Moshe Yaniv laboratory

Unit of Gene Expression and Diseases, Department of Developmental Biology, Pasteur Institute, Paris

Curriculum Vitae

Name and surname: Anna D’Angelo
Birthdate: January 20th, 1972
Birthplace: New Haven, CT. (U.S.A.)
Citizenship: Italian
Marital status: Unmarried
Home address: Via Torone, 26
cap. 81020 - Castel Morrone (Caserta), Italy.
Phone numbers: +39-0823-390072
+39-347-3088303
Work address: Unité « Expression génétique et Maladies »
Département de Biologie du Développement
Institut Pasteur
Site Fernbach
25, rue du Dr. Roux
75724 Paris cedex 15
France
Phone number : +33 1 45 68 85 14
Fax : +33 1 40 61 30 33

Academic Career

July 1991: High School Diploma at the “Liceo Scientifico Statale - A. Diaz", Caserta, Italy.
July 1997: University degree in Biological Sciences at “Federico II - University of Naples” with 110/110 cum laude.
November 1998: Passed State Examination at University of Naples “Federico II” to become a Qualified Biologist.
November 2004: award of the degree of Doctor of Philosophy of the Open University (UK) with the Telethon Institute of Genetics and Medicine (TIGEM) as sponsoring establishment.

Scientific Career

March 1996 - July 1997: Thesis in biological chemistry in the laboratory of Prof. Simonetta Bartolucci at the Department of Biological Chemistry of the University of Naples “Federico II". Title of the thesis: “Proteine extracellulari di Sulfolobus solfataricus: induzione, produzione, identificazione and caratterizzazione”.

September 1997 - September 1998: Postgraduate training in the laboratory of Prof. Simonetta Bartolucci at the Department of Biological Chemistry of the University of Naples “Federico II".

November 1998 – November 1999: winner of a CIB (Consorzio Italiano Biotecnologie) italian fellowship “Construction of shuttle extremophile/bacteria vectors for the expression of proteins adapted to cool and hot environments: extracellular proteins from Sulfolobus solfataricus” in the laboratory of Prof. Simonetta Bartolucci at the Department of Biological Chemistry of the University of Naples “Federico II".

January 2000 – January 2003: winner of an AIRC-FIRC, Mario & Valeria Rindi fellowship: “Functional characterization of the human homologue PRUNE protein: implication in Neuroblastoma” at TIGEM (Telethon Institute of Genetics and Medicine), Naples, Italy.

January 2003 to January 2005: winner of a two year fellowship “New prognostic markers in breast cancer” at TIGEM (Telethon Institute of Genetics and Medicine), Naples, Italy.

January 2005 to date: working at the Unité « Expression génétique et Maladies », Département de Biologie du Développement (Institut Pasteur, Paris) on “HNF1a and HNF1ß in the dynamic gut epithelium and AP1 expression”.

Supplemental information

Good knowledge of written and spoken English.

Good knowledge of Windows applications and of the “Internet based” systems for databases.

Publications

a) Cannio R., D'Angelo A., Rossi M. and Bartolucci S. A superoxide dismutase from the archaeon Sulfolobus solfataricus is an extracellular enzyme and prevents the deactivation by superoxide of cell-bound proteins. Eur J Biochem. 2000 Jan;267(1):235-43.

b) Forus A, D'Angelo A, Henriksen J, Merla G, Maelandsmo GM, Florenes VA, Olivieri S, Bjerkehagen B, Meza-Zepeda LA, del Vecchio Blanco F, Muller C, Sanvito F, Kononen J, Nesland JM, Fodstad O, Reymond A, Kallioniemi OP, Arrigoni G, Ballabio A, Myklebost O, Zollo M. Amplification and overexpression of PRUNE in human sarcomas and breast carcinomas-a possible mechanism for altering the nm23-H1 activity. Oncogene 2001 Oct 18;20(47):6881-90.

c) Larsen ZM, D’Angelo A, Cattaneo M, Nerup J, Biunno I, Zollo M, Pociot F. Complete mutation scanning of the human SEL 1L gene: a candidate gene for type 1 diabetes. Acta Diabetol. 2001 Dec;38(4):191-2.

d) Cattaneo M, Zollo M, Malferrari G, Orlandi R, D'Angelo A, Menard S, Biunno I. Allelic polymorphisms in the transcriptional regulatory region of human SEL1L. Mutat Res. 2001 Dec;458(3-4):71-6.

e) Garzia L, Andre A, Amoresano A, D'Angelo A, Martusciello R, Cirulli C, Tsurumi T, Marino G, Zollo M. Method to express and purify nm23-H2 protein from baculovirus-infected cells. Biotechniques 2003 Aug;35(2):384-8, 390-1.

f) D'Angelo A, Garzia L, Andre A, Carotenuto P, Aglio V, Guardiola O, Arrigoni G, Cossu A, Palmieri G, Aravind L, Zollo M Prune cAMP phosphodiesterase binds nm23-H1 and promotes cancer metastasis. Cancer Cell 2004 Feb;5(2):137-49

g) D’Angelo A. and Zollo M. Unraveling genes and pathways influenced by h-prune PDE overexpression: a model to study cellular motility. Cell cycle June 2004, Volume 3, Issue 6.

h) Zollo M., André A., Cossu A., Sini MC., D'Angelo A., Marino N., Budroni M., Tanda F., Arrigoni G., and Palmieri G. Overexpression of h-prune in breast cancer is correlated with advanced disease status. Clin Cancer Res. 2005 Jan 1;11(1):199-205.

AP-1 Network Project

HNF1alpha, HNF1beta and AP1 in the dynamic gut epithelium.
One of the most fascinating model systems for studying processes of cell proliferation, differentiation, and migration is the gut epithelium. To date, it is known that several transcription factors regulate proliferation or differentiation into the intestine (Blache et al., 2004; Boudreau et al., 2002; Mann et al., 1999).
The gut epithelium also expresses Hepatocyte nuclear factor1 alpha (HNF1alpha), hepatocyte nuclear factor1 beta (HNF1beta) and activator protein-1 (AP-1).
HNF1alpha and HNF1beta are transcription factors that are coexpressed in polarized epithelia of liver, kidney, and digestive tract. The inactivation of the two HNF1 genes has revealed that they are involved in the control of cell proliferation and differentiation during organogenesis and development. HNF1alpha-deficient mice are born normally, but suffer from hepatic, pancreatic and renal functional defects (Pontoglio et al., 1996; Pontoglio et al., 1997; Pontoglio et al., 1998; Lee et al., 1998; Pontoglio et al., 2001). On the other hand, HNF1beta-deficient embryos die early, between 6.5 and 7.5 days post coitum (dpc) because of defective differentiation of extra-embryonic visceral endoderm (Barbacci et al., 1999; Coffinier et al., 1999). Liver-specific HNF1beta-deficient mice present a drastically reduced number of bile ducts and multilayered epithelial structures in the few residual large bile ducts (Coffinier et al., 2002). Mice with a renal-specific inactivation of the HNF1beta gene develop polycystic kidney disease (Gresh et al., 2004). To date, the animal models produced by inactivation of HNF1alpha or HNF1beta genes (using null or conditional knock-out strategies) strongly suggest an involvement of the two genes in proliferation and differentiation of specific cells during organogenesis and development. In addition, biallelic inactivation of HNF1alpha or HNF1beta in human is associated with hyperproliferation and cancer (Bluteau et al., 2002; Zucman-Rossi, 2004).

AP-1 plays a central role in the decision whether a given cell divides, stays alive or dies. AP-1 is composed of Jun family members (C-JUN, JUNB, and JUND) that can form either homo- or heterodimers among themselves or with the Fos family members (C-FOS, FOSB, FRA1, FRA2). The different AP-1 dimers exhibit rather similar DNA binding specificities but differ in their transactivation efficiencies (reviewed in Wagner, 2001). C-JUN and FRA-1 are target genes of the beta-catenin–T cell-factor lymphoid-enhancer factor (beta-catenin/TCF) complex which is the transcriptional component of the Wnt pathway, one of the most relevant in the physiology of gut epithelium (Mann et al., 1999). Interestingly, apoptosis triggered by butyric acid involves transcriptional stimulation of the Bax gene via activation of the JNK/AP1 pathway in colonic epithelial cells (Mandal et al., 2001). In addition, interleukin 2 (IL-2) had an anti-proliferative effect in a human colon adenocarcinoma line (HT-29 D4) and of an untransformed rat intestinal cell clone (IEC-6) in vitro. IL-2 enhances the expression of JUN and FOS (Taheri et al., 1993).

The aim of this proposed project is to study a potential cross-talk or hierarchic relation between HNF1alpha, HNF1beta and AP1 in the renewal and maintenance of the intestine architecture. To this end, we will analyze the gut phenotype of mice deficient for either HNF1alpha or HNF1beta. Since we cannot rule out a possible redundancy between the two proteins, we will also generate double mutants.
We have preliminary evidence that deletion of both HNF1alpha and HNF1beta in the gut epithelium lead to defective differentiation of enterocytes and/or to an increase in proliferation. By following nuclear localization of beta-catenin, we will analyze the Wnt pathway in the mouse models produced. Since C-JUN is a target gene of the beta-catenin/TCF complex, we will analyze the specific expression of C-JUN, both at mRNA and protein level, in the HNF1 mouse models produced.
We will also analyze the expression of other members of the AP1 family as well as follow the activation of the JNK and p38 pathways. If an increased level of AP1 proteins will be observed we will cross HNF1alpha- or HNF1beta-deficient mice with mice carrying floxed alleles for C-JUN or other AP1 family members. In this way, we will obtain data on the contribution of C-JUN (or other AP1 members) to the process of colon differentiation and/or hyperproliferation.

Barbacci, E., M. Reber, M. O. Ott, C. Breillat, F. Huetz, and S. Cereghini, 1999: Variant hepatocyte nuclear factor 1 is required for visceral endoderm specification. Development, 126, 4795-805.
Blache P, van de Wetering M, Duluc I, Domon C, Berta P, Freund JN, Clevers H, Jay P. 2004: SOX9 is an intestine crypt transcription factor, is regulated by the Wnt pathway, and represses the CDX2 and MUC2 genes. J Cell Biol. Jul 5;166(1):37-47.
Bluteau, O., E. Jeannot, P. Bioulac-Sage, J. M. Marques, J. F. Blanc, H. Bui, J. C. Beaudoin, D. Franco, C. Balabaud, P. Laurent-Puig, and J. Zucman-Rossi, 2002: Bi-allelic inactivation of TCF1 in hepatic adenomas. Nat Genet, 32, 312-5.
Boudreau F, Rings EH, van Wering HM, Kim RK, Swain GP, Krasinski SD, Moffett J, Grand RJ, Suh ER, Traber PG., 2002: Hepatocyte nuclear factor-1 alpha, GATA-4, and caudal related homeodomain protein Cdx2 interact functionally to modulate intestinal gene transcription. Implication for the developmental regulation of the sucrase-isomaltase gene. J Biol Chem. 2002 Aug 30;277(35):31909-17. Epub 2002 Jun 11.
Coffinier, C., J. Barra, C. Babinet, and M. Yaniv, 1999: Expression of the vHNF1/HNF1beta homeoprotein gene during mouse organogenesis. Mech Dev, 89, 211-3.
Coffinier, C., L. Gresh, L. Fiette, F. Tronche, G. Schutz, C. Babinet, M. Pontoglio, M. Yaniv, and J. Barra, 2002: Bile system morphogenesis defects and liver dysfunction upon targeted deletion of HNF1beta. Development, 129, 1829-38.
Gresh, L., E. Fischer, A. Reimann, M. Tanguy, S. Garbay, X. Shao, T. Hiesberger, L. Fiette, P. Igarashi, M. Yaniv, and M. Pontoglio, 2004: A transcriptional network in polycystic kidney disease. Embo J, 23, 1657-68.
Lee YH, Sauer B, Gonzalez FJ., 1998: Laron dwarfism and non-insulin-dependent diabetes mellitus in the Hnf-1alpha knockout mouse.
Mol Cell Biol., 18(5):3059-68.
Mandal M, Olson DJ, Sharma T, Vadlamudi RK, Kumar R. Butyric acid induces apoptosis by up-regulating Bax expression via stimulation of the c-Jun N-terminal kinase/activation protein-1 pathway in human colon cancer cells.
Gastroenterology. 2001 Jan;120(1):71-8.
Mann B, Gelos M, Siedow A, Hanski ML, Gratchev A, Ilyas M, Bodmer WF, Moyer MP, Riecken EO, Buhr HJ, Hanski C. 1999: Target genes of beta-catenin-T cell-factor/lymphoid-enhancer-factor signaling in human colorectal carcinomas.Proc Natl Acad Sci US A Feb 16;96(4):1603-8.
Pontoglio, M., D. M. Faust, A. Doyen, M. Yaniv, and M. C. Weiss, 1997: Hepatocyte nuclear factor 1alpha gene inactivation impairs chromatin remodeling and demethylation of the phenylalanine hydroxylase gene. Mol Cell Biol, 17, 4948-56.
Pontoglio, M., M. Pausa, A. Doyen, B. Viollet, M. Yaniv, and F. Tedesco, 2001: Hepatocyte nuclear factor 1alpha controls the expression of terminal complement genes. J Exp Med, 194, 1683-9.
Pontoglio, M., J. Barra, M. Hadchouel, A. Doyen, C. Kress, J. P. Bach, C. Babinet, and M. Yaniv, 1996: Hepatocyte nuclear factor 1 inactivation results in hepatic dysfunction, phenylketonuria, and renal Fanconi syndrome. Cell, 84, 575-85.
Pontoglio, M., S. Sreenan, M. Roe, W. Pugh, D. Ostrega, A. Doyen, A. J. Pick, A. Baldwin, G. Velho, P. Froguel, M. Levisetti, S. Bonner-Weir, G. I. Bell, M. Yaniv, and K. S. Polonsky, 1998: Defective insulin secretion in hepatocyte nuclear factor 1alpha-deficient mice. J Clin Invest, 101, 2215-22.
Taheri A, Lavagna C, Rampal P. 1993: Effect of interleukin 2 on the proliferation of two intestinal cell lines and on the expression of TGF-beta gene and JUN/FOS oncogenes.
Gastroenterol Clin Biol.;17(12):925-31. French.
Wagner, E.F., 2001. AP-1—Introductory remarks. Oncogene 20, pp. 2334–2335.
Zucman-Rossi J., 2004: Genetic alterations in hepatocellular adenomas: recent findings and new challenges. J Hepatol, 40(6),1036-9.