Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review
  • Published:

Tumor suppressors govern insulin-like growth factor signaling pathways: implications in metabolism and cancer

Oncogene volume 31, pages 2703–2714 (2012)Cite this article

Abstract

The insulin-like growth factor (IGF) axis mediates growth, differentiation and developmental processes, and is also involved in control of metabolic activities. Deregulation of IGF axis expression and action is linked to a number of pathologies, ranging from metabolic disorders to growth deficits and cancer development. Activation of the IGF signaling pathway is a crucial prerequisite for malignant transformation. In addition, overexpression of the IGF-1 receptor (IGF-1R) constitutes a typical hallmark of most types of cancer. A series of tumor suppressors have been identified whose mechanisms of action involve transcriptional suppression of the IGF-1R gene. These tumor suppressors include the p53/p63/p73 family, breast cancer gene-1, von-Hippel Lindau protein, Wilms’ tumor-1 and others. Comprehensive analyses have identified a complex bidirectional interplay between the IGF and tumor-suppressor signaling pathways. These interactions are of major importance in terms of cancer development and may also predict responsiveness to IGF-1R-targeted therapies. Furthermore, the insulin/IGF system has a pivotal role in the regulation of cancer cell metabolism. Deregulation of IGF axis components by mutated tumor-suppressor proteins may lead to metabolic perturbations, with ensuing pathological consequences.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3
Figure 4
Figure 5

Similar content being viewed by others

References

  • Abramovitch S, Glaser T, Ouchi T, Werner H . (2003). BRCA1-Sp1 interactions in transcriptional regulation of the IGF-IR gene. FEBS Lett 541: 149–154.

    CAS  PubMed  Google Scholar 

  • Abuzzahab MJ, Schneider A, Goddard A, Grigorescu F, Lautier C, Keller E et al. (2003). IGF-I receptor mutations resulting in intrauterine and postnatal growth retardation. N Engl J Med 349: 2211–2222.

    CAS  PubMed  Google Scholar 

  • Aylon Y, Oren M . (2011). New plays in the p53 theater. Curr Opinion Genet Dev 38: 86–92.

    Google Scholar 

  • Baserga R, Peruzzi F, Reiss K . (2003). The IGF-1 receptor in cancer biology. Int J Cancer 107: 873–877.

    Article  CAS  PubMed  Google Scholar 

  • Belfiore A, Frasca F . (2008). IGF and insulin receptor signaling in breast cancer. J Mammary Gland Biol Neoplasia 13: 381–406.

    PubMed  Google Scholar 

  • Belfiore A, Malaguarnera R . (2011). Insulin receptor and cancer. Endocrine Related Cancer 18: R125–R147.

    CAS  PubMed  Google Scholar 

  • Bentov I, Narla G, Schayek H, Akita K, Plymate SR, LeRoith D et al. (2008). Insulin-like growth factor-I regulates kruppel-like factor-6 gene expression in a p53-dependent manner. Endocrinology 149: 1890–1897.

    CAS  PubMed  Google Scholar 

  • Bentov I, Werner H . (2004). IGF, IGF receptor and overgrowth syndromes. Pediatr Endocrinol Rev 1: 352–360.

    PubMed  Google Scholar 

  • Bondy CA, Werner H, Roberts Jr CT, LeRoith D . (1990). Cellular pattern of insulin-like growth factor I (IGF-I) and type I IGF receptor gene expression in early organogenesis: comparison with IGF-II gene expression. Mol Endocrinol 4: 1386–1398.

    CAS  PubMed  Google Scholar 

  • Boulton SJ . (2006). Cellular functions of the BRCA tumour-suppressor proteins. Biochem Soc Trans 34: 633–645.

    CAS  PubMed  Google Scholar 

  • Brase JC, Wuttig D, Kuner R, Sueltmann H . (2010). Serum microRNAs as non-invasive biomarkers for cancer. Mol Cancer 9: 306.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Bruchim I, Attias Z, Werner H . (2009). Targeting the IGF1 axis in cancer proliferation. Exp Opinion Ther Targets 13: 1179–1192.

    CAS  Google Scholar 

  • Buckbinder L, Talbott R, Velasco-Miguel S, Takenaka I, Faha B, Seizinger BR et al. (1995). Induction of the growth inhibitor IGF-binding protein 3 by p53. Nature 377: 1367–1373.

    Google Scholar 

  • Cairns RA, Harris IS, Mak TW . (2011). Regulation of cancer cell metabolism. Nat Rev Cancer 11: 85–95.

    CAS  PubMed  Google Scholar 

  • Chan JM, Stampfer MJ, Giovannucci E, Gann PH, Ma J, Wilkinson P et al. (1998). Plasma insulin-like growth factor-I and prostate cancer risk: a prospective study. Science 279: 563–566.

    CAS  PubMed  Google Scholar 

  • Chott A, Sun Z, Morganstern D, Pan J, Li T, Susani M et al. (1999). Tyrosine kinases expressed in vivo by human prostate cancer bone marrow metastases and loss of type 1 insulin-like growth factor receptor. Am J Pathol 155: 1271–1279.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Christofori G, Naik P, Hanahan D . (1994). A second signal supplied by insulin-like growth factor II in oncogene-induced tumorigenesis. Nature 369: 414–418.

    CAS  PubMed  Google Scholar 

  • Conaway RC, Conaway JW . (2002). The von Hippel-Lindau tumor suppressor complex and regulation of hypoxia-inducible transcription. Adv Cancer Res 85: 1–12.

    CAS  PubMed  Google Scholar 

  • Dossus L, Kaaks R . (2008). Nutrition, metabolic factors and cancer risk. Best Pract Res Clin Endocrinol Metab 22: 551–571.

    CAS  PubMed  Google Scholar 

  • Eshet R, Werner H, Klinger B, Silbergeld A, Laron Z, LeRoith D et al. (1993). Up-regulation of insulin-like growth factor-I (IGF-I) receptor gene expression in patients with reduced serum IGF-I levels. J Mol Endocrinol 10: 115–120.

    CAS  PubMed  Google Scholar 

  • Finkeltov I, Kuhn S, Glaser T, Idelman G, Wright JJ, Roberts Jr CT et al. (2002). Transcriptional regulation of IGF-I receptor gene expression by novel isoforms of the EWS-WT1 fusion protein. Oncogene 21: 1890–1898.

    CAS  PubMed  Google Scholar 

  • Gerald WL, Haber DA . (2005). The EWS-WT1 gene fusion in desmoplastic small round cell tumor. Sem Cancer Biol 15: 197–205.

    CAS  Google Scholar 

  • Gerald WL, Ladanyi M, de Alava E, Cuatrecasas M, Kushner BH, LaQuaglia MP et al. (1998). Clinical, pathologic, and molecular spectrum of tumors associated with t(11;22)(p13;q12): desmoplastic small round-cell tumor and its variants. J Clin Oncol 16: 3028–3036.

    CAS  PubMed  Google Scholar 

  • Girnita L, Girnita A, Larsson O . (2003). Mdm2-dependent ubiquitination and degradation of the insulin-like growth factor-1 receptor. Proc Natl Acad Sci USA 100: 8247–8252.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Gualberto A, Pollak M . (2009). Emerging role of insulin-like growth factor receptor inhibitors in oncology: early clinical trial results and future directions. Oncogene 28: 3009–3021.

    CAS  PubMed  Google Scholar 

  • Guertin DA, Sabatini DM . (2007). Defining the role of mTOR in cancer. Cancer Cell 12: 9–22.

    CAS  PubMed  Google Scholar 

  • Guevara-Aguirre J, Balasubramanian P, Guevara-Aguirre M, Wei M, Madia F, Cheng CW et al. (2011). Growth hormone receptor deficiency is associated with a major reduction in pro-aging signaling, cancer, and diabetes in humans. Sci Transl Med 3: 70ra13.

    PubMed  PubMed Central  Google Scholar 

  • Guler HP, Schmid C, Zapf J, Froesch ER . (1989). Effects of recombinant insulin-like growth factor I on insulin secretion and renal function in normal human subjects. Proc Natl Acad Sci USA 86: 2868–2872.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Guler HP, Zapf J, Froesch ER . (1987). Short-term metabolic effects of recombinant human insulin-like growth factor I in healthy adults. N Engl J Med 317: 137–140.

    CAS  PubMed  Google Scholar 

  • Hankinson SE, Willett WC, Colditz GA, Hunter DJ, Michaud DS, Deroo B et al. (1998). Circulating concentrations of insulin-like growth factor-I and risk of breast cancer. Lancet 351: 1393–1396.

    CAS  PubMed  Google Scholar 

  • Happerfield LC, Miles DW, Barnes DM, Thomsen LL, Smith P, Hanby AM . (1997). The localization of the insulin-like growth factor receptor 1 (IGFR-1) in benign and malignant breast tissue. J Pathol 183: 412–417.

    CAS  PubMed  Google Scholar 

  • Harrington EA, Bennett MR, Fanidi A, Evan GI . (1994). c-Myc-induced apoptosis in fibroblasts is inhibited by specific cytokines. EMBO J 13: 3286–3295.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Hellawell GO, Turner GD, Davies DR, Poulsom R, Brewster SF, Macaulay VM . (2002). Expression of the type 1 insulin-like growth factor receptor is up-regulated in primary prostate cancer and commonly persists in metastatic disease. Cancer Res 62: 2942–2950.

    CAS  PubMed  Google Scholar 

  • Hernandez-Sanchez C, Werner H, Roberts Jr CT, Woo EJ, Hun DW, Rosenthal SM et al. (1997). Differential regulation of IGF-I receptor gene expression by IGF-I and basic fibroblast growth factor. J Biol Chem 272: 4663–4670.

    CAS  PubMed  Google Scholar 

  • Heron-Milhavet L, LeRoith D . (2002). Insulin-like growth factor I induces MDM2-dependent degradation of p53 via the p38 MAPK pathway in response to DNA damage. J Biol Chem 277: 15600–15606.

    CAS  PubMed  Google Scholar 

  • Hornstein E, Shomron N . (2006). Canalization of development by microRNAs. Nat Genet 38 (Suppl): S20–S24.

    CAS  PubMed  Google Scholar 

  • Huff V . (2011). Wilms’ tumours: about tumour suppressor genes, an oncogene and a chameleon gene. Nat Rev Cancer 11: 111–121.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Idelman G, Glaser T, Roberts Jr CT, Werner H . (2003). WT1-p53 interactions in IGF-I receptor gene regulation. J Biol Chem 278: 3474–3482.

    CAS  PubMed  Google Scholar 

  • Irwin MS, Kaelin WG . (2001). p53 family update: p73 and p63 develop their own identities. Cell Growth Differ 12: 337–349.

    CAS  PubMed  Google Scholar 

  • Jacob R, Barrett E, Plewe G, Fagin JD, Sherwin RS . (1989). Acute effects of insulin-like growth factor I on glucose and amino acid metabolism in the awake fasted rat. Comparison with insulin. J Clin Invest 83: 1717–1723.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Jiang L, Liu X, Chen Z, Jin Y, Heidbreder CE, Kolokythas A et al. (2010). MicroRNA-7 targets IGF1R (insulin-like growth factor 1 receptor) in tongue squamous cell carcinoma cells. Biochem J 432: 199–205.

    CAS  PubMed  Google Scholar 

  • Kim SO, Park JG, Lee YI . (1996). Increased expression of the insulin-like growth factor I (IGF-I) receptor gene in hepatocellular carcinoma cell lines: implications of IGF-I receptor gene activation by hepatitis B virus X gene product. Cancer Res 56: 3831–3836.

    CAS  PubMed  Google Scholar 

  • Klammt J, Kiess W, Pfaffle R . (2011). IGF1R mutations as cause of SGA. Best Pract Res Clin Endocrinol Metab 25: 191–206.

    CAS  PubMed  Google Scholar 

  • Klammt J, Pfaffle R, Werner H, Kiess W . (2008). IGF signaling defects as causes of growth failure and IUGR. Trends Endocrinol Metab 19: 197–205.

    CAS  PubMed  Google Scholar 

  • Kozma LM, Weber MJ . (1990). Constitutive phosphorylation of the receptor for insulin-like growth factor I in cells transformed by the src oncogene. Mol Cell Biol 10: 3626–3634.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Kruis T, Klammt J, Galli-Tsinopoulou A, Wallborn T, Schlicke M, MĂĽller E et al. (2010). Heterozygous mutation within a kinase-conserved motif of the insulin-like growth factor I receptor causes intrauterine and postnatal growth retardation. J Clin Endocrinol Metab 95: 1137–1142.

    CAS  PubMed  Google Scholar 

  • Lakin ND, Jackson SP . (1999). Regulation of p53 in response to DNA damage. Oncogene 18: 7644–7655.

    CAS  PubMed  Google Scholar 

  • Laron Z . (2004). Extensive personal experience Laron syndrome (primary growth hormone resistance or insensitivity): the personal experience 1958–2003. J Clin Endocrinol Metab 89: 1031–1044.

    CAS  PubMed  Google Scholar 

  • Laron Z, Weinberger D . (2004). Diabetic retinopathy in two patients with congenital IGF-I deficiency (Laron syndrome). Eur J Endocrinol 151: 103–106.

    CAS  PubMed  Google Scholar 

  • Law JH, Habibi G, Hu K, Masoudi H, Wang MYC, Stratford AL et al. (2008). Phosphorylated insulin-like growth factor-I/insulin receptor is present in all breast cancer subtypes and is related to poor survival. Cancer Res 68: 10238–10246.

    CAS  PubMed  Google Scholar 

  • LeRoith D, Bondy C, Yakar S, Liu J-L, Butler A . (2001). The somatomedin hypothesis: 2001. Endocrine Rev 22: 53–74.

    CAS  Google Scholar 

  • LeRoith D, Yakar S . (2007). Mechanisms of disease: metabolic effects of growth hormone and insulin-like growth factor-1. Nat Clin Pract Endocrinol Metab 3: 302–310.

    CAS  PubMed  Google Scholar 

  • Levine AJ . (1997). p53, the cellular gatekeeper for growth and division. Cell 88: 323–331.

    CAS  PubMed  Google Scholar 

  • Levine AJ, Feng Z, Mak TW, You H, Jin S . (2006). Coordination and communication between the p53 and IGF-1-AKT-TOR signal transduction pathways. Genes Dev 20: 267–275.

    CAS  PubMed  Google Scholar 

  • Maki RG . (2010). Small is beautiful: insulin-like growth factors and their role in growth, development, and cancer. J Clin Oncol 28: 4985–4995.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Maor S, Mayer D, Yarden RI, Lee AV, Sarfstein R, Werner H et al. (2006). Estrogen receptor regulates insulin-like growth factor-I receptor gene expression in breast tumor cells: involvement of transcription factor Sp1. J Endocrinol 191: 605–612.

    CAS  PubMed  Google Scholar 

  • Maor S, Papa MZ, Yarden RI, Friedman E, Lerenthal Y, Lee SW et al. (2007a). Insulin-like growth factor-I controls BRCA1 gene expression through activation of transcription factor Sp1. Horm Metab Res 39: 179–185.

    CAS  PubMed  Google Scholar 

  • Maor S, Yosepovich A, Papa MZ, Yarden RI, Mayer D, Friedman E et al. (2007b). Elevated insulin-like growth factor-I receptor (IGF-IR) levels in primary breast tumors associated with BRCA1 mutations. Cancer Lett 257: 236–243.

    CAS  PubMed  Google Scholar 

  • Maor SB, Abramovitch S, Erdos MR, Brody LC, Werner H . (2000). BRCA1 suppresses insulin-like growth factor-I receptor promoter activity: potential interaction between BRCA1 and Sp1. Mol Gen Metab 69: 130–136.

    CAS  Google Scholar 

  • McKinsey EL, Parrish JK, Irwin AE, Niemeyer BF, Kern HB, Birks DK et al. (2011). A novel oncogenic mechanism in Ewing sarcoma involving IGF pathway targeting by EWS/Fli1-regulated microRNAs. Oncogene 30: 4910–4920.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Miki Y, Swensen J, Shattuck-Eidens D, Futreal PA, Harshman K, Tavtigian S et al. (1994). A strong candidate for the breast and ovarian cancer susceptibility gene BRCA1. Science 266: 66–71.

    CAS  PubMed  Google Scholar 

  • Mitsiades CS, Mitsiades NS, McMullan CJ, Poulaki V, Shringarpure R, Akiyama M et al. (2004). Inhibition of the insulin-like growth factor receptor-1 tyrosine kinase activity as a therapeutic strategy for multiple myeloma, other hematologic malignancies, and solid tumors. Cancer Cell 5: 221–230.

    CAS  PubMed  Google Scholar 

  • Nahor I, Abramovitch S, Engeland K, Werner H . (2005). The p53-family members p63 and p73 inhibit insulin-like growth factor-I receptor gene expression in colon cancer cells. Growth Hormone IGF Res 15: 388–396.

    CAS  Google Scholar 

  • Nakae J, Kido Y, Accili D . (2001). Distinct and overlapping functions of insulin and IGF-I receptors. Endocrine Rev 22: 818–835.

    CAS  Google Scholar 

  • Nana-Sinkam SP, Croce CM . (2011). MicroRNAs as therapeutic targets in cancer. Transl Res 157: 216–225.

    CAS  PubMed  Google Scholar 

  • Narod SA . (2010). BRCA mutations in the management of breast cancer: the state of the art. Nat Rev Clin Oncol 7: 702–707.

    CAS  PubMed  Google Scholar 

  • O'Connor R, Kauffmann-Zeh A, Liu Y, Lehar S, Evan GI, Baserga R et al. (1997). Identification of domains of the insulin-like growth factor I receptor that are required for protection from apoptosis. Mol Cell Biol 17: 427–435.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Ohlsson C, Kley N, Werner H, LeRoith D . (1998). p53 regulates IGF-I receptor expression and IGF-I induced tyrosine phosphorylation in an osteosarcoma cell line: interaction between p53 and Sp1. Endocrinology 139: 1101–1107.

    CAS  PubMed  Google Scholar 

  • Pandini G, Mineo R, Frasca F, Roberts Jr CT, Marcelli M, Vigneri R et al. (2005). Androgens up-regulate the insulin-like growth factor-I receptor in prostate cancer cells. Cancer Res 65: 1849–1857.

    CAS  PubMed  Google Scholar 

  • Peterson JE, Jelinek T, Kaleko M, Siddle K, Weber MJ . (1994). C phosphorylation and activation of the IGF-I receptor in src-transformed cells. J Biol Chem 269: 27315–27321.

    CAS  PubMed  Google Scholar 

  • Plas DR, Thompson CB . (2005). Akt-dependent transformation: there is more to growth than just surviving. Oncogene 24: 7435–7442.

    CAS  PubMed  Google Scholar 

  • Plymate S, Bae V, Madison L, Quinn L, Ware J . (1997). Re-expression of the type I insulin-like growth factor receptor inhibits the malignant phenotype of simian virus 40T antigen inmortalized human prostate epithelial cells. Endocrinology 138: 1728–1735.

    CAS  PubMed  Google Scholar 

  • Pollak M . (2008). Insulin and insulin-like growth factor signalling in neoplasia. Nat Rev Cancer 8: 915–928.

    CAS  PubMed  Google Scholar 

  • Reiss K, Ferber A, Travali S, Porcu P, Phillips PD, Baserga R . (1991). The protooncogene c-myb increases the expression of insulin-like growth factor I and insulin-like growth factor I receptor messenger RNAs by a transcriptional mechanism. Cancer Res 51: 5997–6000.

    CAS  PubMed  Google Scholar 

  • Renehan AG, Frystyk J, Flyvbjerg A . (2006). Obesity and cancer risk: the role of the insulin-IGF axis. Trends Endocrinol Metab 17: 328–336.

    CAS  PubMed  Google Scholar 

  • Renehan AG, Zwahlen M, Minder C, O'Dwyer ST, Shalet SM, Egger M . (2004). Insulin-like growth factor-I, IGF binding protein-3, and cancer risk: systematic review and meta-regression analysis. Lancet 363: 1346–1353.

    CAS  PubMed  Google Scholar 

  • Resnicoff M, Abraham D, Yutanawiboonchai W, Rotman HL, Kajstura J, Rubin R et al. (1995). The insulin-like growth factor I receptor protects tumor cells from apoptosis in vivo. Cancer Res 55: 2463–2469.

    CAS  PubMed  Google Scholar 

  • Rubinstein M, Idelman G, Plymate SR, Narla G, Friedman SL, Werner H . (2004). Transcriptional activation of the IGF-I receptor gene by the Kruppel-like factor-6 (KLF6) tumor suppressor protein: potential interactions between KLF6 and p53. Endocrinology 145: 3769–3777.

    CAS  PubMed  Google Scholar 

  • Salmon WD, Daughaday WH . (1957). A hormonally controlled serum factor which stimulates sulfate incorporation by cartilage in vitro. J Lab Clin Med 49: 825–836.

    CAS  PubMed  Google Scholar 

  • Samani AA, Yakar S, LeRoith D, Brodt P . (2007). The role of the IGF system in cancer growth and metastasis: overview and recent insights. Endocrine Rev 28: 20–47.

    CAS  Google Scholar 

  • Sarfstein R, Belfiore A, Werner H . (2010). Identification of insulin-like growth factor-I receptor gene promoter-binding proteins in estrogen receptor (ER)-positive and ER-depleted breast cancer cells. Cancers 2: 233–261.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Schayek H, Bentov I, Rotem I, Pasmanik-Chor M, Ginsberg D, Plymate SR et al. (2010a). Transcription factor E2F1 is a potent transactivator of the insulin-like growth factor-I receptor gene. Growth Hormone IGF Res 20: 68–72.

    CAS  Google Scholar 

  • Schayek H, Seti H, Greenberg NM, Sun S, Werner H, Plymate SR . (2010b). Differential regulation of insulin-like growth factor-I receptor gene expression by wild type and mutant androgen receptor in prostate cancer cells. Mol Cell Endocrinol 323: 239–245.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Schnarr B, Strunz K, Ohsam J, Benner A, Wacker J, Mayer D . (2000). Down-regulation of insulin-like growth factor-I receptor and insulin receptor substrate-1 expression in advanced human breast cancer. Int J Cancer 89: 506–513.

    CAS  PubMed  Google Scholar 

  • Scotlandi K, Picci P . (2008). Targeting insulin-like growth factor 1 receptor in sarcomas. Curr Opinion Oncol 20: 419–427.

    CAS  Google Scholar 

  • Sell C, Dumenil G, Deveaud C, Miura M, Coppola D, DeAngelis T et al. (1994). Effect of a null mutation of the insulin-like growth factor I receptor gene on growth and transformation of mouse embryo fibroblasts. Mol Cell Biol 14: 3604–3612.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Sell C, Rubini M, Rubin R, Liu J-P, Efstratiadis A, Baserga R . (1993). Simian virus 40 large tumor antigen is unable to transform mouse embryonic fibroblasts lacking type 1 insulin-like growth factor receptor. Proc Natl Acad Sci USA 90: 11217–11221.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Shackelford DB, Shaw RJ . (2009). The LKB1-AMPK pathway: metabolism and growth control in tumor suppression. Nat Rev Cancer 9: 563–575.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Steuerman R, Shevah O, Laron Z . (2011). Congenital IGF1 deficiency tends to confer protection against post-natal development of malignancies. Eur J Endocrinol 164: 485–489.

    CAS  PubMed  Google Scholar 

  • Tang D, Lotze MT, Kang R, Zeh HJ . (2011). Apoptosis promotes early tumorigenesis. Oncogene 30: 1851–1854.

    CAS  PubMed  Google Scholar 

  • Travali S, Reiss K, Ferber A, Petralia S, Mercer WE, Calabreta B et al. (1991). Constitutively expressed c-myb abrogates the requirement for insulin-like growth factor I in 3T3 fibroblasts. Mol Cell Biol 11: 731–736.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Ungewitter E, Scrable H . (2010). Delta40p53 controls the switch from pluripotency to differentiation by regulating IGF signaling in ESCs. Genes Dev 24: 2408–2419.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Voskuil DW, Bosma A, Vrieling A, Rookus MA, van't Veer LJ . (2004). Insulin-like growth factor system mRNA quantities in normal and tumor breast tissue of women with sporadic and familial breast cancer risk. Breast Cancer Res Treat 84: 225–233.

    CAS  PubMed  Google Scholar 

  • Vousden KH, Ryan KM . (2009). p53 and metabolism. Nat Rev Cancer 9: 691–700.

    CAS  PubMed  Google Scholar 

  • Wallborn T, WĂĽller S, Klammt J, Kruis T, Kratzsch J, Schmidt G et al. (2010). A heterozygous mutation of the insulin-like growth factor-I receptor causes retention of the nascent protein in the endoplasmic reticulum and results in intrauterine and postnatal growth retardation. J Clin Endocrinol Metab 95: 2316–2324.

    CAS  PubMed  Google Scholar 

  • Warburg O . (1956). On the origin of cancer cells. Science 123: 309–314.

    CAS  PubMed  Google Scholar 

  • Werner H . (2009). The pathophysiological significance of IGF-I receptor overexpression: new insights. Ped Endocrinol Rev 7: 2–5.

    Google Scholar 

  • Werner H, Bruchim I . (2009). The insulin-like growth factor-I receptor as an onogene. Arch Physiol Biochem 115: 58–71.

    CAS  PubMed  Google Scholar 

  • Werner H, Bruchim I . (2010). Basic and clinical significance of IGF-1-induced signatures in cancer. BMC Med 8: 2.

    PubMed  PubMed Central  Google Scholar 

  • Werner H, Idelman G, Rubinstein M, Pattee P, Nagalla SR, Roberts Jr CT . (2007). A novel EWS-WT1 gene fusion product in desmoplastic small round cell tumor is a potent transactivator of the insulin-like growth factor-I receptor (IGF-IR) gene. Cancer Lett 247: 84–90.

    CAS  PubMed  Google Scholar 

  • Werner H, Karnieli E, Rauscher III FJ, LeRoith D . (1996). Wild type and mutant p53 differentially regulate transcription of the insulin-like growth factor I receptor gene. Proc Natl Acad Sci USA 93: 8318–8323.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Werner H, Raizada MK, Mudd LM, Foyt HL, Simpon IA, Roberts Jr CT et al. (1989). Regulation of rat brain/HepG2 glucose transporter gene expression by insulin and insulin-like growth factor-I in primary cultures of neuronal and glial cells. Endocrinology 125: 314–320.

    CAS  PubMed  Google Scholar 

  • Werner H, Re GG, Drummond IA, Sukhatme VP, Rauscher III FJ, Sens DA et al. (1993). Increased expression of the insulin-like growth factor-I receptor gene, IGFIR, in Wilms’ tumor is correlated with modulation of IGFIR promoter activity by the WT1 Wilms’ tumor gene product. Proc Natl Acad Sci USA 90: 5828–5832.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Werner H, Roberts Jr CT . (2003). The IGF-I receptor gene: a molecular target for disrupted transcription factors. Genes Chromosomes Cancer 36: 113–120.

    CAS  PubMed  Google Scholar 

  • Werner H, Shen-Orr Z, Rauscher III FJ, Morris JF, Roberts Jr CT, LeRoith D . (1995). Inhibition of cellular proliferation by the Wilms’ tumor suppressor WT1 is associated with suppression of insulin-like growth factor I receptor gene expression. Mol Cell Biol 15: 3516–3522.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Wiesener MS, Maxwell PH, Eckardt KU . (2009). New insights into the role of the tumor suppressor von hippel lindau in cellular differentiation, ciliary biology, and cyst repression. J Mol Med 87: 871–877.

    PubMed  Google Scholar 

  • Yakar S, Pennisi P, Kim CH, Zhao H, Toyoshima Y, Gavrilova O et al. (2005). Studies involving the GH-IGF axis: Lessons from IGF-I and IGF-I receptor gene targeting mouse models. J Endocrinol Invest 26: 19–22.

    Google Scholar 

  • Yang A, McKeon F . (2000). P63 and p73: p53 mimics, menaces and more. Nat Rev 1: 199–207.

    CAS  Google Scholar 

  • Yerushalmi R, Gelmon KA, Leung S, Gao D, Cheang M, Pollak M et al. (2011). Insulin-like growth factor receptor (IGF-IR) in breast cancer subtypes. Breast Cancer Res Treat (Epub ahead of print).

  • Yuen JS, Macaulay VM . (2008). Targeting the type 1 insulin-like growth factor receptor as a treatment for cancer. Exp Opinion Ther Targets 12: 589–603.

    CAS  Google Scholar 

  • Yuen JSP, Cockman ME, Sullivan M, Protheroe A, Turner GDH, Roberts IS et al. (2007). The VHL tumor suppressor inhibits expression of the IGF1R and its loss induces IGF1R upregulation in human clear cell renal carcinoma. Oncogene 26: 6499–6508.

    CAS  PubMed  Google Scholar 

  • Zalts H, Shomron N . (2011). The impact of microRNAs on endocrinology. Ped Endocrinol Rev 8: 354–362.

    Google Scholar 

  • Zhang L, Kashanchi F, Zhan Q, Zhan S, Brady JN, Fornace AJ et al. (1996). Regulation of insulin-like growth factor II P3 promoter by p53: a potential mechanism for tumorigenesis. Cancer Res 56: 1367–1373.

    CAS  PubMed  Google Scholar 

  • Zhou BP, Liao Y, Xia W, Zou Y, Spohn B, Hung MC . (2001). HER-2/neu induces p53 ubiquitination via Akt-mediated Mdm2 phosphorylation. Nat Cell Biol 3: 973–982.

    CAS  PubMed  Google Scholar 

Download references

Acknowledgements

Work in the laboratory of HW is supported by grants from the Israel Science Foundation, Israel Cancer Association, Insulin-Dependent Diabetes Trust (IDDT, UK), Israel Cancer Research Fund (ICRF, New York and Montreal) and US-Israel Binational Science Foundation.

Author information

Authors and Affiliations

  1. Department of Human Molecular Genetics and Biochemistry, Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel

    H Werner

Authors
  1. H Werner
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to H Werner.

Ethics declarations

Competing interests

The author declares no conflict of interest.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Werner, H. Tumor suppressors govern insulin-like growth factor signaling pathways: implications in metabolism and cancer. Oncogene 31, 2703–2714 (2012). https://doi.org/10.1038/onc.2011.447

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/onc.2011.447

Keywords

This article is cited by

Search

Advanced search

Quick links