Oxidative Stress, Antioxidant Genes, Aging & Longevity
Aging has been described for multicellular and asymmetrically dividing organisms, but the mechanisms are poorly understood. We try to identify genes manuplation of which either extend or shorten cellular life span. We mostly concentrate on antioxidant genes and different aspects of mitochondrial functions. We have identified many genes that deletion of which shorten or extend replicative life span in yeast. We are trying the understand the molecular mechanisms behind life span alterations in these cells.Multidrug Resistance Mechanisms (Antifungal drugs, anticancer drugs and boric acid)
Drug resistance is a major challenge in treatment of infections and tumors. We are using the awesome power of yeast genetics to identify genes that are responsible for different antifungal and anticancer drugs.
The rapid progress in medicine lead an increase in both average life span and number of patients who need intensive care. The morbidity and mortality of systemic fungal infections have become a serious problem because of suppressed immunity due to chemotherapy or intentional use of suppressants after tissue/organ transplantations. The number of systemic antifungal drugs is not so many; even worse, many fungi have gained resistance to these drugs. Thus, the elucidation of antifungal drug resistance mechanisms will prevent the aggravation of this unfavorable situation; help using new drug combinations and developing new drugs. We use yeast as a model system to study the mechanisms of drug resistance developed for antifungals. Yeast is such a great organism for antifungal drug resistance studies because, it is a fungus and it has the broadest spectrum of molecular biology tools that can be applied to an organism. We mostly try to find genes that provide resistance to drugs that are used systemically in combatting invasive fungal infections in human. This project is in collobaration with Dr. Hana Sychrova (Check Academy of Sciences)
Similarly, certain cancer drugs are under investigation in our lab to identify the mechanisms how cells gain resistance to them.
We are also in the process of characterizing genetic mechanisms that underlie boron transport and toxicity in yeast. Boron is essential for plant growth and beneficial for animals. Its biological functions are not clear in animals; however it plays structural roles in plant cell wall. Excess amount of boron is toxic to organisms, but the mechanism of this toxicity is not known. Since boron toxicity affects all type of organisms, it is thought that mechanism of its toxicity is conserved between different species. Plants that are distributed in boron rich fields are affected the most from boron toxicity. Previously we have identified and characterized Atr1 as a boron eflaks pump which provides boron resistance to yeast cells, and its expression is controlled by the Gcn4 transcription factor. Further analyses showed that boron stress induces general amino acid control in yeast and activates Gcn2 kinase which phosphorylates translation initiation factor eIF2α and inhibits protein synthesis at the initiation stage. In addition, screening of yeast deletion collection mutants (4700 mutants) for boron resistance and sensitive phenotypes and proteomic approaches have identified over 30 genes that enrolled in boron stress paths. In spite of these investigations, there still exist many questions about boron toxicity in cells and we are currently investigating the signal trunsduction paths that regulate boron stress response.
Redox Regulation of Human p53 Tumor Suppressor Gene
p53 protein has a central importance in cell cycle control and cancer development. More than half of human solid tumors result from mutations in p53 gene. We are investigating oxidative stress-dependent deregulation of p53 to understand the etiology of oxidative stress dependent cancer development.We transferred both human p53 and a p21 diriven-Beta Gal reporter system into yeast cells to functionally characterize oxidative conditions that down regulate p53 activity.