Dessislava Dimova
 Assistant Professor

The E2F/RB pathway - Study of transcriptional regulatory networks through genomics

We are interested transcriptional regulatory networks that govern cell division and differentiation and the molecular mechanisms behind such regulation. Specifically our studies have focused on the E2F/RB pathway. which is frequently deregulated in human tumors. The E2F and RB proteins are a family of transcription factors that are required for the expression of many genes. with diverse functions: cell cycle progression. differentiation. programmed cell death. etc. In mammals the pathway consists of a large number of interrelated complexes comprised of members of at least 3 multi-gene families (E2F. DP. RB). The mechanisms behind the diverse biological activities and the precise functions of each individual network component are not well understood.

We study the E2F/RB pathway and other related pathways using Drosophila as a model organism. These pathways are very well conserved. yet simpler in flies. We have taken advantage of recent methods for genome-wide studies such DNA Microarray analysis of global transcriptional changes. RNA interference (RNAi) techniques for knock-downs in tissue culture cells and high-throughput screening techniques to study the pathway and its regulators in fly cells. Some of the questions we are studying:

1) What are the individual contributions of each pathway member and how are their different activities integrated. We know that individual components can have overlapping (redundant). opposing and unique functions. and we are trying to identify these functions.
2) What are the molecular mechanisms that control the diverse activities of the different pathway members. The best studied regulation of E2F/RB is by cyclin-dependent kinases (CDKs) during the cell cycle. We and others have identified cell cycle-independent functions of E2F/RB and the goal is to understand these functions and how they are regulated.
3) Understanding which activities/functions of the pathway are important and which context - developmental and in respect to tumor formation. The diverse and sometimes opposing activities of E2F and RB family members. and the fact that they have different modes of regulation. indicate that the biological responses of the pathway will vary in different settings.

Selected Publications

Williams. J.P.. Steward. T.. Li. B.. Mulloy R.. Wojtukiewicz. L.J.. Dimova D. and Classon M. (2006) The retinoblastoma protein is required for Ras-induced oncogenic transformation. Mol Cell Biol. 26(4):1170-82.

Dimova D.K. . Stevaux O. . Frolov M.V.. Moon N.-S.. and Dyson N. (2005) Retinoblastoma family 2 is required in vivo for the tissue-specific repression of dE2F2 target genes. Cell Cycle Sep 4(9):1272-80.

Dimova D.K. and Dyson N. (2005) The E2F Transcriptional Network - Old Acquaintances with New Faces. (Review) Oncogene 24:2810-2826.

Moon N.-S.. Frolov M.V.. Kwon E.J.. Di Stefano L.. Dimova D.K.. Morris E.J.. and Dyson N.J. (2005) Drosophila E2F1 has context-specific pro- and antiapoptotic properties during development. Dev Cell. Oct;9(4):463-75.

Frolov M.V.. Stevaux O.. Moon N.-S.. Dimova D.. Kwon E.-J.. Morris E.J.. and Dyson N.J. (2003) G1 cyclin-dependent kinases are insufficient to reverse dE2F2-mediated repression. Genes & Development 17:723-28.

Dimova D.K. . Stevaux O.. Frolov M.V. and Dyson N. (2003) Cell cycle dependent and cell cycle independent control of transcription by the Drosophila E2F/RB pathway. Genes & Development 17: 2308-20.

Stevaux O.. Dimova D.. Frolov M.V.. Taylor-Harding B.. Morris E.. and Dyson N. (2002) Distinct mechanisms of E2F regulation by Drosophila RBF1 and RBF2. EMBO J. 21:4927-37.

Frolov M.V.. Huen D.S.. Stevaux O.. Dimova D.. Balczarek-Strang K.. Elsdon M.. and Dyson N.J. (2001) Functional antagonism between E2F family members. Genes & Development 15:2146-60.