Many kinds of cancer cells possess defects in the pathways of apoptosis. Members of the Bcl-2 family of proteins play pivotal roles in regulating apoptosis and possess at least 1 of 4 conserved Bcl-2-Homology (BH) domains, designated, BH1, BH2, BH3, and BH4. The BH3 domain is the only one (1) present in pro-apoptotic """"""""BH3-only"""""""" molecules and plays important roles in protein-protein interactions and apoptosis by regulating dimerization and multimerization of the Bcl-2 family members. To date, approximately 21 human genes have been found that encode proteins belonging to the Bcl-2 family, 14 of which are BH3-only pro-apoptotic proteins. This shows that the BH3-only proteins are important and possess overlapping, complementary and/or specific roles in different types of cells in apoptosis. Therefore, the overall goals of this study are to identify and characterize novel BH3-only proteins from the human proteome and to delineate functions of the newly identified proteins in cancer cell death. We hypothesized that there are additional genes encoding BH3-only proteins in the human genome that interact with other members of the Bcl-2 family and/or other molecules in regulating apoptosis in cell type and/or signaling-specific manners. We further hypothesize that some of the newly identified BH3-only proteins possess additional (i.e., non-apoptogenic) functions in normal physiology. In the preliminary studies, we utilized the bioinformatic data-mining approach to identify 3 novel BH3-only proteins. The candidate genes, apolipoprotein L6 (ApoL6), ApoL.1 and BH3- Only Member B (BOMB), were cloned and functionally expressed in cancer models. By transient expression analysis, we showed that ApoL6, ApoL1 and BOMB promoted cell death 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 expression of ApoL6 induced a mitochondria-mediated apoptosis in DLD-1 cells. These hypotheses will be tested further with 5 specific aims. Deciphering functions of the novel BH3-only proteins and their interacting molecules should enhance our understanding, and potential utilization, of BH3-only proteins and lipid-mediated apoptosis in treatment of cancer.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA106644-04
Application #
7393738
Study Section
Cancer Genetics Study Section (CG)
Program Officer
Salnikow, Konstantin
Project Start
2005-05-16
Project End
2010-03-31
Budget Start
2008-04-01
Budget End
2009-03-31
Support Year
4
Fiscal Year
2008
Total Cost
$211,686
Indirect Cost
Name
University of New Mexico
Department
Biochemistry
Type
Schools of Medicine
DUNS #
868853094
City
Albuquerque
State
NM
Country
United States
Zip Code
87131
Wu, Zhenlong; Hu, Chien-An A; Wu, Guoyao et al. (2015) Intimacy and a deadly feud: the interplay of autophagy and apoptosis mediated by amino acids. Amino Acids 47:2089-99
Hu, Chien-An A; Wu, Zhenlong; Wang, Junjun (2015) Amino acids and autophagy: their crosstalk, interplay and interlock. Amino Acids 47:2035-6
Hu, Chien-An A; Klopfer, Edward I; Ray, Patricio E (2012) Human apolipoprotein L1 (ApoL1) in cancer and chronic kidney disease. FEBS Lett 586:947-55
Kaini, Ramesh R; Hu, Chien-An A (2012) Synergistic killing effect of chloroquine and androgen deprivation in LNCaP cells. Biochem Biophys Res Commun 425:150-6
Kaini, Ramesh R; Sillerud, Laurel O; Zhaorigetu, Siqin et al. (2012) Autophagy regulates lipolysis and cell survival through lipid droplet degradation in androgen-sensitive prostate cancer cells. Prostate 72:1412-22
Zhaorigetu, Siqin; Yang, Zhaoqing; Toma, Ian et al. (2011) Apolipoprotein L6, induced in atherosclerotic lesions, promotes apoptosis and blocks Beclin 1-dependent autophagy in atherosclerotic cells. J Biol Chem 286:27389-98
Hu, C-A A; Khalil, S; Zhaorigetu, S et al. (2008) Human Delta1-pyrroline-5-carboxylate synthase: function and regulation. Amino Acids 35:665-72
Hu, Chien-An A; Bart Williams, D; Zhaorigetu, Siqin et al. (2008) Functional genomics and SNP analysis of human genes encoding proline metabolic enzymes. Amino Acids 35:655-64
Hu, Chien-An A; Phang, James M; Valle, David (2008) Proline metabolism in health and disease. Preface. Amino Acids 35:651-2
Zhaorigetu, Siqin; Wan, Guanghua; Kaini, Ramesh et al. (2008) ApoL1, a BH3-only lipid-binding protein, induces autophagic cell death. Autophagy 4:1079-82

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