Gustavo Leone

Focus

The RB/E2F pathway in cellular differenitation and in cancer

Research interests

n tMy 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.

Leone Lab Members

Postdocs: Lizhao Wu, Harold I. Saavedra, Cynthia Timmers, Rene Opavsky
Anthony Trimboli (co-mentor with Mike Ostrowski), Alain de Bruin, Prashant Trikha

Graduate Students: Pamela Wilson, Wen-Yi Chen, Jing Li, Shih-Yin Tsai

Undergraduate Students: Oliver Glass, Leo Maymind, Gary Chou Kuang Ti  

Research Staff: Jana Opavska, Steven Geary

Publications

• Li J., Ran C., Li E., Gordon F., Siddiqui H., Cleghorn W., Chen H., Pandit S., Khanizadeh M., Weinstein M., Leone G*., and de Bruin A. 2007. Synergistic function of E2F7and E2F8 is essential for cell survival and embryonic development. Devel Cell. (in press). *corresponding author
• 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. 104:39, 15400-15405.
• McClellan K., Ruzhynsky V., Douda D., Vanderluit J., Ferguson K., Chen D., Bremner R., Park D., Leone G., and Slack R. 2007. Unique requirement for Rb/E2F3 in neuronal migration: evidence for cell cycle-independent functions. Mol Cell Biol 27:4825-43.
• Chen D., Opavsky R., Pacal M., Tanimoto N., Wenzel P., Seeliger M., Leone G., and Bremner R. 2007. R.Rb-mediated neuronal differentiation through cell cycle independent regulation of E2f3a. PLoS Biology 5 (in press).
• 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 (in press). *corresponding authors
• Trimboli A.J., Fukino K., de Bruin A., Wei G., Shen L., Tanner S.M., Rosol T.J., Eng C., Ostrowski M.C., and Leone G. 2007. In Vivo Visualization of Myc-induced Epithelial-Mesenchymal Transitions in Breast Cancer. Cancer Research (in press).
• Saenz-Robles M., Markovics J.A., Chong J-L., Opavsky R., Whitehead R.H., Leone G., Pipas J.M. 2007. Intestinal hyperplasia induced by SV40 large tumor antigen requires E2F2. J. Virology. (in press)
• Timmers C., Opavsky R., Maiti B., Wu L., Wu J., Orringer D., Sharma N., Saavedra HI., Leone G. 2007. E2f1-3 control E2F-target expression and cellular proliferation via a p53-dependent negative feedback loop. Mol Cell Biol. 27:65-78.
• Sharp R., Ridgway R., Mosaliganti K., Wenzel P., Pan T., de Bruin A., Machiraju R., Huang K., Leone G., Saltz J. 2007. Volume rendering phenotype differences in mouse placenta microscopy data. Comp. Sci and Eng. 9:38-47.
• 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., Leone, G. 2007 Rb is critical in a mammalian tissue stem cell population. Genes & Development 21:85-97.
• Wenzel, P., Leone, G. 2007. Expression of Cre recombinase in early diploid trophoblast cells of the mouse placenta. Genesis 45:129-134.
• Mosaliganti K, Janoos F, Sharp R, Ridgway R, Machiraju R, Huang K, Wenzel P, deBruin A, Leone G, Saltz J. 2007. Detection and visualization of surface-pockets to enable phenotyping studies. IEEE Trans. Medical Imaging 26:1283-1290.
• Janoos F, Irfanoglu O, Mosaliganti K, Machiraju R, Huang K, Wenzel P, de Bruin A, Leone G. 2007. Multiple-resolution image segmentation using the 2-point correlation functions. Proc. IEEE Internat. Symp. Medical Imaging.
• Dorrance, A, Liu, S., Yuan, W., Becknell, B., Arnoczky, K., Guimond, M., Strout, M., Feng, L., Nakamura, T., Yu, L., Rush, L., Weinstein, M., Leone, G., Wu, L., Ferketich, A., Whitman, S., Marcucci, G., and Caligiuri, M., 2006. The Mll partial tandem duplication induces aberrant Hox expression in vivo via specific epigenetic alterations. J. Clin. Invest. 116:2707-16.
• Mosaliganti R, Pan T, Sharp R, Ridgway R, Iyengar S, Gulacy A, Wenzel P, de Bruin A, Machiraju R, Huang K, Leone G, Saltz J. 2006. Registration and 3D visualization of large microscopy images, Proc. SPIE Ann. Med. Ima. Meet. 923-34.
• Sharp R, Ridgway R, Mosalignati K, Irfanoglu O, Wenzel P, Machiraju R, Pan T, de Bruin A, Machuraju R, Leone G, Huang K, Saltz J. 2006. Examining Phenotype Differences in Mouse Placenta with Volume Rendering and Segmentation. Proc. IEEE/NLM Life Sc. Syst. & Appl. 70-71.
• Sharma, N., Timmers, C., Trikkha, P., Saavedra, H., Obery, A., and Leone, G. 2006. Control of the p53-p21CIP1 axis by E2f1, E2f2 and E2f3 is essential for G1/S progression and cellular transformation. J. Biol. Chem. 281:36124-31
• Sharp, R., Ridgway, R., Mosaliganti, K., Wenzel, P., Pan, T., deBruin, A., Machiraju, R., Huang, K., Leone, G., and Saltz, J. 2007. Volume rendering phenotype differences in mouse placenta microscopy data. Comp. Sci. and Eng. 9:38-47.