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Chien-an Andy Hu, PhD University of New Mexico ahu@salud.unm.edu Phone:(505) 272-8816 Personal Website |
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Title: Functions of Apolipoproteins in Cancer Apoptosis
Project Description:Many kinds of cancer cells possess defects in the pathways of apoptosis (programmed cell death). Members of the Bcl-2 family play pivotal roles in regulating apoptosis and possess at least one of four conserved protein sequences Bcl-2-Homology (BH)1 domains, designated, BH1, BH2, BH3, and BH4. The BH3 domain is the only one present in pro-apoptotic "BH3-only" molecules and plays an important role in protein-protein interactions and in apoptosis by regulating dimerization and multimerization of the Bcl-2 family members. To date, approximately 19 genes have been found to encode proteins that belong to the Bcl-2 family in humans, twelve of which are BH3-only pro-apoptotic proteins. We hypothesize that there are additional genes encoding BH3-only proteins in the human genome that interact with other members of the Bcl-2 family in regulating apoptosis in cancer. The goals of this study are to identify and characterize novel BH3-only proteins from the human proteome, and to delineate functions of two of those, apolipoprotein L1 and L6, in cancer cell death. We utilized the bioinformatic data-mining approach to identify novel BH3-containing proteins. One candidate gene, apolipoprotein L6 (ApoL6), was identified, cloned and functionally expressed in cancer models. We showed that transient expression of ApoL6 promoted apoptosis in p53-null HCT116 cells. Furthermore, by constructing and characterizing an inducible ApoL6 gene in another p53-null cancer model, DLD-1, we found that over expression of ApoL6 intracellularly induced a mitochondria-mediated apoptosis in DLD-1 cells. Finally, we found that another member of the apolipoprotein L family, namely, ApoL1, may also possess BH3 domain and, therefore, possess pro-apoptotic activity.
Specific Aims:
AIM 1:
To identify novel BH3-only and BH3-containing
proteins.
AIM 2:
To investigate functions of ApoL1 and ApoL6 in
cancer apoptosis.
AIM 3:
To delineate roles of ApoL1 and ApoL6 in normal
and disease
states.
AIM 4:
To investigate if gene expression of ApoL1 and
ApoL6 is altered in gender-specific cancers.
