| title: | Characterization of mechanisms of stress response and apoptosis. |
|---|---|
| reg no: | ETF6000 |
| project type: | Estonian Science Foundation research grant |
| subject: |
1.8. Molecular Biology 1.9. Genetics, Physiology and Microbiology 3.1. Basic Medicine |
| status: | accepted |
| institution: | Estonian Biocentre |
| head of project: | Tõnis Örd |
| duration: | 01.01.2004 - 31.12.2007 |
| description: | Conditions disrupting homeostasis initiate cellular mechanisms, which help to repair the damage and regain homeostatic state of the cell. The damage extending beyond a certain limit may initiate the process of apoptotic death (called also programmed or "physiological" cell death), which is necessary for the elimination of the damaged cell, reducing in this way its deleterious influence on the surrounding tissue and removing a potential source of danger to the whole organism. Inhibitors of transcription and translation block apoptosis triggered by a variety of insults (disruption of calcium homeostasis, hypoxia, trophic factor withdrawal, oxidative stress), suggesting that de novo RNA and protein synthesis may play an important role in the process of cell death. In order to identify genes induced in neuronal cells under oxidative stress and disturbed calcium homeostasis (thought to be associated with neuropathological states), we carried out differential cloning of genes upregulated in a murine neuronal cell-line in response to butionine sulfoximine (the inhibitor of glutathion synthesis) and in response to thapsigargin (the inhibitor of endoplasmic reticular Ca-ATPase). One of the genes isolated, which we refer as mNIPK, encodes a kinase-like protein residing predominantly in the nucleus. The examination of interactions between mNIPK and other proteins revealed that mNIPK binds to bZip transcription factor ATF4 and inhibits its trancriptional activity. A goal of the project is to study functions and properties of mNIPK (and its human homolog) and elucidate regulation of NIPK gene expression. ATF4 plays an important role in memory formation and in regulation of gene expression during various conditions of stress (amino acid deficiency, oxidative stress, disturbed calcium metabolism, endoplasmic reticulum stress), and it is essential for normal development of an organism (ATF4 is involved in lens formation and hematopoiesis). ATF4 has been implicated in activation of cytoprotective genes (like HO-1) as well as genes which sensitize cells to stress (like CHOP), and therefore, NIPK acting as a repressor of ATF4 may have connections to both anti- and proapoptotic pathways of the cell. In addition to mNIPK, we have identified three undescribed genes induced by oxydative stress or by an antiapoptotic factor, and characterization of these genes is also a goal of the project. |
| project group | ||||
|---|---|---|---|---|
| no | name | institution | position | |
| 1. | Olev Kahre | TÜ TI | spetsialist | |
| 2. | Daima Örd | TÜ MRI | doktorant; vanemlaborant | |
| 3. | Tõnis Örd | Estonian Biocentre | senior scientist | |