclear interaction attenuated HRR. JCV T-antigen was not required for HRR inhibition, since IRS-1 mutant with artificial nuclear localization signal also interacted with nuclear Rad51 and inhibited HRR. Their recent study demonstrated that ERbeta participated in the translocation of IRS-1 to the nucleus. IGFBPs Mascarenhas et al showed that 22 amino acid metal binding domain from the C-terminus of IGFBP-3 was useful for targeting and intracellular delivery of inhibitor peptide. Cunming showed that IGFBP-5 played a critical role in the development of craniofacial skeleton by promoting cell differentiation and survival in an IGF dependent manner using zebrafish model and cultured human U2 osteosarcoma cells. Cobb et al showed that multi-site phosphorylation of IGFBP-3 regulated its apoptotic potential both positively and negatively. Lee et al demonstrated that humanin treated NOD mice were protected against diabetes and pancreata from humanin treated NOD mice showed decreased lymphocyte infiltration. Hoeflich et al showed that IGFBP-2 increased life expectancy in female but not in male transgenic mice. In addition, IGFBP-2 potently reduced tumor incidence in highly senescent mice, particularly in the liver. Longevity With a cohort of Ashkenazi Jewish individuals with exceptional longevity, their offspring, and their spouse, Barzilai et al studied a prominent phenotype of increased HDL and small lipoprotein particle sizes in centenarians. They observed a significant overrepresentation of 2-3 folds in the frequency of homozygosity in the favorable genotype for a polymorphism in the cholesteryl ester transfer protein (CETP) gene, an apolipoprotein C-3 (APOC-3) promoter variant, and a deletion at the 3’ UTR of the adiponection gene. They also observed that female offspring of centenarians have higher serum IGF-I but are shorter than age-matched controls. Atzmon et al reported that rate of homozygosity for the exon 3 deleted GH receptor gene variant (GHRd3), which was recently reported to confer higher GH-sensitivity, was significantly higher in male centenarians and their offspring than in controls (14% and 12% vs. 4%, p=0.05 respectively). Male centenarian GHRd3 carriers were 3 inches shorter than their cohort, had lower serum IGF-I levels, and more insulin resistant as measured by HOMA. Guest EditorsMakoto Anzo, M.D. Tomonobu Hasegawa, M.D. « Back to Volume 23, Issue 2, June 2007 - Table of Contents
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Volume 24 Number 1
May 2008
www.GGHjournal.com
ISSN 1932-9032
