{"id":18,"date":"2014-07-10T13:59:12","date_gmt":"2014-07-10T17:59:12","guid":{"rendered":"https:\/\/sites.bu.edu\/dominguezlab\/?page_id=18"},"modified":"2015-06-27T14:28:50","modified_gmt":"2015-06-27T18:28:50","slug":"research","status":"publish","type":"page","link":"https:\/\/sites.bu.edu\/dominguezlab\/research\/","title":{"rendered":"Research and Publications"},"content":{"rendered":"

1. Study the cascade of intracellular events that leads to the activation of Wnt\/\u03b2-catenin signaling<\/strong><\/p>\n

Since the Wnt pathway was first identified, a number of studies in many animal models and in vitro<\/i> have delineated an intracellular pathway made of core components including receptors, positive regulators like Dvl, negative regulators Axin and Apc, and co-transcriptional activators \u03b2-catenin and TCF\/LEF. In addition, a number of other components that modify the activity, stability or localization of these core components have been identified. Despite these advances, our understanding of the molecular mechanism of Wnt\/\u03b2-catenin signaling is not complete, and a number of steps have not been fully characterized, including the mechanism of \u03b2-catenin and Dvl activation.<\/p>\n

We have shown that CK2 is essential for Wnt\/\u03b2-catenin signaling in Xenopus laevis<\/i> embryos and cell lines. Biochemical experiments indicate that CK2 acts through phosphorylation of the core Wnt\/\u03b2-catenin components \u03b2-catenin and Dvl. Therefore, we are characterizing the molecular mechanism leading to activation of Dvl and \u03b2-catenin, the key intracellular Wnt\/\u03b2-catenin signaling component that is upregulated in many human tumors. As we acquire a better understanding of the molecular events leading to Wnt\/\u03b2-catenin signaling activation, we will be able to develop novel and specific inhibitors for the treatment of cancers with upregulated nuclear \u03b2-catenin levels.<\/p>\n

\"Microinjection<\/a>
Microinjection of CK2 alpha\/beta leads to axis duplication.<\/figcaption><\/figure>\n

2. Understand the role of Wnt signaling in cellular processes during embryo development<\/strong><\/p>\n

The Wnt\/\u03b2-catenin pathway regulates progenitor expansion, proliferation, fate specification and differentiation. Our focus is to determine how Wnt\/\u03b2-catenin signaling controls cellular processes such as cell fate determination and proliferation and contractility in collaboration with Dr. E. Ehler, by investigating the role of differential cytoplasmic localization and how signaling activation controls the function of proteins.<\/p>\n

In Xenopus laevis<\/em>, we have implicated CK2 and GSK3\u03b2 in regulating dorsal fate determination. Currently, we aim to determine how these two kinases are regulated endogenously during early Xenopus laevis<\/em> development and during oogenesis. In the mouse, through the study of CK2\u03b1 ablated embryos, we have implicated CK2 in regulating cellular proliferation. We are pursuing biochemical, molecular and genetic approaches to determine the downstream targets of CK2 during cell proliferation in vivo<\/em>.<\/p>\n

\"<\/a>
Proliferation and apoptosis in E10.5 CK2alpha-\/- embryos stained by WIHC for phH3 (middle pannel) and TUNEL (right pannel). Photographs show bright field (BF), PhH3 and TUNEL staining.0.5 mm. Abbreviations: fl forelimb bud, h heart, hl hindlimb bud, p1 first pharyngeal arch, s somite (from Dominguez et al<\/em>. 2008).<\/figcaption><\/figure>\n

3. Determine the role of the Wnt\/\u03b2-catenin signaling pathway during organ development and maintenance, such as heart formation<\/strong><\/p>\n

Wnt signaling is essential for heart development and is proposed to be involved in congenital heart disease. We have shown that CK2\u03b1 is essential for proper heart formation. We are now dissecting the mechanism(s) that CK2\u03b1 utilizes to control heart development. We are studying precise localization of Wnt\/\u03b2-catenin activation and determine the downstream targets of CK2 during cardiogenesis in vivo. Understanding how deficient Wnt\/\u03b2-catenin signaling leads to embryonic malformations will help develop strategies to prevent or correct defects in morphogenetic processes that lead to congenital heart defects.<\/p>\n

\"CK2\u03b1<\/a>
CK2\u03b1 (Csnk2a1) homozygous mutant mice die by embryonic day (E)11 and display defects in the heart, neural tube, pharyngeal arches, tailbud and somites.<\/figcaption><\/figure>\n

SELECTED PUBLICATIONS:<\/strong><\/p>\n

Ortega C, Seidner Y, and\u00a0Dominguez I.<\/strong>\u00a0Mining CK2 in cancer<\/a>.\u00a0PLOS ONE\u00a02014 Dec 26;9(12):e115609<\/p>\n

Siriwardana NS, Meyer R, Havasi A,\u00a0Dominguez I<\/strong>, Panchenko MV.\u00a0Cell cycle-dependent chromatin shuttling of HBO1-JADE1 histone acetyl transferase (HAT) complex.<\/a>\u00a0Cell Cycle. 2014 Apr 16;13(12)<\/p>\n

Iskratsch T., Reijntjes S., Dwyer, J., Toselli P., Degano I.R.,Dominguez I<\/b>. and Ehler E.\u00a0\u00a0Two distinct phosphorylation events govern the function of muscle FHOD3.<\/a>\u00a0Cell Mol Life Sci.\u00a02013, 70(5):893-908<\/p>\n

Papanicolaou K.N., Kikuchi R., Ngoh G.A., Coughlan K.A.,Dominguez I.<\/b>, Stanley W.C., Walsh K.\u00a0\u00a0Mitofusins 1 and 2 are essential for postnatal metabolic remodeling in heart.<\/a>\u00a0Circ. Res. 2012; 111(8):1012-26<\/p>\n

Imbrie, G.A., Wu H., Seldin, D.C.\u00a0Dominguez, I<\/b>.\u00a0Asymmetric localization of CK2\u03b1 during\u00a0Xenopus<\/i>\u00a0oogenesis.<\/a>\u00a0Human Genet Embryol\u00a0\u00a02012; S4:001<\/p>\n

Dominguez I\u00a0<\/b>(Corresponding author<\/i>), Degano IR, Chea K, Toselli P, Seldin DC.\u00a0CK2\u03b1 is Essential for Embryonic Morphogenesis.<\/a>\u00a0Mol Cell Biochem. 2011 Oct; 356(1-2): 209-16<\/p>\n

Currier N., Chea K., Hlavacova M., Sussman D.J., Seldin D.C.Dominguez I<\/b>.\u00a0Dynamic expression of a LEF-EGFP Wnt reporter in mouse development and cancer.<\/a>\u00a0Genesis\u00a02010 Mar; 48(3): 183-94<\/p>\n

Wu H, Symes K, Seldin DC,\u00a0Dominguez I<\/b>.\u00a0Threonine 393 of \u03b2-catenin regulates interaction with Axin.<\/a>\u00a0J Cell Biochem.\u00a02009; Sep 1;108(1):52-63<\/p>\n

Seldin DC (Corresponding author<\/i>), Lou DY, Toselli P, Landesman-Bollag E,\u00a0Dominguez I<\/b>.\u00a0Gene targeting of CK2 catalytic subunits.<\/a>\u00a0Mol Cell Biochem. 2008; 316 (1-2):141-7<\/p>\n

Bryja V., Schambony A., \u010caj\u00e1nek L.,\u00a0Dominguez I<\/b>., Arenas, E. Schulte G.\u00a0\u03b2-arrestin and casein kinase 1\/2 define distinct branches of non-canonical WNT signaling pathways.<\/a>\u00a0EMBO Rep.2008; 9(12):1244-50<\/p>\n

Chitalia VC, Foy RL, Bachschmid MM, Zeng L, Panchenko MV, Zhou MI, Bharti A, Seldin DC, Lecker SH,\u00a0Dominguez I<\/b>, Cohen HT.\u00a0Jade-1 inhibits Wnt signaling by ubiquitinating\u00a0<\/a>\u03b2<\/a>-catenin\u00a0and mediates Wnt pathway inhibition by pVHL.\u00a0Nat Cell Biol.\u00a02008; 10(10):1208-16<\/p>\n

Lou DY,\u00a0Dominguez I<\/b>, Toselli P, Landesman-Bollag E, O’Brien C, Seldin DC.\u00a0The alpha catalytic subunit of protein kinase CK2 is required for normal embryonic development Mol.<\/a>\u00a0 2008; 28(1):131-9<\/p>\n

Seldin DC (Corresponding author<\/i>), Landesman-Bollag E, Farago M, Currier N, Lou D,\u00a0Dominguez I<\/b>.\u00a0CK2 as a positive regulator of Wnt signaling and tumorigenesis.<\/a>\u00a0Mol Cell Biochem.2005; 274(1-2):63-7<\/p>\n

Dominguez I\u00a0<\/b>(Corresponding author<\/i>), Mizuno J, Wu H, Imbrie GA, Symes K, Seldin DC.\u00a0A role for CK2\u03b1\/\u03b2 in\u00a0Xenopus<\/em>\u00a0early embryonic development<\/a>,\u00a0Mol Cell Biochem\u00a02005; 274(1-2):125-31<\/p>\n

Currier N, Solomon SE, Demicco EG, Chang DL, Farago M, Ying H,\u00a0Dominguez I<\/b>, Sonenshein GE, Cardiff RD, Xiao ZX, Sherr DH, Seldin DC. \u00a0\u00a0Oncogenic signaling pathways activated in DMBA-induced mouse mammary tumors<\/a>\u00a0Toxicologic Pathology2005; 33(6):726-37<\/p>\n

Farago M,\u00a0Dominguez I<\/b>, Landesman-Bollag E, Xu X, Rosner A, Cardiff RD, Seldin DC.\u00a0Kinase inactive GSK3\u03b2\u00a0promotes Wnt signaling and mammary tumorigenesis.<\/a>\u00a0Cancer Research\u00a02005; 65(13):5792-801<\/p>\n

Green JB,\u00a0Dominguez I<\/b>, Davidson LA.\u00a0Self-organization of vertebrate mesoderm based on simple boundary conditions.<\/a>\u00a0Dev Dyn\u00a02004; 31(3):576-81<\/p>\n

Dominguez I\u00a0<\/b>(Corresponding author<\/i>), Mizuno J, Wu H, Song DH, Symes K, Seldin DC.\u00a0Protein kinase CK2 is required for dorsal axis formation in\u00a0Xenopus<\/i>\u00a0embryos.<\/a>\u00a0Dev Biol\u00a02004; 274(1):110-24<\/p>\n

Song DH,\u00a0Dominguez I<\/b>, Mizuno J, Kaut M, Mohr S”C, Seldin DC.\u00a0CK2 Phosphorylation of the armadillo repeat region of \u03b2-catenin potenciates Wnt signaling<\/a>\u00a0\u00a0J Biol Chem\u00a02003; 278(26):24018-25<\/p>\n

Dominguez I<\/b>, Green JB.\u00a0Dorsal downregulation of GSK3b\u00a0by a non-Wnt-like mechanism is an early molecular consequence of cortical rotation in early\u00a0Xenopus<\/i>\u00a0embryos.<\/a>\u00a0Development\u00a02000; 127(4): 861-8<\/p>\n

These results on Wnt\/\u03b2-catenin signaling in\u00a0Xenopus\u00a0<\/i>early development are included in the textbook \u201cAnalysis of Biological Development\u201d<\/i>\u00a0by Klaus Kalthoff, published by McGraw-Hill.<\/p>\n

Dominguez I\u00a0<\/b>(Co-first author<\/i>), Itoh K, Sokol SY.\u00a0Role of glycogen synthase kinase-3\u03b2 as a negative regulator of dorsoventral axis formation in\u00a0Xenopus<\/i>\u00a0embryos.<\/a>\u00a0Proc Natl Acad Sci USA\u00a01995; 92(18): 8498-502<\/p>\n

Mart\u00ednez-Gimeno C, D\u00edaz-Meco MT,\u00a0Dom\u00ednguez I<\/strong>, Moscat J.\u00a0Alterations in levels of different protein kinase C isotypes and their influence on behavior of squamous cell carcinoma of the oral cavity: epsilon PKC, a novel prognostic factor for relapse and survival.<\/a>\u00a0Head Neck. 1995; 17(6):516-25<\/p>\n

Sanz L, Berra E, Municio MM,\u00a0Dominguez I<\/b>, Lozano J, Johansen T, Moscat J, Diaz-Meco MT.\u00a0\u03b6\u00a0PKC plays a critical role during stromelysin promoter activation by platelet-derived growth factor through a novel palindromic element.<\/a>\u00a0J Biol Chem\u00a01994; 269(13):10044-9<\/p>\n

Lozano J, Berra E, Municio MM, Diaz-Meco MT,\u00a0Dominguez I<\/b>, Sanz L, Moscat J.\u00a0Protein kinase C \u03b6\u00a0isoform is critical for kappa \u03b2-dependent promoter activation by phingomyelinase.<\/a>\u00a0J Biol Chem\u00a01994; 269(30):19200-2<\/p>\n

Diaz-Meco MT,\u00a0Dominguez I\u00a0<\/b>(Co-first author<\/i>), Sanz L, Dent P, Lozano J, Municio MM, Berra E, Hay RT, Sturgill TW, Moscat J.\u00a0\u03b6\u00a0PKC\u00a0induces phosphorylation and inactivation of I kappa \u03b2-\u03b1\u00a0in vitro<\/i>.\u00a0<\/a>\u00a0\u00a0EMBO J\u00a01994; 13(12):2842-8<\/p>\n

Diaz-Meco MT, Berra E, Municio MM, Sanz L, Lozano J,Dominguez I<\/b>, Diaz-Golpe V, Lain de Lera MT, Alcam\u00ed J, Pay\u00e1 CV, Moscat J.\u00a0A dominant negative protein kinase C \u03b6\u00a0subspecies blocks NF-\u03ba\u00a0B\u00a0activation.<\/a>\u00a0Mol Cell Biol\u00a01993; 13(8):4770-5<\/p>\n

Arenzana-Seisdedos F, Fernandez B,\u00a0Dominguez I<\/b>, Jacqu\u00e9 JM, Thomas D, Diaz-Meco MT, Moscat J, Virelizier JL.\u00a0\u00a0Phosphatidylcholine hydrolysis activates NF-\u03baB and increases human immunodeficiency virus replication in human monocytes and T lymphocytes.<\/a>\u00a0J Virol\u00a01993; 67(11):6596-604<\/p>\n

Berra E, Diaz-Meco MT,\u00a0Dominguez I\u00a0<\/b>(Co-first author<\/i>), Municio MM, Sanz L, Lozano J, Chapkin RS, Moscat J.\u00a0Protein kinase C\u00a0\u03b6\u00a0 isoform is critical for mitogenic signal transduction.\u00a0<\/a>Cell\u00a01993; 74(3):555-63<\/p>\n

Dominguez I\u00a0<\/b>(Co-first author<\/i>), Sanz L, Arenzana-Seisdedos F, Diaz-Meco MT, Virelizier JL, Moscat J.\u00a0Inhibition of protein kinase C\u00a0\u03b6\u00a0subspecies blocks the activation of an NF-\u03ba B-like activity in\u00a0Xenopus laevis<\/i>\u00a0oocytes.\u00a0<\/a>Mol Cell Biol\u00a01993; 13(2):1290-5<\/p>\n

Dominguez I<\/b>, Diaz-Meco MT, Municio MM, Berra E, Garc\u00eda de Herreros A, Cornet ME, Sanz L, Moscat J.\u00a0Evidence for a role of protein kinase C \u03b6\u00a0subspecies in maturation of\u00a0Xenopus laevis<\/em>\u00a0oocytes.<\/a>\u00a0Mol Cell Biol\u00a01992; 12(9):3776-83<\/p>\n

Diaz-Meco MT,\u00a0Dominguez I\u00a0<\/b>(Co-first author<\/i>), Sanz L, Municio MM, Berra E, Cornet ME, Garcia de Herreros A, Johansen T, Moscat J.\u00a0Phospholipase C-mediated hydrolysis of phosphatidyl-choline is a target of transforming growth factor \u03b2\u00a01 inhibitory signals.<\/a>\u00a0Mol Cell Biol\u00a01992; 12(1):302-8<\/p>\n

Dominguez I<\/b>, Marshall MS, Gibbs JB, Garc\u00eda de Herreros A, Cornet ME, Graziani G, Diaz-Meco MT, Johansen T, McCormick F, Moscat J.\u00a0Role of GTPase activating protein in mitogenic signalling through phosphatidylcholine-hydrolysing phospholipase C.<\/a>\u00a0EMBO J\u00a01991; 10(11):3215-20<\/p>\n

Garc\u00eda de Herreros A,\u00a0Dominguez I<\/b>, Diaz-Meco MT, Graziani G, Cornett ME, Guddal PH, Johansen T, Moscat J.\u00a0Requirement of phospholipase C-catalyzed hydrolysis of phosphatidylcholine for maturation of\u00a0Xenopus\u00a0laevis<\/em>\u00a0oocytes in response to insulin and ras p21.<\/a>\u00a0J Biol Chem.\u00a01991; 266(11):6825-9<\/p>\n

 <\/p>\n

BOOK CHAPTERS:<\/strong><\/p>\n

Revuelta-Cervantes, J, Macias Alvarez, L.,\u00a0Dominguez I<\/b>. CK2 in embryonic development. The Wiley-IUBMB Series on Biochemistry and Molecular Biology: Protein Kinase CK2. Editor: Lorenzo Pinna. Wiley-Blackwell Publishing. John Wiley & Sons, Inc (2012)<\/p>\n

Ortega C, Prince-Wright L,\u00a0Dominguez I<\/b>. Role of CK2 in organ formation. Proceedings of the CK2-VII meeting. Editors Khalil Ahmed, Olaf Issinger and Ryszard Szyska (2014)<\/p>\n

Apfel J., Parikh J.R., Reischmann P., Ewing R.M., M\u00fcller O, Xia Y,\u00a0Dominguez I<\/b>. The Wnt signaling network in Cancer. Systems Biology of Cancer. Editor: Sam Thiagalingam. Cambridge University Press\u00a0(2015)<\/p>\n","protected":false},"excerpt":{"rendered":"

1. Study the cascade of intracellular events that leads to the activation of Wnt\/\u03b2-catenin signaling Since the Wnt pathway was first identified, a number of studies in many animal models and in vitro have delineated an intracellular pathway made of core components including receptors, positive regulators like Dvl, negative regulators Axin and Apc, and co-transcriptional […]<\/p>\n","protected":false},"author":8246,"featured_media":0,"parent":0,"menu_order":2,"comment_status":"closed","ping_status":"closed","template":"","meta":[],"_links":{"self":[{"href":"https:\/\/sites.bu.edu\/dominguezlab\/wp-json\/wp\/v2\/pages\/18"}],"collection":[{"href":"https:\/\/sites.bu.edu\/dominguezlab\/wp-json\/wp\/v2\/pages"}],"about":[{"href":"https:\/\/sites.bu.edu\/dominguezlab\/wp-json\/wp\/v2\/types\/page"}],"author":[{"embeddable":true,"href":"https:\/\/sites.bu.edu\/dominguezlab\/wp-json\/wp\/v2\/users\/8246"}],"replies":[{"embeddable":true,"href":"https:\/\/sites.bu.edu\/dominguezlab\/wp-json\/wp\/v2\/comments?post=18"}],"version-history":[{"count":22,"href":"https:\/\/sites.bu.edu\/dominguezlab\/wp-json\/wp\/v2\/pages\/18\/revisions"}],"predecessor-version":[{"id":409,"href":"https:\/\/sites.bu.edu\/dominguezlab\/wp-json\/wp\/v2\/pages\/18\/revisions\/409"}],"wp:attachment":[{"href":"https:\/\/sites.bu.edu\/dominguezlab\/wp-json\/wp\/v2\/media?parent=18"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}