) The development of colonic carcinoma is associated with the mutation of a specific set of genes. One of these, DCC (Deleted in Colorectal Cancer), is a candidate tumor-suppressor gene, and encodes a transmembrane cell surface receptor belonging to the Ig superfamily. At least one ligand for DCC is netrin-1, a molecule involved in axon guidance. Loss of DCC expression in tumors is not restricted to colon carcinoma, and although there is no increase in the frequency of tumor formation in DCC hemizygous mice, re-establishment of DCC expression suppresses tumorigenicity. However, the mechanism of action of DCC is unknown. We have recently shown that DCC induces apoptosis in the absence of ligand binding, but blocks apoptosis when engaged by netrin-1. These results indicate that DCC may function as a tumor-suppressor protein by inducing apoptosis in settings in which ligand is unavailable (for example, during metastasis or tumor growth beyond local blood supply). The effect of DCC is mediated through functional caspase cascades, which is typical for most apoptotic pathways. Furthermore, DCC is a caspase substrate, and mutation of the site at which caspase-3 cleaves DCC (Asp 1290) suppresses its pro-apoptotic effect. This indicates that proteolysis of DCC is required for its pro-apoptotic function, and that signals originating from ligand withdrawal must somehow drive this proteolysis. Additional preliminary evidence suggests that DCC triggers apoptosis through the intrinsic apoptotic pathway by activating caspase-9. We plan to explore the molecular mechanism of apoptosis triggered by DCC, working from the following general hypothesis. The cytosolic tail of DCC recruits and activates caspase-9, bypassing the mitochondrial components required for the activation of caspases by the intrinsic apoptotic pathway. We seek funding for this proposal within the scope of the expertise on basic apoptotic mechanisms within this Program Project.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Program Projects (P01)
Project #
3P01CA069381-06S1
Application #
6502427
Study Section
Subcommittee G - Education (NCI)
Project Start
2001-05-01
Project End
2002-04-30
Budget Start
1997-10-01
Budget End
1998-09-30
Support Year
6
Fiscal Year
2001
Total Cost
$168,360
Indirect Cost
Name
Sanford-Burnham Medical Research Institute
Department
Type
DUNS #
009214214
City
La Jolla
State
CA
Country
United States
Zip Code
92037
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