Gene knockout studies have recently established beclin 1 as a tumor suppressor gene. However, it is unclear how beclin 1 plays such a role in protection of malignancies. Results from our preliminary studies revealed a compromised p53 response in beclin 1- or hVps34-deficient breast epithelial cells. Of interest are the preliminary evidences that hVps34 binds to hdm2 and the expression of hdm2 is elevated in hVps34 deficient cells. Since beclin 1 and hVps34 are the major components of class III PI-3 kinase, we hypothesize that the tumor suppressor function of beclin 1 is mediated by the ability of beclin 1/class III PI-3 kinase to regulate the p53 response.
The aim of this study is to fully characterize the link between p53/hdm2 and beclin 1/class III PI-3 kinase. A multidisciplinary approach will be taken to identify pathways and mechanisms involved in beclin 1/class III PI-3 kinase control, and in turn clarify how they impact on the p53 response in the context of breast carcinogenesis.
Three aims are proposed: 1) To characterize the interaction between p53/hdm2 and beclin 1/class III PI-3 kinase. 2) To elucidate pathways involved in the class III PI-3 kinase-mediated p53 control. 3) To examine the role of beclin 1/class III PI-3 kinase-mediated regulation of p53 in vivo and in breast tumorigenesis. Through these lines of investigation, we are confident that we will be able to offer insights into the mechanisms of beclin 1-dependent tumor suppressor function. The functional interaction between beclin 1/class III PI-3 kinase and hdm2/p53 would not only represent a novel mechanism of p53 regulation but also shed some light on the observations that the expression of hdm2 is elevated in as many as 50% of human breast cancer where few p53 mutation is found and, beclin 1 is monoallelic deleted in 50% of breast cancer.

Public Health Relevance

The proposed study will enable us to able to offer insights into the mechanisms of beclin 1-dependent tumor suppressor function. The functional interaction between beclin 1/class III PI-3 kinase and hdm2/p53 would not only represent a novel mechanism of p53 regulation but also shed some light on the observations that the expression of hdm2 is elevated in as many as 50% of human breast cancer where few p53 mutation is found and, beclin 1 is monoallelic deleted in 50% of breast cancer.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
7R01CA125144-05
Application #
8305136
Study Section
Cancer Etiology Study Section (CE)
Program Officer
Salnikow, Konstantin
Project Start
2008-09-15
Project End
2014-07-31
Budget Start
2012-08-01
Budget End
2014-07-31
Support Year
5
Fiscal Year
2012
Total Cost
$325,059
Indirect Cost
$123,784
Name
Harvard University
Department
Genetics
Type
Schools of Public Health
DUNS #
149617367
City
Boston
State
MA
Country
United States
Zip Code
02115
Ganapathy, Suthakar; Xiao, Shaowen; Yang, Mei et al. (2014) A low-dose arsenic-induced p53 protein-mediated metabolic mechanism of radiotherapy protection. J Biol Chem 289:5340-7
Ganapathy, S; Xiao, S; Seo, S-J et al. (2014) Low-dose arsenic induces chemotherapy protection via p53/NF-*B-mediated metabolic regulation. Oncogene 33:1359-66
Su, H; Xu, T; Ganapathy, S et al. (2014) Elevated snoRNA biogenesis is essential in breast cancer. Oncogene 33:1348-58
Liu, Xue-Song; Haines, Jenna E; Mehanna, Elie K et al. (2014) ZBTB7A acts as a tumor suppressor through the transcriptional repression of glycolysis. Genes Dev 28:1917-28
Lall, R; Ganapathy, S; Yang, M et al. (2014) Low-dose radiation exposure induces a HIF-1-mediated adaptive and protective metabolic response. Cell Death Differ 21:836-44
Rico-Bautista, Elizabeth; Zhu, Wenhong; Kitada, Shinichi et al. (2013) Small molecule-induced mitochondrial disruption directs prostate cancer inhibition via UPR signaling. Oncotarget 4:1212-29
Huang, Lei; Yan, Zheng; Liao, Xiaodong et al. (2011) The p53 inhibitors MDM2/MDMX complex is required for control of p53 activity in vivo. Proc Natl Acad Sci U S A 108:12001-6
Xu, Teng; Su, Hang; Ganapathy, Suthakar et al. (2011) Modulation of autophagic activity by extracellular pH. Autophagy 7:1316-22