Prof. Doron Ginsberg is an Associate Professor in the Mina Everard Goodman Faculty of Life Sciences.
Together with his research group, Ginsberg studies a family of transcription factors called E2F, which regulate many genes involved in cell proliferation.
They study the mechanisms by which the E2F family of transcription factors sensitizes cells to chemotherapeutic treatments, as well as the crosstalk between E2Fs and signal transduction pathways.
The team isolates and characterizes novel E2F-regulated genes that affect autophagy in order to elucidate their role in the regulation of autophagy. In addition, Ginsberg and his group aim to identify novel molecular links between E2F1 and the tumor suppressor p53.
Work in Ginsberg’s lab focuses on the molecular mechanism that mediates the effects of E2F on cell fate and intracellular signaling.
The E2F family of transcription factors plays a critical role in the control of cell proliferation by regulating the timely expression of many genes required for cell cycle progression. E2F activity is essential for cell proliferation and its inhibition leads to cessation of cell growth.
In normal cells, E2F is tightly regulated to prevent uncontrolled growth. In cancer cells, its regulation is often abrogated and most human tumors exhibit deregulated and hyperactive E2F, leading to uncontrolled cell proliferation. Transcriptional activation of cell-cycle-related genes is only one facet of E2F activity and one member of this family, E2F1, can also mediate apoptosis.
A recent study conducted by Ginsberg and his group showed that E2F1 could also induce autophagy. The complex autophagy pathway involves over 30 genes, and Ginsberg and his team are investigating the involvement of E2F in regulating the autophagy process.
In addition, their studies have shown that E2F1 can activate a number of major signal transduction pathways including the PI3K/AKT, MEK/ERK, and p38 MAPK pathways.
In another project, Ginsberg and his group, along with others, have demonstrated that cells containing hyperactive E2F are more sensitive to chemotherapy.
Practically, this implies that if E2F could be introduced into tumor cells, such cells could then be treated with lower levels of chemotherapy. Using bone tumor (osteocercoma) cells and lung carcinoma cells, the team showed that hyperactive E2F sensitizes to chemotherapy, and especially to a combination of the traditional chemotherapy drugs, doxorubicin and cisplatin.
The team is investigating the mechanisms underlying this sensitization, and is looking for particular genes that are activated by E2F and contribute to this increased sensitivity to chemotherapy.
While E2F is a transcription factor that switches on the transcription of genes that encode proteins, there are genes in the human genome that encode RNA that is not later translated to proteins. These general non-coding RNAs, which regulate the expression of other genes, are an additional focus of research in Ginsberg’s lab.
The team isolates such non-coding RNAs that are regulated by E2F, studies their functions, and investigates how they affect E2F-induced proliferations or apoptosis. Their main work is conducted on two major groups of RNA, micro RNA and LINC RNA.
E2F plays a critical role in almost all forms of human cancer. Ginsberg and his team aim to continue to elucidate the basic mechanisms by which E2F contributes to cell transformation and tumorigenicity.
In the future, applications of their work could facilitate the design of cancer-treating drugs that would specifically inactivate various E2F activities.