Department of Metabolic Diseases
University Medical Center Utrecht
Room KE.03.139.2
Lundlaan 6
3484 EA Utrecht
The Netherlands
phone: 088 - 75 549 87 / 553 18
fax: 088 - 75 542 95
e-mail:
J.W.M.Hoeppener@umcutrecht.nlDate and place of birth: June 3, 1956, Brunssum
1981
Biology degree at Utrecht University (cum laude).
Research projects:
- Comparative Endocrinology (Dr. M. Terlouw and Dr. H. Goos)
- Molecular Genetics (Dr. M. Borrias and Dr. C. van den Hondel)
1988
Ph.D. at Utrecht University (cum laude).
Thesis: The human calcitonin / CGRP genes: structure, chromosomal localization and expression in tumours.
Promotor: Prof. H.S. Jansz, co-promotores: Dr. C.J.M. Lips and Dr. P. H. Steenbergh.
Part of the Ph.D. study (financed by NWO and Ciba Geigy) was performed in Johns Hopkins Hospital (Baltimore, USA).
1988 - 1989
Post-doctoral fellow at Utrecht University (Dept. Physiological Chemistry), financed by STW.
1989 - 1994
Research Fellowship awarded by the Royal Dutch Academy of Sciences (KNAW), performed at the Dept. Physiological Chemistry of Utrecht University, headed by Prof. H.S. Jansz.
1994 - Oct. 2004
Senior scientists and staff member of the Dept. of Clinical Endocrinology (Division of Internal Medicine and Dermatology , DIGD) of the University Medical Center Utrecht (UMCU), headed by Prof. C.J.M. Lips.
From Oct. 2004 onwards
Senior scientists and staff member of the Dept. of Metabolic and Endocrine Diseases (Division of Biomedical Genetics, DBG) of UMCU, headed by Prof. R. Berger.
Dr. Höppener has been working in the field of molecular endocrinology since 1981, focussing on peptides belonging to the calcitonin/calcitonin gene-related peptide (CGRP) gene family. In 1986, islet amyloid polypeptide (IAPP/amylin) was identified as the main protein component of amyloid deposits in pancreatic islets of patients with type 2 diabetes mellitus (“ouderdomssuikerziekte”). We isolated and characterized the human IAPP gene, which appeared to be the fourth member of the calcitonin/CGRP gene family (Mosselman et al., FEBS letters 239: 227-232,1988).
At present, two lines of research are being pursued (for more info, see links at the bottom of this page):
- The role of human IAPP, and particularly of its (pre-)fibrillary depositions, in pancreatic islet ß-cell dysfunction in type 2 diabetes mellitus, the most common metabolic disease worldwide.
- The molecular dissection of tumour formation in the hereditary cancer syndromes Multiple Endocrine Neoplasia type 1 (MEN1) and 2 (MEN 2).
For both research lines, appropriate transgenic mouse models have been generated, which are used to study the pathogenesis, but also to develop and validate novel approaches for diagnosis and therapy.
Both the IAPP/amyloid research and the MEN research are incorporated in the Utrecht Graduate School of Life Sciences (Institute of Biomembranes and Cancer Genomics & Developmental Biology).
The above described research lines are supported by grants from the Dutch Diabetes Fund (for the IAPP/amyloid research) and from the Dutch Cancer Foundation [NKB/KWF], NWO and the European Community (for the MEN research). In addition, our IAPP research has generated interest from biotechnological companies. Collaborative projects involve development and validation of novel anti-diabetic, i.e. novel anti-amyloidogenic, therapy.
For the IAPP research we collaborate with Prof. B. Ahrén and Prof. F. Sundler (Lund University, Sweden) on glucose tolerance tests in mice (see e.g. our joint papers, Ahrén et al., 1998; Höppener et al., 2008) and on morphological/histological analyses (see Wong et al., 2003). With Prof. M. Pepys (London, UK) we are presently investigating the role of serum amyloid P component (SAP) in islet amyloid formation, using cross-breeding of human SAP transgenic and SAP knock-out mice with our human IAPP transgenic mice. With Dr. T. M. Hackeng (Univ. Maastricht) we collaborate on synthesis and analysis of synthetic IAPP-derivatives. With Dr. F. van Leeuwen (Univ. Maastricht) and Dr. M. Cnop (Brussels) we collaborate on ER stress and ubiquitin-proteasome dysfunction in human IAPP expressing beta cells.
In Utrecht, collaborative research on IAPP-amyloidosis is being performed with the group of Prof. A.J. Killian (Faculty of Chemistry) on IAPP-membrane interactions (see Sparr et al., 2004; Engel et al., 2006, 2008) and with Prof. Liskamp (Faculty of Pharmacy), on development of anti-amyloid therapy using ß-sheet blockers (see Rijkers et al., 2002). For electron microscopy analysis we collaborate with Dr. G. Posthuma (Dept. Cell Biology). More recently we have initiated a collaboration with Dr. H.C. Gerritsen (Mol. Biophysics) on imaging of amyloid formation and beta cell death in human IAPP transgenic mouse pancreatic islets.
For the MEN2 research we collaborate with Prof. Franklin (Purdue Univ. USA) on the role of the cellcycle regulator P18 in MTC development (see Joshi et al., 2007; Van Veelen et al., 2008 a,b), with Prof. L. Mulligan on the role of beta-catenin in MTC development (Gujral et al., 2008), and with the Dept. Pathology of UMCU (Prof. A. Kummer, Dr. M.Canninga) on immunohistochemical analysis of MEN2 tumours.
For the MEN1 research we collaborate with the Dept. Physiological Chemistry of UMCU (Prof. Timmers) on the role of the menin protein in transcription regulation (see Dreijerink et al., 2006a,b).
- van Veelen W, Klompmaker R, Gloerich M, van Gasteren CJ, Kalkhoven E, Berger R,
Lips CJ, Medema RH, Höppener JW, Acton DS. P18 is a tumor suppressor gene involved in human medullary thyroid carcinoma and pheochromocytoma development. Int J Cancer. (2008) Sep 2. [Epub ahead of print]
- Engel MF, Khemtémourian L, Kleijer CC, Meeldijk HJ, Jacobs J, Verkleij AJ, de Kruijff B,
Killian JA, Höppener JW. Membrane damage by human islet amyloid polypeptide through fibril growth at the membrane. Proc Natl Acad Sci U S A. (2008) 105:6033-8.
- Gujral TS, van Veelen W, Richardson DS, Myers SM, Meens JA, Acton DS, Duñach M,
Elliott BE, Höppener JW, Mulligan LM. A novel RET kinase-beta-catenin signaling pathway contributes to tumorigenesis in thyroid carcinoma. Cancer Res. (2008) 68:1338-46
- van Veelen W, van Gasteren CJ, Acton DS, Franklin DS, Berger R, Lips CJ, Höppener JW.
Synergistic effect of oncogenic RET and loss of p18 on medullary thyroid carcinoma development. Cancer Res. (2008) 68:1329-37
- Hollestelle MJ, Timmerman P, Meloen RH, Höppener JW. Characterization of gastrin-
cholecystokinin 2 receptor interaction in relation to c-fos induction. Endocr Relat Cancer (2008) 15:301-9.
- Joshi PP, Kulkarni MV, Yu BK, Smith KR, Norton DL, Veelen W, Höppener JW, Franklin DS. Simultaneous downregulation of CDK inhibitors p18(Ink4c) and p27(Kip1) is required for MEN2A-RET-mediated mitogenesis. Oncogene. (2007) 26:554-70.
-Dreijerink KM, Höppener JW, Timmers HM, Lips CJ. Mechanisms of disease: multiple endocrine neoplasia type 1-relation to chromatin modifications and transcription regulation. Nat Clin Pract Endocrinol Metab. (2006) 2:562-70.
-Dreijerink KM, Mulder KW, Winkler GS, Höppener JW, Lips CJ, Timmers HT. Menin links estrogen receptor activation to histone H3K4 trimethylation. Cancer Res. (2006) 66:4929-35.
- Höppener JW, Lips CJ. Role of islet amyloid in type 2 diabetes mellitus. Int J Biochem Cell Biol. (2006) 38:726-36.
- Engel MF, Yigittop H, Elgersma RC, Rijkers DT, Liskamp RM, de Kruijff B, Höppener JW, Killian AJ. Islet amyloid polypeptide inserts into phospholipid monolayers as monomer. J Mol Biol. (2006) 356:783-9.
- Sparr E, Engel MFM, Sakharov DV, Sprong M, Jacobs J, de Kruijff B, Höppener JWM and Killian JA. Islet amyloid polypeptide-induced membrane leakage involves uptake of lipids by forming amyloid fibers. FEBS Lett. (2004) 577:117-20.
- Wong HY, Ahren B, Lips CJ, Höppener JWM, Sundler F. Postnatally disturbed pancreatic islet cell distribution in human islet amyloid polypeptide transgenic mice. Regul Pept. (2003) 113:89-94.
- Hes FJ, Höppener JWM, Lips CJ. Clinical review 155: Pheochromocytoma in Von Hippel-Lindau disease. J Clin Endocrinol Metab. (2003) 88:969-74.
- Lips CJ, Lentjes EG, Höppener JWM (2003). The spectrum of carcinoid tumours and carcinoid syndromes. Ann Clin Biochem (2003), 6:612-27.
- Höppener JWM, Nieuwenhuis MG, Vroom TM, Ahren B, Lips, CJ. Role of islet amyloid in type 2 diabetes mellitus: consequence or cause? Mol Cell Endocrinol (2002) 197:205-12.
- Rijkers DT, Höppener JWM, Posthuma G, Lips CJ, Liskamp RM..Inhibition of amyloid fibril formation of human amylin by N-alkylated amino acid and alpha-hydroxy acid residue containing peptides. Chemistry (2002) 8:4285-91.
- Lips CJM, Höppener JWM and Thijssen JHH. Medullary thyroid .carcinoma: role of genetic testing and calcitonin measurement. Ann. Clin. Biochem. (2001) 38:168-79.
- Acton DS, Velthuyzen D, Lips CJM and Höppener JWM. Multiple endocrine neoplasia type2B mutation in human RET oncogene induces medullary thyroid carcinoma in transgenic mice. Oncogene (2000) 19:3121-5.
- Höppener JWM, Ahrén B and Lips CJM. Islet amyloid and type 2 diabetes mellitus. N. Engl. J. Med. (2000) 343:411-9.
- Roijers JFM, Apel T, Neumann HPH, Von Arnim U, Lips CJM and Höppener JWM. Internally shortened menin protein as a consequence of alternative RNA splicing due to a germline deletion in the multiple endocrine neoplasia type 1 gene. Int. J. Mol. Med. (2000) 5:611-4.
- Höppener JWM, Oosterwijk C, Nieuwenhuis MG, Posthuma G, Thijssen JJH, Vroom ThM, Ahrén B, Lips CJM.. Extensive islet amyloid formation is induced by development of type 2 diabetes mellitus and contributes to its progression: pathogenesis of diabetes in a mouse model. Diabetologia (1999) 42:427-34.
- Van Hulst KL, Oosterwijk C, Born W, Vroom ThM, Nieuwenhuis MG, Blankenstein MA, Lips CJM, Fischer JA, Höppener JWM. Islet amyloid polypeptide (IAPP) /amylin messenger RNA and protein expression in human insulinomas. Eur. J. Endocrinol (1999) 140:69-78.
- Ahrén B, Oosterwijk C, Lips CJM, Höppener JWM. Transgenic overexpression of human islet amyloid polypeptide inhibits insulin secretion and glucose elimination after gastric glucose gavage in mice. Diabetologia (1998) 41:1374-80.
- Höppener JWM, De Wit M, Simarro-Doorten AY, Roijers JFM, Van Herrewaarden HMC, Lips CJM, Parente F, Quincy D, Gaudray P, Khodaei S, Weber G, Teh BT, Farnebo F, Larsson C, Zhang CX, Calender A, Pannett AAJ, Forbes SA, Bassett JHD, Thakker RV, Lemmens I, Van de Ven, WJM, Kas K. A putative human zinc finger gene (ZFPL1) on 11q13, highly conserved in the mouse and expressed in exocrine pancreas. Genomics (1998) 50:251-9.
- Van Hulst KL, Born W, Muff R, Oosterwijk C, Blan¬kenstein MA, Lips CJM, Fischer JA, Höppener JWM.. Biologically active human islet amyloid polypeptide in transgenic mice. Eur. J. Endocrinol. (1997) 136:107-13.
- Oosterwijk C, Van Hulst KL, Visser CJT, Woutersen RA, Lips CJM, Van den Tweel JG, HöppenerJWM. Pancreatic cancer in rats and hamsters does not induce IAPP-related hyperglycemia. Int. J. Cancer (1997) 72:637-41.
- De Wit MJ, Landsvater RM, Sinke RJ, Geurts Van Kessel A, Lips CJM, Höppener JWM. Exclusion of the phosphatidylinositol-specific phospholipase-C ß3 (PLC ß) gene as candidate for the multiple endocrine neoplasia type 1 (MEN 1) gene. Hum. Genet. (1997) 99:133-7.
- Höppener JWM, Lips CJM. RET receptor tyrosine kinase gene mutations: molecular biological, physiological and clinical aspects. Eur. J. Clin. Invest. (1996) 26:613-24.
- Landsvater RM, De Wit MJ, Zewald RA, Hofstra RMW, Buys CHCM, Ploos van Amstel HK, Höppener JWM, Lips CJM. Somatic mutations of the Ret proto-oncogene are not required for tumor development in multiple endocrine neoplasia type 2 (MEN 2) gene carriers. Cancer Res. (1996) 56:4853-5.
- Oosterwijk C, Höppener JWM, Van Hulst KL, Lips CJM. Pancreatic islet amyloid formation in patients with non-in¬su¬lin-dependent diabetes mellitus; implications for therapeutic strategy. Int. J. Pancreatology (1995) 18:7-13.
- Lips CJM, Landsvater RM, Höppener JWM, Geerdink RA, Blijham GH, Jansen-Schillhorn van Veen JM, Feldberg MAM, Van Gils APG, Hoogenboom H, Berends MJH, Beemer FA, Ploos van Amstel HK, Van Vroonhoven ThJMV, Vroom ThM. From medical history and biochemical tests to presymptomatic treatment in a large MEN 2A family. J. Intern. Med. (1995) 238:347-56.
- Höppener JWM, Oosterwijk C, Van Hulst KL, Verbeek JS, Capel PJA, De Koning EJP, Clark A, Jansz HS, Lips CJM. Molecular physiology of the islet amyloid polypeptide (IAPP)/amylin gene in man, rat and transgenic mice. J. Cell. Biochem.(1994) 55S:39-53.
- De Koning EJP, Höppener JWM, Verbeek JS, Oosterwijk C, Van Hulst KL, Baker CA, Lips CJM, Morris JF,Clark A. Human islet amyloid polypeptide (IAPP)accumulates at similar sites in islets of transgenic mice as in man. Diabetes (1994) 43:640-4.
- Lips CJM, Landsvater RM, Höppener JWM, Geerdink RA, Blijham GH, Jansen-Schillhorn van Veen J, van Gils APG, de Wit MJ, Zewald RA, Berends MJH, Beemer FA, Brouwers-Smalbraak J, Jansen RPM, Ploos van Amstel HK, van Vroonhoven ThJMV, Vroom ThM. Clinical screening as compared with DNA analysis in families with multiple endocrine neoplasia syndrome type 2A. N. Engl. J. Med. ¬(1994) 331:828-35.
- Hofstra RMW, Landsvater RM, Ceccherini I, Stulp RP, Stelwagen T, Luo Y, Pasini B, Höppener JWM, Ploos van Amstel HK, Romeo G, Lips CJM, Buys CHCM. A mutation in the RET proto-oncogene associated with mul¬tiple endocrine neoplasia type 2B and sporadic medullary thyroid carcinoma. Nature (1994) 367:375-6.
- Höppener JWM, Verbeek JS, de Koning EJP, Oosterwijk C, van Hulst KL, Visser-Vernooy HJ, Hofhuis FMA, van Gaalen S, Berends MJH, Hackeng WHL, Jansz HS, Morris JF, Clark A, Lips CJM. Chronic overproduction of islet amyloid polypeptide/amylin in transgenic mice: lysosomal localization of human islet amyloid polypeptide and lack of marked hyperglycaemia or hyper-insulinaemia. Diabetologia (1993) 36:1258-65
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