Apoptosis is a cell suicide process involved in various physiological and pathological activities, such as embryonic development, cancer and autoimmune diseases. Induction of apoptosis can be mediated through both caspase dependent and independent processes. The mechanisms of caspase-independent apoptosis have not been well understood. AIF is a mitochondrial flavoprotein that triggers caspase-independent apoptosis. We have cloned a novel AIF homologous molecule designated as AMID. AMID is localized to the outer membrane of mitochondria. Overexpression of AMID induces caspase-independent apoptosis. Moreover, AMID is induced by the tumor suppressor p53 and expression of AMID is down-regulated in tumors in comparison to their individually matched normal tissues. We hypothesize that AMID induces caspase-independent apoptosis through novel mechanisms and AMID is a tumor suppressor involved in p53-mediated downstream effects. To test our hypotheses, we have proposed three specific aims: 1). To investigate the mechanisms of AMID-induced caspase-independent apoptosis; 2). To investigate the roles of AMID in p53-mediated apoptosis and cell growth arrest; 3). To determine whether AMID is a tumor suppressor gene using in vitro cell culture systems and in vivo gene knock-out studies in mice. Successful completion of the proposed studies will help to understand the molecular mechanisms of caspase-independent apoptosis and roles of AMID in p53-mediated biological effects and tumorigenesis.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA108771-04
Application #
7227149
Study Section
Cell Development and Function Integrated Review Group (CDF)
Program Officer
Spalholz, Barbara A
Project Start
2004-07-14
Project End
2009-04-30
Budget Start
2007-05-01
Budget End
2008-04-30
Support Year
4
Fiscal Year
2007
Total Cost
$265,208
Indirect Cost
Name
National Jewish Health
Department
Type
DUNS #
076443019
City
Denver
State
CO
Country
United States
Zip Code
80206
Zhang, Bicheng; Huang, Jun; Li, Hong-Liang et al. (2008) GIDE is a mitochondrial E3 ubiquitin ligase that induces apoptosis and slows growth. Cell Res 18:900-10
Hildeman, David; Jorgensen, Trine; Kappler, John et al. (2007) Apoptosis and the homeostatic control of immune responses. Curr Opin Immunol 19:516-21
Mei, J; Webb, S; Zhang, B et al. (2006) The p53-inducible apoptotic protein AMID is not required for normal development and tumor suppression. Oncogene 25:849-56