Γιώργος Μαυροθαλασσίτης
Το ενδιαφέρον μας εστιάζεται στην σηματοδοτική ρύθμιση της μεταγραφής κατά την φυσιολογική ανάπτυξη και την ασθένεια. Ειδικότερα στο ρόλο των γονιδίων ETS στην ανάπτυξη και τον καρκίνο. Τα τελευταία χρόνια έχουμε αναλύσει εκτεταμένα τον μεταγραφικό παράγοντα ERF ως παράδειγμα της σηματοδοτικής ρύθμισης της μεταγραφής.
Μελετήσαμε τους μηχανισμούς ρύθμισης του ERF από τις κινάσες Erk και ταυτοποιήσαμε επικράτειες που ευθύνονται για την αλληλεπίδραση και φωσφορυλίωση του ERF. Δείξαμε ότι η φοσφορυλίωση ρυθμίζει την υποκυτταρική διαμερισματοποίηση και άρα την ενεργότητα της πρωτεΐνης. Μελετήσαμε τον ρόλο του ERF ως ογκοκαταστολέα και δείξαμε ότι αναστέλλει τον κυτταρικό πολλαπλασιασμό σε συνάρτηση με τις πρωτεΐνες του ρετινοβλαστόματος. Δείξαμε ακόμα ότι μη-ρυθμιζόμενες μορφές του ERF μπορούν και καταστέλλουν την ras- επαγόμενη ογκογένεση. Ο πιθανός του ρόλος στην ογκογένεση ενισχύεται και από τα πειράματα μας που δείχνουν ότι ο ERF μπορεί να καταστέλλει την επιθηλιο-μεσεγχυματική μετάβαση (ΕΜΤ) σε συνάρτηση με τις σεμαφορίνες. Μελετώντας το ρόλο του ERF σε επίπεδο οργανισμού, βρήκαμε ότι η απαλοιφή του οδηγεί σε εμβρυϊκό θάνατο, σε στάδιο που ισοδυναμεί με το τέλος του 1ου τριμήνου στον άνθρωπο, λόγω βλαβών στα τροφοβλαστικά κύτταρα του πλακούντα. Πρόσφατα δείξαμε ότι η απλοανεπάρκεια του ERF οδηγεί σε κρανιοσυνοστέωση στον ποντικό και τον άνθρωπο.
Η μέχρι τώρα δουλεία μας οδηγεί στην υπόθεση ότι «τα σηματοδοτικά μονοπάτια σηματοδοτούν ποσοτικά και την ανενεργή τους κατάσταση μέσω αναστολέων και καταστολέων». Η τρέχουσα εργασία μας εξετάζει την υπόθεση αυτή σε διάφορα συστήματα που σχετίζονται με συγκεκριμένες ασθένειες.
Twigg SR, Vorgia E, McGowan SJ, Peraki I, Fenwick AL, Sharma VP, Allegra M, Zaragkoulias A, Akha ES, Knight SJ, Lord H, Lester T, Izatt L, Lampe AK, Mohammed SN, Stewart FJ, Verloes A, Wilson LC, Healy C, Sharpe PT, Hammond P, Hughes J, Taylor S, Johnson D, Wall SA, Mavrothalassitis G, Wilkie AO. (2013) Reduced dosage of ERF causes complex craniosynostosis in humans and mice and links ERK1/2 signaling to regulation of osteogenesis. Nat Genet. 45:308-13.
Allegra M, Zaragkoulias A, Vorgia E, Ioannou M, Litos G, Beug H, Mavrothalassitis G. (2012) Semaphorin-7a reverses the ERF-induced inhibition of EMT in Ras-dependent mouse mammary epithelial cells. Mol Biol Cell 23:3873-81.
Papadaki, C, Alexiou M, Cecena G, Verykokakis M, Bilitou A, Cross JC, Oshima RG, Mavrothalassitis G. (2007) Transcriptional repressor erf determines extraembryonic ectoderm differentiation. Mol Cell Biol 27: 5201-5213.
Le Gallic L, Virgilio L, Cohen P, Biteau B, Mavrothalassitis G. (2004) ERF nuclear shuttling, a continuous monitor of Erk activity that links it to cell cycle progression. Mol. Cell. Biol. 24:1206-1218.
Sgouras DN, Athanasiou MA, Beal GJ, Fisher RJ, Blair DG, Mavrothalassitis G. (1995) An ETS domain protein with strong transcriptional repressor activity, can suppress ets-associated tumorigenesis and regulated by phosphorylation during cell cycle and mitogenic stimulation. EMBO J. 14:4781-4793.
Mavrothalassitis, G. J. and Georgatsos, J. G.: Purification and properties of three cytosolic ribonucleases of mouse liver. Eur. J. Biochem. 142: 481-486, 1984.
Mavrothalassitis, G. J., Thanos, D. and Papamatheakis, J.: Molecular analysis of the class II gene Ea. Immunogenetics 27: 426-430, 1988.
Thanos, D., Mavrothalassitis, G. J. and Papamatheakis, J.: Multiple regulatory regions on the 5' side of the Ea gene. Proc. Natl. Acad. Sci. USA 85: 3073-3079, 1988.
Thanos, D., Mavrothalassitis, G. J., Gregoriou, M., Bygrave, A. and Papamatheakis, J: Multiple control reagions regulate the constitutive expression of Eα gene. Molecular basis of immune responce. Ann. N.Y. Acad. Sci. 546:255-257,1988.
Mavrothalassitis, G. J., Tzimagiorgis, G., Mitsialis, A., Zanis, B., Plaitakis, A., Papamatheakis, J. and Moschonas, N.: Isolation and characterization of cDNA clones encoding human liver glutemate dehydrogenase: Evidence for a small gene family. Proc. Natl. Acad. Sci. USA 85: 3494-3498, 1988.
Mavrothalassitis, G. J., Watson, D. K. and Papas, T. S.: Molecular and functional characterization of the promoter of ETS2, the human c-ets-2 gene. Proc. Natl. Acad. Sci. USA 87: 1047-1051, 1990.
Mavrothalassitis, G. J., Watson, D. K., Ascione, R. and Papas, T. S.: The promoter of the human ets-2 oncogene: Structural and functional characterization. In Papas, T.S. (Ed.): Oncogenesis. Houston, Gulf Publishing Co., 1990, pp. 233-247.
Papas, T. S., Watson, D. K., Sacchi, N., Fujiwara, S., Seth, A. K., Fisher, R. J., Bhat, N. K., Mavrothalassitis, G., Koizumi, S., Jorcyk, C. L., Schweinfest, C. W., Kottaridis, S. D. and Ascione, R.: The ETS family of genes in leukemia and Down syndrome. Am. J. Med. Genet., Suppl. 7: 251-261, 1990.
Papas, T. S., Blair, D. G., Watson, D. K., Yuan, C.-C., Ruscetti, S. K., Fujiwara, S., Seth, A. K., Fisher, R. J., Bhat, N. K., Mavrothalassitis, G., Koizumi, S., Jorcyk, C. L., Schweinfest, C. W. and Ascione, R.: The ETS family of genes: Structural analysis, gene products, and involvement in neoplasia and other pathologies. In Patterson, D. and Epstein, C.J. (Eds.): Molecular Genetics of Chromosome 21 and Down Syndrome. New York, Wiley-Liss, 1990, pp. 137-168.
Mavrothalassitis, G., Watson, D. K. and Papas, T. S.: The human ETS-2 gene promoter: Molecular dissection and nuclease hypersensitivity. Oncogene 5: 1337-1342, 1990.
Papas, T. S., Blair, D. G., Watson, D. K., Yuan, C-C., Ruscetti, S. K., Fujiwara, S., Seth, A. K., Fisher, R. J., Bhat, N. K., Mavrothalassitis, G., Koizumi, S., Jorcyk, C. L., Schweinfest, C. W. and Ascione, R.: The ETS family of genes: Structural analysis, gene products, and involvement in neoplasia and other pathologies. Prog. Clin. Biol. Res. 360: 137-168, 1990.
Watson, D. K., Mavrothalassitis, G. J., Jorcyk, C. L., Smyth, F. E. and Papas, T. S.: Molecular organization and differential polyadenylation sites of human ETS2 gene. Oncogene 5: 1521-1527, 1990.
Mavrothalassitis, G., Beal, G. and Papas, T. S.: Defining target sequence(s) of a DNA binding protein by random selection and PCR: Determination of the GCN4 binding sequence repertoire. DNA and Cell Biology 9: 783-788, 1990.
Papas, T. S., Mavrothalassitis, G., Seth, A., Watson, D. K., Lautenberger, J. A., Fisher, R. J., Bhat, N. K. and Ascione, R.: The ets gene family as a paradigm for the study of cellular transcriptional processes. In Verna, R. and Nishizuka, Y. (Eds.): Biotechnology of Cell Regulation, Serono Symposia Series: Advances in Experimental Medicine, Vol. 4. New York: Raven Press, 1991, pp. 211-226.
Seth, A., Ascione, R., Fisher, R. J., Mavrothalassitis, G. J., Bhat, N. K. and Papas, T. S.: The ets gene family. Cell Growth Differ. 3: 327-334, 1992.
Mavrothalassitis, G. J. and Papas, T. S.: Positive and negative factors regulate the transcription of the ETS2 gene via an oncogene responsive-like unit within the ETS2 promoter region. Cell Growth Differ. 2: 215-224, 1991.
Jorcyk, C. L., Watson, D. K., Mavrothalassitis, G. J. and Papas, T. S.: The human ETS1 gene: Genomic structure, promoter characterization and alternative splicing. Oncogene 6: 523-534, 1991.
Fisher, R. J., Mavrothalassitis, G., Kondoh, A. and Papas, T. S.: High affinity DNA:protein interactions of the cellular ETS1 protein: The determination of the ETS binding motif. Oncogene 6: 2249-2254, 1991.
Fisher, R. J., Koizumi, S., Kondoh, A., Mariano, J., Mavrothalassitis, G., Bhat, N. K. and Papas, T. S.: Human ETS1 oncoprotein: Purification, isoforms, -SH modification and DNA sequence-specific binding. J. Biol. Chem. 267: 17957-17965, 1992.
Murakami, K., Mavrothalassitis, G., Bhat, N. K., Fisher, R. J. and Papas, T. S.: Human ERG-2 protein is a phosphorylated DNA binding protein - 1 distinct member of the ets-protein family. Oncogene 8: 1559-1566, 1993.
Mavrothalassitis, G., Fisher, R. J., Smyth, F., Watson, D. K. and Papas, T. S.: Structural inferences of the ETS1 DNA-binding domain determined by mutational analysis. Oncogene 9: 425-435, 1994.
Fleischman, L. F., Holtzclae, L., Russell, J. T., Mavrothalassitis, G. J. and Fisher, R. J.: ETS-1 in astrocytes: Expression and transmitter-evoked phosphorylation. Mol. Cell. Biol. 15: 925-931, 1995.
Sgouras, D. N., Athanasiou, M. A., Beal, G. J., Fisher, R. J., Blair, D. G. and Mavrothalassitis, G. J.: ERF: An ETS domain protein with strong transcriptional repressor activity, can suppress ets-associated tumorigenesis and regulated by phosphorylation during cell cycle and mitogenic stimulation. EMBO J. 14: 4781-4793, 1995.
Athanasiou, M., Mavrothalassitis, G., Yuan, C. C. and Blair, D. G.: The gag-myb-ets fusion oncogene alters the apoptotic response and growth factor dependence of interleukin-3 dependent murine cells. Oncogene 12:337-344, 1996.
Paliogianni, F., Hama, N., Mavrothalassitis, G. J., Thyphronitis, G. and Boumpas, D. T.: Signal requirements for interleukin 4 promoter activation in human T cells. Cell. Immunol. 168: 33-38,1996.
Athanasiou, M., Clausen, P.A., Mavrothalassitis, G.J., Zhang, X., Watson, D.K., and Blair, D.G.: Increased expression of the ets-related transcription factor Fli1/ERGB correlates with and can induce the megakaryocytic phenotype. Cell Growth Diff. 7:1525-1534, 1996.
Liu, D., Pavlopoulos, E., Modi, W., Moschonas, N. and Mavrothalassitis, G.J.: ERF: genomic organization, chromosomal localization and promoter analysis of the human and the mouse genes. Oncogene. 14:1445-1451, 1997
Clausen P.A., Athanasiou, M.A., Zhang-qun, C., Dunn, K.J., Lautenberger, J.L., Mavrothalassitis, G.J. and Blair, D.G.: ETS1 induces incresed expression of erythroid markers in the pluripotent eruthroleukemic cell lines K562 and HEL. Leukemia 11:1224-1233, 1997
Lionel Le Gallic, Dionyssios Sgouras, Gregory Beal Jr and George Mavrothalassitis. The transcriptional repressor ERF, is a ras/MAPK target that regulates cellular proliferation. Mol. Cell. Biol. 19: 4121-4133, 1999
Meropi Athanasiou, George Mavrothalassitis, Lin Sun-Hoffman, and Donald G. Blair. FLI-1 is a Suppressor of Erythroid Differentiation in Human Hematopoietic Cells Leukemia 14: 439-445, 2000
Meropi Athanasiou, Lionel LeGallic, Dennis K. Watson, Donald G. Blair, and George Mavrothalassitis. Suppression of the Ewing’s Sarcoma phenotype by FLI1/ERF repressor hybrids. Cancer Gene Ther. 7: 1188-1195, 2000
George Mavrothalassitis and Jacques Ghydael. Proteins of the ETS family with transcriptional repressor activity. Oncogene, 19: 6524-6532, 2000
Watson, D.K., Li, R., Sementchenko, V.I., Mavrothalassitis, G. and Seth, A.: ETS Family of Transcription Factors. In: Encyclopedia of Cancer, 2nd edition. Betino JR (Ed), Academic Press, 189-196, 2002
Athanasiou M, Blair DG, Mavrothalassitis G. ERF, an ETS-related transcriptional repressor, can induce erythroid differentiation. Anticancer Res 23: 2143-2153, 2003
Le Gallic L; Virgilio L; Cohen P; Biteau B; Mavrothalassitis G ERF nuclear shuttling, a continuous monitor of Erk activity that links it to cell cycle progression Mol. Cell. Biol. 24: 1206-1218, 2004
Veiopoulou C, Kogopoulou O, Tzakos E, Mavrothalassitis G, Mitsias D, Karafoulidou A, Paliogianni F, Moutsopoulos HM, Thyphronitis GIL-2 and IL-10 production by human CD4+T cells is differentially regulated by p38: Mode of stimulation-dependent regulation of IL-2 Neuroimmunomodulation 11: 199-208, 2004
Kogkopoulou O, Tzakos E, Mavrothalassitis G, Baldari CT, Paliogianni F, Young HA, Thyphronitis G. Conditional up-regulation of IL-2 production by p38 MAPK inactivation is mediated by increased Erk1/2 activity.J Leukoc Biol. 79:1052-60, 2006
Polychronopoulos S, Verykokakis M, Yazicioglu MN, Sakarellos-Daitsiotis M, Cobb MH, Mavrothalassitis G. The transcriptional ETS2 repressor factor associates with active and inactive Erks through distinct FXF motifs. J Biol Chem. 281:25601-11, 2006
Papadaki, C., Alexiou, M., Cecena, G., Verykokakis, M., Bilitou, A., Cross, J. C., Oshima, R. G., and Mavrothalassitis, G. Transcriptional repressor erf determines extraembryonic ectoderm differentiation Mol Cell Biol 27:5201-5213, 2007
Verykokakis Μ, Papadaki C, Vorgia E, Le Gallic L and Mavrothalassitis G. The Ras-dependent Erf control of cell proliferation and differentiation is mediated by c-Myc repression J Biol Chem. 282:30285-94, 2007
Wen F, Tynan JA, Cecena C, Williams R, Munera J, Mavrothalassitis G and Oshima RG. Ets2 is required for trophoblast stem cell self renewal. Dev. Biol. 312:284-99, 2007
K. Liopeta, S. Boubali, L. Virgilio, G. Thyphronitis, G. Mavrothalassitis, G. Dimitracopoulos and F. Paliogianni. cAMP regulates IL-10 Production by normal human T lymphocytes at multiple levels: a potential role for MEF2. Mol Immunol,46:345-54, 2009
Tarcic, G., Avraham, R., Pines, G., Amit, I., Shay, T., Lu, Y., Zwang, Y., Katz, M., Ben-Chetrit, N., Jacob-Hirsch, J., Virgilio, L., Rechavi, G., Mavrothalassitis, G., Mills, G.B., Domany, E., and Yarden, Y. EGR1 and the ERK-ERF axis drive mammary cell migration in response to EGF. FASEB J. 26:1582-92, 2012
Boubali S, Liopeta K, Virgilio L, Thyphronitis G, Mavrothalassitis G, Dimitracopoulos G, Paliogianni F. Calcium/calmodulin-dependent protein kinase II regulates IL-10 production by human T lymphocytes: a distinct target in the calcium dependent pathway. Mol Immunol. 52:51-60, 2012
Allegra M, Zaragkoulias A, Vorgia E, Ioannou M, Litos G, Beug H, Mavrothalassitis G. Semaphorin-7a reverses the ERF-induced inhibition of EMT in Ras-dependent mouse mammary epithelial cells. Mol Biol Cell, 23:3873-81, 2012
Twigg SR, Vorgia E, McGowan SJ, Peraki I, Fenwick AL, Sharma VP, Allegra M, Zaragkoulias A, Akha ES, Knight SJ, Lord H, Lester T, Izatt L, Lampe AK, Mohammed SN, Stewart FJ, Verloes A, Wilson LC, Healy C, Sharpe PT, Hammond P, Hughes J, Taylor S, Johnson D, Wall SA, Mavrothalassitis G, Wilkie AO. Reduced dosage of ERF causes complex craniosynostosis in humans and mice and links ERK1/2 signaling to regulation of osteogenesis. Nat Genet. 45:308-13, 2013
Vorgia E, Zaragkoulias A, Peraki I, Mavrothalassitis G. Suppression of Fgf2 by ETS2 repressor factor (ERF) is required for chorionic trophoblast differentiation. Mol Reprod Dev. 84(4):286-295, 2017