Regulation of normal and malignant cell growth. One of the key questions in modern biology is what governs the normal proliferation and life span of mammalian cells and what "goes wrong" in cancer cells. Unraveling these molecular events should lead to a better understanding of the malignant transformation process and to the rational development of novel cancer-therapy approaches. In our lab, we study the involvement of stress response circuits in the adaptation of cells to stress insults and in the growth of cancer cells. Three proteins which "cross-talk" with each other are currently being studied in our lab. The first protein is the intracellular tyrosine kinase Fer. This enzyme resides in both the cytoplasm and nucleus of cells and it supports the withstanding of cells in various stress cues such as oxidative stress and nutrient deprivation. We have recently discovered a previously unknown oncogenic form of Fer which is solely expressed in malignant cells. Specific knock-down of this oncogenic form led to the apoptotic death of the treated cancer cells. Thus, the oncogenic Fer is a novel target for cancer intervention. To translate these findings into the development of a new anti-cancer drug, we developed a yeast-based high-through screening assay which was implemented in a most advanced robotic system. This enabled the development of a highly potent and selective Fer inhibitor that induces apoptotic death in malignant but not in normal cells, and which paves the way for the development of a new anti-cancer drug.
The two other proteins involved in cellular responses to imposed stress regimes are TMF/ARA160 and TRNP. While TRNP supports the survival of cells under defined stress conditions, TMF/ARA160 dictates the onset of cellular death under extended stress insults. TRNP is a nuclear protein that associates with chromatin and is highly expressed in neuronal brain cells. RNA expression analysis using DNA chip arrays, revealed the suppression of pro-apoptotic genes by TRNP. Hence, TRNP is a transcription regulator that supports the survival of neuronal cells. The malfunctioning of TRNP may, therefore, contribute to the onset of neuronal cell death and consequent neurodegenerative diseases. We are currently examining the functioning of TRNP in mice models under normal and pathological conditions.
Finally, we are studying the role of TMF in modulating the response of mammalian cells to genotoxic and metabolic stress. TMF is a Golgi-associated protein. However, under stress conditions, TMF is translocated from the Golgi and is dispersed in the cytoplasm, where it directs key transcription regulators to degradation. This can be carried out by substrate ubiquitination and proteasomal degradation, or by lysosome-mediated degradation in an autophagy-dependent manner. Recently, we have characterized a key role of TMF in the acquired resistance of cancer cells to chemotherapeutic agents. Thus, TMF is a master regulator which modulates the response of cells to stress insults. We are currently devising molecular approaches for manipulating the TMF system and, thereby, restoring the sensitivity of cancer cells to chemotherapeutic treatments.