Cell death has been regarded as the consequence of an externally initiated event. However, with the concept of apoptosis as a normal linear continuation of the differentiation process and evidence showing that, similar to differentiation, apoptosis is a gene-regulated event, a new model of cell death is emerging. In this model, molecular mechanisms involved in the commitment of differentiate are also the initiating factor in apoptosis. While they are required for this commitment, these mechanisms may be dispensable in apoptosis itself. In human colonic epithelial cells, such a commitment may be linked to expression of bc12 or to mitochondrial (mt) activity. Regional localization of bc12 in normal colonic mucosa suggests that its down regulation may have a role in a differentiation pathway of colonic epithelial cells in vivo while over expression of bc12 has been shown to block apoptosis in may cell types. We have reported down-regulation coincident with differentiation pathway exists in colonic carcinoma cell lines which, similar to that induced by fatty acids, involves up-regulation of mt gene expression and commitment to subsequent apoptosis. The proposed studies will define relationships between mt function, bc12 expression, and differentiation and apoptosis in colonic epithelial cells induced with fatty acids, a metabolite of vitamin D3 or polar solvents. We will modulate bc12 levels and mt activities, and use alkaline phosphatase activity and non-random DNA fragmentation as markers of differentiation and apoptosis.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
First Independent Research Support & Transition (FIRST) Awards (R29)
Project #
5R29CA059932-05
Application #
2633852
Study Section
Chemical Pathology Study Section (CPA)
Program Officer
Spalholz, Barbara A
Project Start
1994-01-01
Project End
1999-12-31
Budget Start
1998-01-01
Budget End
1999-12-31
Support Year
5
Fiscal Year
1998
Total Cost
Indirect Cost
Name
Montefiore Medical Center (Bronx, NY)
Department
Type
DUNS #
City
New York
State
NY
Country
United States
Zip Code
10467