Ohio State Navbar

Sign In

Leone, Gustavo W., Ph.D.

Professor

Department of Cancer Biology and Genetics

Joint Appointments

Director, Solid Tumor Biology Program

Associate Director for Basic Research, Comprehensive Cancer Center

Klotz Chair in Cancer Research

Professor, Molecular Genetics

Contact Information:

Office:

592 Biomedical Research Tower
460 W 12th Ave
Columbus, OH 43210
Ph. (614) 688-4567
Fax: (614) 292-6356
E-Mail: gustavo.leone@osumc.edu

Research Interests:

My lab is currently studying the role of the Ras pathway in coordinating cell growth and cell death signals elicited by the E2F and Myc transcription programs.

Uncontrolled cell proliferation is the hallmark of cancer, and tumor cells have typically acquired damage to genes that directly regulate their cell cycles. Mounting evidence implicates the E2F transcription family as an important regulator of the cell cycle. It is now clear that the disruption of various components of the pathway controlling E2F accumulation, either the activation of positive acting components such as Ras, Myc, G1 cyclins and their kinase subunits (CDKs), or the inactivation of negative components such as Rb, p53 and the CDK inhibitors (INK4 genes), can lead to the loss of cell growth control underlying the development of various forms of human cancer.

Mammalian E2F is composed of a family of heterodimers encoded by six distinct genes. Our recent work has highlighted the roles of the E2F3 and E2F1 gene products as key regulators of cellular proliferation and apoptosis, respectively. The focus in my lab will be threefold:

First, using in vivo KO mouse models we will investigate the role of the E2F3 gene locus in the control of the cell cycle and cellular proliferation. The E2F3 locus encodes two distinct gene products, the E2F3a and E2F3b proteins. Particularly important is the observation that this novel E2F3b gene product is the predominant partner for the Rb tumor suppressor in non-proliferating cells. We will investigate the in vivo role of E2F3a in promoting cell cycle progression and the potential function of the novel E2F3b protein as a tumor suppressor.

Second, we will take advantage of a recombinant adenovirus expression system and of fibroblasts deficient for various cell cycle regulators in order to elucidate the mechanism by which E2F1 elicits an apoptotic signal. In addition we will employ fibroblasts deficient for E2F1, E2F2 and E2F3a/b in order to determine the relative contributions of these family members towards the E2F apoptotic program and to identify, using gene chip expression arrays, novel E2F targets important for executing the cell death program.

Finally, our lab is interested in determining how signal transduction pathways important for normal cellular proliferation may intersect and modulate E2F- and Myc-mediated apoptotic signals. In particular, our recent experiments have elucidated a Ras dependent pathway important for countering an E2F1- or Myc-mediated death signal, but the identity and regulation of the key activities important for coordinating these cell survival and cell death signals have yet to be determined.

Through these studies we will not only further our molecular understanding of the control of cell growth and apoptosis, but we hope to also achieve an understanding of how these two fundamental processes are coordinated during the cell cycle to regulate normal proliferation, the disruption of which often leads to the development of human cancers.

Education:

University of Calgary, Calgary, Canada 1988 B.S. Biochemistry
University of Calgary, Calgary, Canada 1994 Ph.D. Molecular Virology
Duke University Medical Center, Durham, N.C. 1998 Post-doc Genetics

Professional Experience:

1987-88 Undergraduate Research Assistant, Department of Microbiology and Infectious Diseases, University of Calgary
1988-94 Graduate Student, Department of Microbiology and Infectious Diseases, University of Calgary
1990-94 Graduate student assistant, University of Calgary, Project Lab (intensive laboratory training  for undergraduates in virology and molecular biology)
1994-98 Postdoctoral Fellow, Department of Genetics, Duke University Medical Center (HHMI), Durham, North Carolina. Role of E2F in Cell Cycle Control
1999-present Professor, Human Cancer Genetics Program, Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio.

Honors:

1989-94 Alberta Heritage Foundation for Medical Research Studentship
1994-97 Medical Research Council of Canada Fellowship and Alberta Heritage Foundation for Medical   Research Fellowship
1997-99 Medical Research Council of Canada Centennial Fellowship
1999 The Robert M. and Barbara R. Bell Basic Science of Cancer Award
1999-01 The 1999 V - Foundation Scholar Award
2001-2005 The PEW Scholar Award
2004-2009 Scholar, Leukemia and Lymphoma Society
2011 Outstanding Teaching Award, College of Medicine
2012 Klotz Chair in Cancer Research

Selected Publications:

Wu L., Timmers C., Maiti B., Saavedra H.I., Sang L., Chong G.T., Nuckolls F., Giangrande P., Wright F.A., Field S.J., Greenberg M.E., Orkin S., Nevins J.R., Robinson M.L. and Leone G. (2001). The E2F1-3 transcription factors are essential for cellular proliferation. Nature. 414:457-462.

Wu L., de Bruin A., Saavedra H.I., Trimboli A., Yang Y., Opavska J., Wilson P., Starovic M., Ostrowski M.C., Cross J.C., Weinstein M., Rosol T.J., Robinson M. L. and Leone G. (2003). Extraembryonic function of Rb is essential for embryonic development and viability. Nature. 421:942-942. (N&V; 421:903-1004.

Saavedra H.I., Maiti B., Timmers C., Altura R., Fukasawa K. and Leone G. (2003). Inactivation of E2F3 results in premature centriole separation and centrosome amplification. Cancer Cell. 3:333-346. (Cover).

de Bruin A., Wu L., Saavedra H.I., Wilson P., Yang Y., Weinstein M., Rosol T.J., Robinson M.L. and Leone G. (2003). Rb function in extraembryonic lineages is critical for the control of apoptosis in the central nervous system of Rb-deficient mice. Proc. Natl. Acad. Sci. USA.100:6546-6551.

Iavarone A., King E.R., Dai X., Leone G., Stanley E.R. and Lasorella A. (2004). Retinoblastoma promotes definitive erythropoiesis by repressing Id2 in fetal liver macrophages. Nature. 432:1040-1045.

Maiti B., Li J., de Bruin A., Gordon F., Timmers C, Opavsky R., Patil K., Tuttle J., Cleghorn W. and Leone G. (2005). Cloning and characterization of mouse E2F8, a novel mammalian E2F family member capable of blocking cellular proliferation. J. Biol. Chem. 280:18211-18220.

Timmers C., Opavsky R., Maiti B., Wu L., Wu J., Orringer D., Sharma N., Saavedra H.I. and Leone G. (2006). E2f1-3 control E2F-target expression and cellular proliferation via a p53-dependent negative feedback loop. Mol. Cell Biol. 27:65-78.

Wenzel P., Wu L., de Bruin A., Chong J-L., Chen, W-Y., Dureska G., Sites E., Pan T., Sharma A., Huang K., Ridgway R., Mosaliganti K., Sharp R., Machiraju R., Saltz J., Yamamoto H., Cross J., Robinson M. and Leone G. (2007). Rb is critical in a mammalian tissue stem cell population. Genes & Dev. 21:85-97.

Opavsky R., Wang S-H., Trikha P., Raval A., Huang Y., Wu Y-A., Rodriguez B., Keller B., Liyanarachi S., Wei G., Davuluri R., Weinstein M., Felsher D., Ostrowski M.C., Leone G.* and Plass C*. (2007). CpG island methylation in cancer is driven by the genetic configuration of tumor cells. PLoS Genetics. 3:1757-1769. *corresponding authors.

Opavsky R., Tsai S-Y., Guimond M., Arora A., Opavska J., Becknell B., Kauffman M., Walton N., Stephens J., Fernandez S., Muthusamy N., Felsher W., Porcu P., Caligiuri M. and Leone G. (2007). Specific tumor suppressor function for E2F2 in Myc-induced T cell lymphomagenesis. Proc. Natl. Acad. Sci.USA. 104:15400-15405.

Li J., Ran C., Li E., Gordon F., Comstock G., Siddiqui H., Cleghorn W., Chen H-Z., Kornacker K., Liu C-G., Pandit S., Khanizadeh M., Weinstein M., Leone G*. and de Bruin A. (2008). Synergistic function of E2F7and E2F8 is essential for cell survival and embryonic development. Dev. Cell.14:62-75. *corresponding author. PMCID:PMC22253677.

Tsai S-Y., Opavsky R., Sharma N., Wu L., Naidu S., Nolan E., Ferias-Arias E., Timmers C., Opavska J., de Bruin A., Chong J-L., Trikha P., Stromberg P., Rosol J.R. and Leone G. (2008). Mouse development with a single E2F activator. Nature. 454:1137-1141.

Trimboli A.J., Cantemir-Stone C.Z., Li F., Wallace J.A., Merchant A., Creasap N., Thompson J.C., Caserta E., Wang H., Chong J-L, Naidu S, Wei G, Sharma S.M., Stephens J.A., Fernandez S.A., Gurcan M.N., Weinstein M.B., Barsky S.H., Yee L., Rosol T.J., Stromberg P.C., Robinson M.L., Pepin F., Hallett M., Park M., Ostrowski M.C. and Leone G. (2009). Pten in stromal fibroblasts suppresses mammary epithelial tumors. Nature. 461:1084-1091. PMCID:PMC2767301.

Chen D., Pacal M., Wenzel P., Knoepfler P.S., Leone G. and Bremner R. (2009). Division and apoptosis in the absence of activating E2fs. Nature. 462:925-929. PMCID:PMC2813224.

Chong J-L., Wenzel P., Sáenz-Robles, M., Nair V., Ferrey A., Hagan, J., Gomez, Y.M., Sharma, N., Chen, H-Z., Ouseph M., Wang S-H., Trikha, P., Culp B., Mezache L., Winton D.J., Sansom O.J., Chen, D., Bremner, R., Cantalupo P.G., Robinson, M.L., Pipas J.M. and Leone G. (2009). A switch of E2F1-3 function from activators in progenitor cells to repressors in differentiating cells. Nature. 462:930-934. PMCID:PMC2806193.

Chen H-Z., Tsai S-Y. and Leone G. (2009). Emerging roles of E2Fs in cancer: an exit from cell cycle control. Nature Reviews Cancer. 11:785-797.

Wang H., Karikomi M., Naidu S., Rajmohan R., Caserta E., Chen H-Z., Rawahneh M., Moffitt J., Stephens J.A., Fernandez S.A., Weinstein M., Wang D., Sadee W., La Perle K., Stromberg P., Rosol T.J., Eng C., Ostrowski M.C. and Leone G. (2010) Allele-specific tumor spectrum in Pten knockin mice. Proc. Natl. Acad. Sci. USA. 107:5142-5147. PMCID:PMC2841921.

Trikha P., Sharma N., Opavsky R., Reyes R., Pena C., Ostrowski M.C., Roussel M.F. and Leone G. (2011). E2F1-3 are critical for myeloid development. J. Biol. Chem. 286:4783-4795. PMCID:PMC3039366.

Wenzel P., Chong J-L., Saenz-Robles M.T., Ferrey A., Hagan J.P., Gomez Y.M., Rajmohan R., Sharma N., Chen H-Z., Pipas J.M., Robinson M.L. and Leone G. (2011) Cell proliferation in the absence of E2F1-3. Dev. Biology. 351:35-45.

Ouseph M.M., Li J., Chen H-Z., Pécot T., Wenzel P., Thompson J.C., Comstock G., Chokshi V., Byrne M., Forde B., Chong J-L., Huang K., Machiraju R., de Bruin A. and Leone G. (2012). Atypical E2F Repressors and Activators Coordinate Placental Development. Dev Cell. 22:849-862.

Bronisz A., Godlewski J., Wallace J.A., Merchant A.S., Mathsyaraja H., Srinivasan R., Trimboli A.J., Li F., Yu L., Fernandez S.A., Cory S., Hallett M., Park M., Piper M.G., Marsh C.B., Yee L.D., Jimenez R.E., Nuovo G., Lawler S.E., Chiocca E.A., Leone G*. and Ostrowski M.C*. (2012). Nature Cell Biol. 14:159-167. *corresponding authors.

Chen H-Z., Ouseph M., Li J., Pécot T., Liu B., Chokshi V., Byrne M., Duran C., Comstock G., Martin C.K., Trikha P., Senapati S., Huang Y-W., Gandhi S., Wilson N., Thompson J.C., Raman S., Singh S., Leone M., Machiraju R., Huang K., Mo X., Fernandez S., Kalaszczynska I., Wolgemuth D.J., Sicinski P., Huang T., Jin V. and Leone G. Canonical and Atypical E2Fs Regulate the Mammalian Endocycle. Nature Cell Biology.