A5103148863- Metabolism, Diabetes, and Cancer
- Growth Hormone and Insulin-like Growth Factors
- Pancreatic function and diabetes
- Cancer, Lipids, and Metabolism
- Cancer, Hypoxia, and Metabolism
- Adipose Tissue and Metabolism
- Diet and metabolism studies
- Cancer Risks and Factors
- Metabolism and Genetic Disorders
- Protein Kinase Regulation and GTPase Signaling
- Diabetes and associated disorders
- PI3K/AKT/mTOR signaling in cancer
- Estrogen and related hormone effects
- Peroxisome Proliferator-Activated Receptors
- Regulation of Appetite and Obesity
- Diet, Metabolism, and Disease
- Diabetes Treatment and Management
- Cardiomyopathy and Myosin Studies
- Diabetes, Cardiovascular Risks, and Lipoproteins
- Diabetes Management and Research
- Neuroendocrine Tumor Research Advances
- Adipokines, Inflammation, and Metabolic Diseases
- Liver Disease Diagnosis and Treatment
- Hemoglobin structure and function
- Biochemical and Molecular Research
Icahn School of Medicine at Mount Sinai
2014-2024
National Institutes of Health
1999-2018
National Institute of Diabetes and Digestive and Kidney Diseases
1998-2018
Rambam Health Care Campus
2011-2016
Clinical Research Institute
2011-2015
International Prevention Research Institute
2012
Mount Sinai Hospital
2012
Dallas Diabetes Research Center
2012
University of Perugia
2012
University of Strathclyde
2012
Tumor necrosis factor alpha (TNFalpha) or chronic hyperinsulinemia that induce insulin resistance trigger increased Ser/Thr phosphorylation of the receptor (IR) and its major substrates, IRS-1 IRS-2. To unravel molecular basis for this uncoupling in signaling, we undertook to study interaction Ser/Thr-phosphorylated IRS-2 with receptor. We could demonstrate that, similar IRS-1, also interacts juxtamembrane (JM) domain (amino acids 943-984) but not carboxyl-terminal region 1245-1331) IR...
Adipose tissue-derived cytokines (adipokines) are associated with the development of inflammation and insulin resistance. However, which adipokine(s) mediate this linkage mechanisms involved during obesity is poorly understood. Through proteomics microarray screening, we recently identified lipocalin 2 (LCN 2) as an adipokine that potentially connects its related adipose inflammation. Herein show levels LCN2 mRNA dramatically increased in tissue liver ob/ob mice primary cells isolated from...
Two classes of insulin-like growth factor I (IGF-I) cDNAs were isolated from an adult rat liver library using a human IGF-I cDNA probe. The two types differed by the presence or absence 52-base pair insert which altered derived Cterminal amino acid sequence E peptide, but not 3′-untranslated region coding for mature protein. When probes these clones hybridized to Northern blots mRNA, specific bands 8.6, 2.1, and 1.0–1.4 kilobases seen. Hybridization poly(A)+ RNA various tissues GH-treated...
Wilms tumor is a pediatric neoplasm that arises from the metanephric blastema. The expression of gene encoding insulin-like growth factor II (IGF-II) often elevated in these tumors. Since many actions IGF-II are mediated through activation IGF-I receptor (IGF-IR), we have measured levels IGF-IR mRNA normal kidney and samples using solution hybridization/RNase protection assays. tumors were 5.8-fold higher than adjacent tissue. Among themselves, those containing heterologous stromal elements...
A series of the synthetic protein tyrosine kinase inhibitors known as tyrphostins were studied for their effect on insulin-like growth factor-1 and insulin-stimulated cellular proliferation NIH-3T3 fibroblasts overexpressing either receptor, well ability to inhibit ligand-stimulated receptor autophosphorylation activity toward exogenous substrates. Several tested demonstrated a dramatic by inhibiting hormone-stimulated cell proliferation, with IC50s in submicromolar range, while being unable...
The receptors for IGF-I (IGF-IR) and insulin (IR) have been implicated in physiological cardiac growth, but it is unknown whether IGF-IR or IR signaling are critically required. We generated mice with cardiomyocyte-specific knockout of (CIGF1RKO) compared them receptor (CIRKO) response to 5 wk exercise swim training. Cardiac development was normal CIGF1RKO mice, the hypertrophic prevented. In contrast, despite reduced baseline heart size, CIRKO hearts preserved. Exercise increased content...
In response to insulin-like growth factor-I (IGF-I), neonatal rat cardiac myocytes exhibit a hypertrophic response. The elucidation of the IGF-I signal transduction system in these cells remains unknown. We show here that present single class high affinity receptors (12,446 ± 3,669 binding sites/cell) with dissociation constant 0.36 0.10 nm. Two different β-subunits receptor were detected, and their autophosphorylation was followed by increases phosphotyrosine content extracellular...
Incubation of cells with insulin leads to a transient rise in Tyr phosphorylation receptor substrate (IRS) proteins, accompanied by elevation their Ser(P)/Thr(P) content and dissociation from the (IR). Wortmannin, phosphatidylinositol 3-kinase inhibitor, selectively prevented increase IRS-1, its IR, decrease Tyr(P) following 60 min treatment. Four conserved sites within phosphotyrosine binding/SAIN domains IRS-1 IRS-2 served asin vitro substrates for protein kinase B (PKB), Ser/Thr...
Female nonobese diabetic (NOD) mice develop spontaneous autoimmune sialadenitis and loss of salivary flow, are a widely used model Sjögren's syndrome. We examined the feasibility local gland immunomodulatory gene delivery to alter these sequelae in NOD mice. constructed recombinant adeno-associated virus (rAAV) vectors encoding either human interleukin 10 (rAAVhIL-10) or beta-galactosidase (rAAVLacZ, control vector). Mice received rAAVhIL-10 rAAVLacZ by retrograde submandibular ductal...
Abstract Estrogen receptor-α (ERα)-negative breast cancer is clinically aggressive and does not respond to conventional hormonal therapies. Strategies that lead re-expression of ERα could sensitize ERα-negative cancers selective ER modulators. FTY720 (fingolimod, Gilenya), a sphingosine analog, the Food Drug Administration (FDA)-approved prodrug for treatment multiple sclerosis also has anticancer actions are yet well understood. We found phosphorylated in cells by nuclear kinase 2...
To gain insight into the mechanisms involved in cross-talk between IGF-1 receptor (IGF-1R) and estrogen signaling pathways, we used MCF-7-derived cells (SX13), which exhibit a 50% reduction IGF-1R expression. Growth of NEO (control MCF-7 cells) was stimulated by both estradiol (E2), addition mitogens resulted synergistic response. Estrogen enhanced cells, but this effect markedly diminished SX13 cells. also able to potentiate on expression cyclin D1 E phosphorylation retinoblastoma protein...
Incubation of rat hepatoma Fao cells with insulin leads to a transient rise in Tyr phosphorylation receptor substrate (IRS) proteins. This is followed by elevation their P-Ser/Thr content, and dissociation from the (IR). Wortmannin, phosphatidylinositol 3-kinase (PI3K) inhibitor, abolished increase content IRS-1, its IR, decrease P-Tyr following 60 min treatment, indicating that Ser kinases negatively regulate IRS-1 function are downstream effectors PI3K. PKCζ fulfills this criterion, being...
The insulin-like growth factor-I receptor (IGF-I-R) has been implicated in the etiology and/or progression of Wilms' tumor, a pediatric malignancy kidney that is often associated with deletion or mutation WT1 tumor suppressor gene. expression IGF-I-R gene increased as compared normal tissue. Furthermore, levels mRNA individual tumors have shown to be inversely correlated mRNA, suggesting under negative control WT1. activity an promoter/luciferase construct Chinese hamster ovary cells was...
Abstract The insulin‐like growth factors (IGFs) are potent mitogens for malignant cell proliferation. majority of secreted IGFs bound to specific IGF‐binding proteins (IGFBPs) that by a large number cells. These may either inhibit or enhance IGF actions. Breast carcinoma cells secrete variety IGFBPs. We have previously demonstrated retinoic acid (RA) inhibition IGF‐l– stimulated MCF‐7 proliferation is associated with increased IGFBP‐3 levels in the conditioned media. therefore investigated...
The insulin-like growth factor-I receptor (IGF-IR) is involved in tumorigenesis. aim of the present study was to investigate whether IGF-IR a physiological target for p53 osteosarcoma cells. p53-induced regulation levels studied tetracycline-regulated expression system. When expressed Saos-2, cells that lack p53, wild-type decreased, whereas mutated increased expression, and IGF-I-induced tyrosine phosphorylation IGF-IR. Similarly, decreased IRS-1. A functional physical interaction between...
We, and others, have recently reported that the ovary is a site of insulin-like growth factor (IGF)I gene expression. It was objective present studies to assess relative ovarian abundance IGF-I transcripts with alternative 5'-untranslated (UT) regions, their cellular localization, hormonal regulation. To this end, solution hybridization/RNase protection assay employed wherein total rat RNA hybridized 404-base 32P-labelled riboprobe corresponding Class A 5'UT variant. As in liver, three...
McCune-Albright syndrome (MAS) is a disorder characterized by the triad of café-au-lait skin pigmentation, polyostotic fibrous dysplasia bone, and hyperfunctioning endocrinopathies, including GH excess. The molecular etiology disease postzygotic activating mutations GNAS1 gene product, Gsα. term gsp oncogene has been assigned to these due their association with certain neoplasms. aim this study was estimate prevalence excess in MAS, characterize clinical endocrine manifestations, describe...
Obesity increases the risk of many cancers in both males and females. This study describes a link between obesity, obesity-associated metabolic alterations, developing cancer male female mice. The goal this was to evaluate relationship gender obesity determine role estrogen status obese females its effect on tumor growth. We examined susceptibility C57BL/6 mice diet-induced insulin resistance/glucose intolerance, tumors. Mice were injected sc with one two tumorigenic cell lines, Lewis lung...