Home Page About Location Contact  Sitemap
Greek  
 
 
  RNA Processing Programme
  Signal Mediated Gene Expression Programme
  Molecular Endocrinology Programme
  Chemical Carcinogenesis and Genetic Toxicology Programme
  Molecular & Cellular Ageing Programme
  Enzymology Programme
  Biomimetics Programme
  Metabolic Engineering-Bioinformatics Programme
   
   

 

Molecular Endocrinology Programme

Research team

Michael N. Alexis, PhD, Research Professor (Head of the Programme)
Constantine E. Sekeris, MD, PD, Emeritus Research Professor
Dimitra J. Mitsiou, PhD, Research Lecturer
Cédric Gouédard, PhD, Marie Curie Post-doctoral Fellow
Suemyya Warrak, PhD, Marie Curie Post-doctoral Fellow
Xanthippi Alexi, Post-doctoral Fellow
 Aggeliki K. Meligova, PhD student
Niki Chantzi, PhD student (visiting)
Aggela Nastou, Lab assistant


Research objectives

The Molecular Endocrinology Programme (MEP) carries out research on the molecular physiology and pharmacology of steroid receptors with the scope of exploiting their potential in the prognosis and treatment of endocrine-related degenerative diseases. The R&D activities of the Programme are developing in two closely inter-related research directions investigating the role of, 1) estrogen receptors as prognostic markers and therapeutic targets and, 2) glucocorticoid receptors as modulators of gene expression, especially under stress conditions.

The Molecular Endocrinology Programme integrates in-house know-how and the complementary expertise of a large network of collaborators to provide for a multidisciplinary approach involving biochemistry, cell and molecular biology, pathology, animal physiology, medicinal and natural products chemistry and molecu¬lar modelling in the study of the above topics. The R&D activities the Programme from 2002 onwards were supported by 11 competitively funded projects involving training and transfer of know-how as well as innovative research. Several original publications and review articles in international referred journals and an appreciable number of patents have appeared from 2002 onwards as a result of networking of the R&D activities. The researchers of the Programme were directly involved during this period in the training of 9 undergraduates, 5 MSc and 10 PhD students enrolled in universities in Greece and abroad, and in transfer of know-how to the industry in the context of several competitively funded projects.

Fig. 1. Immunostaining of normal (A) and hyperplastic (B) human breast tissue using a home made monoclonal antibody B1C1 to estrogen receptor beta (ERâ1) (DAB, x400).

Fig. 2. The deoxybenzoin way to ERâ-binding selectivity: Two models of the 3/-brominated deoxybenzoin (green) and 17â-estradiol (magenta) fitting the ERâ binding cavity are shown: A) Coloured blue are positively-charged residues, red the negatively-charged and grey the hydrophobic ones. B) Singled out are the positions of the H-bonding residues Glu305, Arg346 and His475, and of a key water molecule.

 

Fig. 3. Localization of estrogen receptor beta in the mitochondria of HepG2 cells. A' ERâ staining, A' mitotracker CMX staining, A" merged images. 

Transfer of know-how and servicing

The Molecular Endocrinology Programme is often engaged in transfer of know-how to the industry (see competitively funded projects for details). In addition, the Programme’s staff is involved in the development of new diagnostic products and services the dissemination and exploitation of which is promoted by the Biomedical Applications Unit of IBRB.

Competitively funded Projects (2002 - ):

Hellenic General Secretariat for Research and Technology:

  1. PENED03-ED644 (2006-09): ''In search of a role for estrogen receptor beta in breast cancer''. Coordinator: Dr M.N. Alexis. Other participants: School of Medicine, Univ. of Athens. MEP budget: 70 K €.
  2. 02DSBEPRO32 (2006-07): ''Assessment of the estrogenic activity of natural compounds and derivatives thereof: Development of novel neutraceuticals and cosmetics''. Coordinator: S. Fotinos, Lavipharm. Other participants: IBRB (MEP) and School of Pharmacy-Univ. of Athens. MEP budget: 50 K €.
  3. Å!3060-SERMS (2004-07): ''Novel Selective Estrogen Receptor Modulators (SERMs): Synthesis and evaluation of biological activities.'' Coordinator: Dr D. Roukounas, ELPEN S.A. Other participants: IBRB (Molecular Endocrinology Programme), Dept of Chemistry-Agricultural Univ. of Athens, School of Pharmacy-Univ. of Athens and Molecular Paracitology Division – Heinrich Heine University, Duesseldorf. MEP budget: 36 K €.
  4. 02PRAKSE97 (2003-05): ''Tissue-specific antiestrogens''. Coordinator: Prof C.E. Sekeris (Budget: 20 K €).
  5. 02PRAKSE98 (2003-05): ''Immunodiagnostics for breast cancer prognosis''. Coordinator: Dr M.N. Alexis. Budget:20 K €.
  6. PENED01-ED258 (2002-06): ''Neurosteroids; Investigation of the mechanism of action of neurosteroids as neuroprotective agents; Development of new neurosteroids of high neuroprotective and marginal hormonal activity''. Coordinator: Prof A. Gravanis, School of Medicine, Univ. of Crete. Other participants: IBRB (MEP), IOPC-NHRF and GALENICA S.A. MEP budget: 32.2 K €.
  7. PAVET2000-00BE199 (2001-04): ''Immunochemical tools for breast cancer prognosis''. Coordinator: N. Rassias, RAFARM S.A. Other participants: IBRB (MEP), School of Pharmacy-Univ. of Patras. MEP budget: 51.4 K €.

European Union:

8.
 MC-Early Stage Research Training (2006-09): ''A European Research Training Site for the Design and Synthesis of Novel Neuroprotective and Hypoglycaemic Agents through a Multi-disciplinary approach''. Coordinator: Dr. N. Oikonomakos, Institute of Organic and Pharmaceutical Chemistry, NHRF. MEP budget: 65 K €.
9.
 ECNIS - Network of Excellence (2005-2009): "Environmental Cancer, Nutrition and Individual Susceptibility". Coordinator: Dr. K. Rydzynski, NOFER Institute, Lodz, Poland. NHRF budget for the first 18 months (50% EC contribution): 216 K€
10.
 MTKD-CT-2004-509836 (2004-08): ''Macromolecular assemblies involved in regulated gene expression: Structure/functional characteristics, interplay and novel functions''. Coordinator: Dr A. Guialis, IBRB-NHRF (Molecular Biology Programme). Other participants: IBRB-NHRF (Signal-Mediated Gene Expression & Molecular Endocrinology Programmes). MEP budget: 261.3 K €.
11.
 HPMD-CT-2001-00116 (2002-05): ''Regulation of transcription and mRNA processing by oncogenic signals''. Coordinator: Dr A. Pintzas, IBRB-NHRF (Signal-mediated gene expression Programme). Other participants: IBRB-NHRF (Molecular Endocrinology and Molecular Biology Programmes). MEP budget: 104.1 K €.
12.
HPMF-CT-2000-00904 (2001-02): ''Effect of glucocorticoid receptor beta isoform on glucocorticoid signaling''. Coordinator: Dr M.N. Alexis. Budget: 53 K €.


Publications in referred journals (2002 - ).  
  1. Wunderlich F, Benten WP, Lieberherr M, Guo Z, Stamm O, Wrehlke C, Sekeris CE, Mossmann H. Testosterone signaling in T cells and macrophages. Steroids. 2002; 67:535-8. Review.
  2. Scheller K, Seibel P, Sekeris CE. Glucocorticoid and thyroid hormone receptors in mitochondria of animal cells. Int Rev Cytol. 2003; 222:1-61. Review.
  3. Scheller K, Sekeris CE. The effects of steroid hormones on the transcription of genes encoding enzymes of oxidative phosphorylation. Exp Physiol. 2003; 88:129-40. Review.
  4. Mitsiou DJ, Siriani D, Katsanou ES, Florentin I, Georgakopoulos A, Alexis MN. Maintenance of glucocorticoid receptor function following severe heat-shock of heat-conditioned cells. Mol Cell Endocrinol. 2003; 201:97-108.
  5. Siriani D, Mitsiou DJ, Alexis MN. Overexpressed glucocorticoid receptor negatively regulates gene expression under conditions that favour accumulation of non-hormone-binding forms of the receptor. J Steroid Biochem Mol Biol. 2003; 84:171-80.
  6. Solakidi S, Sekeris CE. Oligonucleotide sequences similar to transcription factor consensi of nuclear genes are present in the human mitochondrial genome. Anticancer Res. 2003; 23:1389-93.
  7. Gritzapis AD, Baxevanis CN, Missitzis I, Katsanou ES, Alexis MN, Yotis J, Papamichail M. Quantitative fluorescence cytometric measurement of estrogen and progesterone receptors: correlation with the hormone binding assay. Breast Cancer Res Treat. 2003; 80:1-13.
  8. Solakidi S, Tiniakos DG, Petraki K, Stathopoulos GP, Markaki I, Androulakis G, Sekeris CE. Co-expression of trypsin and tumour-associated trypsin inhibitor(TATI) in colorectal adenocarcinomas. Histol Histopathol. 2003; 18:1181-8.
  9. Solakidi S, Dessypris A, Stathopoulos GP, Androulakis G, Sekeris CE. Tumour-associated trypsin inhibitor, carcinoembryonic antigen and acute-phase reactant proteins CRP and alpha1-antitrypsin in patients with gastrointestinal malignancies. Clin Biochem. 2004; 37:56-60.
  10. Kitraki E, Kremmyda O, Youlatos D, Alexis MN, Kittas C. Gender-dependent alterations in corticosteroid receptor status and spatial performance following 21 days of restraint stress. Neuroscience. 2004; 125:47-55.
  11. Fokialakis N, Lambrinidis G, Mitsiou DJ, Aligiannis N, Mitakou S, Skaltsounis AL, Pratsinis H, Mikros E, Alexis MN. A new class of phytoestrogens; evaluation of the estrogenic activity of deoxybenzoins. Chem Biol. 2004; 11:397-406.
  12. Kitraki E, Kremmyda O, Youlatos D, Alexis M, Kittas C. Spatial performance and corticosteroid receptor status in the 21-day restraint stress paradigm. Ann N Y Acad Sci. 2004; 1018:323-7.
  13. Siriani D, Mitsiou DJ, Alexis MN. Heat-induced degradation of overexpressed glucocorticoid receptor Separate protective roles of hsp90 and hsp70. J Steroid Biochem Mol Biol. 2005; 94:93-101.
  14. Mitsiou DJ, Florentin I, Baki L, Georgakopoulos A, Alexis MN. Pronounced enhancement of glucocorticoid-induced gene expression following severe heat shock of heat-conditioned cells hints to intricate cell survival tactics. J Steroid Biochem Mol Biol. 2005; 94:209-17.
  15. Solakidi S, Psarra AM, Sekeris CE. Differential subcellular distribution of estrogen receptor isoforms: Localization of ERalpha in the nucleoli and ERbeta in the mitochondria of human osteosarcoma SaOS-2 and hepatocarcinoma HepG2 cell lines. Biochim Biophys Acta. 2005; 1745:382-92.
  16. Psarra AM, Solakidi S, Trougakos IP, Margaritis LH, Spyrou G, Sekeris CE. Glucocorticoid receptor isoforms in human hepatocarcinoma HepG2 and SaOS-2 osteosarcoma cells: Presence of glucocorticoid receptor alpha in mitochondria and of glucocorticoid receptor beta in nucleoli. Int J Biochem Cell Biol. 2005; 37:2544-58.
  17. Solakidi S, Psarra AM, Nikolaropoulos S, Sekeris CE. Estrogen receptors {alpha} and {beta} (ER{alpha} and ER{beta}) and androgen receptor (AR) in human sperm: localization of ER{beta} and AR in mitochondria of the midpiece. Hum Reprod. 2005;20:3481-7.
  18. Roberts M, Drosopoulos K, Vasileiou G, Stricker M, Taoufik E, Maercker C, Guialis A, Alexis MN and Pintzas A. Microarray analysis of the differential transformation mediated by kirsten and harvey ras oncogenes in a human colon adenocarcinoma cell line. Int J Cancer. 2006;118:616-27.
  19. Kasiotis KM, Mendorou C, Haroutounian SA, Alexis MN. High affinity 17á-substituted estradiol derivatives: Synthesis and evaluation of estrogen receptor agonist activity. Steroids. 2006;71:249-55.
  20. Psarra AM, Solakidi S, Sekeris CE. The mitochondrion as a primary site of action of steroid and thyroid hormones:presence and action of steroid and thyroid hormone receptors in mitochondria of animal cells. Mol Cell Endocrinol. 2006;246:21-33. Review.
  21. Koufaki M, Theodorou E, Galaris D, Nousis L, Katsanou ES,. Alexis MN. Chroman/catechol hybrids: Synthesis and evaluation of their activity against oxidative stress induced cellular damage. J Med Chem. 2006;49:300-6.
  22. Zhou H, Spicuglia S, Hsieh JJ, Mitsiou DJ, Hoiby T, Veenstra GJ, Korsmeyer SJ, Stunnenberg HG. Uncleaved TFIIA is a substrate for taspase 1 and active in transcription. Mol Cell Biol. 2006;26:2728-35.
  23. Halabalaki M, Alexi X, Aligiannis N, Lambrinidis G, Pratsinis H, Florentin I, Mitakou S, Mikros E, Skaltsounis AL, Alexis MN. Estrogenic activity of isoflavonoids from Onobrychis ebenoides. Planta Medica. 2006;72:488-93.
  24. Apostolopoulos V, Pietersz GA, Tsibanis A, Tsikkinis A, Drakaki H, Loveland BE, Piddlesden SJ, Plebanski M, Pouniotis DS, Alexis MN, McKenzie IF, Vassilaros S. Pilot phase III immunotherapy study in early-stage breast cancer patients using oxidized mannan-MUC1. Breast Cancer Res. 2006;8:R27.
  25. Psarra AM, Solakidi S, Sekeris CE. The mitochondrion as a primary site of action of regulatory agents involved in neuroimmunomodulation. Ann N Y Acad Sci. 2006;1088:12-22. Review.
  26. Katsanou ES, Halabalaki M, Aligiannis N, Mitakou S, Skaltsounis AL, Alexi X, Pratsinis H, Alexis MN. Cytotoxic effects of 2-arylbenzofuran phytoestrogens on human cancer cells: Modulation by adrenal and gonadal steroids. J Steroid Biochem Mol Biol. 2007; 104(3-5):228-36.
  27. Hoiby T, Zhou H, Mitsiou DJ, Stunnenberg HG (2007). A Facelift for the General Transcription Factor TFIIA. Biochim Biophys Acta. 2007 May 5 [Epub ahead of print].
  28. Koufaki M, Kiziridi C, Nikoloudaki F, Alexis MN. Design and synthesis of 1,2-dithiolane derivatives and evaluation of their neuroprotective activity. Bioorg Med Chem Lett. 2007 May 17; [Epub ahead of print].
  29. Voutsas IF, Gritzapis AD, Alexis MN, Katsanou ES, Perez S, Baxevanis CN,Papamichail M. A novel quantitative flow cytometric method for measuring glucocorticoid receptor(GR) in cell lines: Correlation with the biochemical determination of GR.J Immunol Methods. 2007 Jun 8; [Epub ahead of print]
  30. Skretas G, Meligova AK, Villalonga-Barber C, Mitsiou DJ, Alexis MN, Micha-Screttas M, Steele BR, Screttas CG, Wood DW (2007). Engineered Chimeric Enzymes as Tools for Drug Discovery: Generating Reliable Bacterial Screens for the Detection, Discovery, and Assessment of Estrogen Receptor Modulators. J Am Chem Soc. 2007 Jun 15; [Epub ahead of print]

Patents and patent applications (2002- ):

31.
 'Ïnobrychis and Genista products for the prevention and treatment of hormone-dependent disorders'- Fokialakis N, Aligiannis N, Mitakou S, Skaltsounis AL, Pratsinis H, Alexis MN. - O.B.I 1004825. INT.CL: Á61Ê 35/78, Á23L 1/30.
32.
 'Monoclonal and polyclonal antibodies to glucococorticoid and estrogen receptors as immunodiagnostics for cancer prognosis' - Alexis MN, Dimolea E, Florentin I, Pechtelidou A and Sekeris CE. O.B.I. 1005417. INT. CL.: C07K 16/26, C07K 16/28, C12N 5/17, C12N 15/12, A61K 39/395.
33.
 'New substituted stilbenoid derivatives with meuroprotective activity'- Micha-Screttas M, Steele BR, Villalonga-Barber C, Alexis MN. O.B.I. 1005435. INT. CL.: C07C 43/315, C07C 43/23, C07C 39/21, A61K 11/05, A61K 31/085, A61P 39/06, A61P 25/28
34.
 Patent application No 20050100282/08-06-2005/O.B.I.: 'Tissue specific antiestrogens selective for estrogen receptor alpha' - Alexis MN, Papahatjis D, Assimomitis N, Siriani D, Sekeris CE.
 
 

 

  
   

Last Update: 11.07.2007
© National Hellenic Research Foundation (NHRF), 48 Vassileos Constantinou Ave., 11635 Athens, Greece, Tel. +302107273700, Fax. +302107246618