Inappropriate control of apoptosis causes health problems such as cancer and degenerative diseases. Therefore, understanding the mechanism of apoptosis is necessary to develop technologies for treating these diseases. Bax is a key mediator of apoptosis. Upon receipt of stress signals, Bax translocates from the cytosol to mitochondria where it promotes the release of apoptogenic factors from this organelle. However, the molecular mechanism controlling Bax activation is not yet understood. We found that Ku70, a 70 kDa protein, binds and inhibits Bax in the cytosol of non-apoptotic cells. Furthermore, we found that apoptotic stresses dissociate Bax from Ku70 by enhancing Ku70 ubiquitinylation. Importantly, Ku70 suppresses a conformational change of Bax, which is an early step of Bax activation in the cytosol.
Aim1 : We hypothesize that formation of the Ku70-Bax complex prevents Bax activation by shielding the protein from activating factors such as BH3 (Bcl-2 homology domain 3)-only proteins.
Aim1 will investigate the molecular mechanisms of how Ku70 inhibits Bax activation.
Aim2 : Ku70 has long been known as a DNA repair factor in the nucleus. Therefore, our finding suggests the existence of a novel pathway for cross talk between signals involved in genomic maintenance (Ku70) and those controlling cellular life (Bax). We propose that genotoxic stress stimulates ubiquitin-dependent degradation of Ku70, thereby increasing the chance of Bax activation and apoptosis;
Aim2 will investigate this hypothesis.
Aim3 : Ku70 null mice show disease phenotypes such as (1) increased incidence of T-cell lymphoma, and (2) premature aging. We hypothesize that increased Bax activity due to the absence of Ku70 contributes to the pathogenesis of these diseases. To test our hypothesis, ku70-/-bax-/- mice will be generated and we will examine whether Bax deletion corrects the disease phenotypes of ku70-/- mice. Importantly, we have already succeeded in obtaining the first generation of ku70-/-bax-/- mice, supporting the feasibility of the proposed experiments. The proposed study will advance our understanding of how cells choose their fate of whether to survive or die. The outcome of this study will contribute to the development of new technologies to eliminate cancer cells as well as to protect cells from apoptosis- related degenerative diseases.

Public Health Relevance

The proposed research plan studies how the cell decides to survive or die when the cell has potentially oncogenic gene mutation. The outcome of this study will contribute the technology development to treat cancer and degenerative diseases.

National Institute of Health (NIH)
National Institute on Aging (NIA)
Research Project (R01)
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Cancer Molecular Pathobiology Study Section (CAMP)
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Finkelstein, David B
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Case Western Reserve University
Internal Medicine/Medicine
Schools of Medicine
United States
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