In cells infected with small DNA tumor viruses, the onset of apoptosis is triggered by the induction of unscheduled cellular DNA synthesis by viral early proteins. In cells infected with human adenoviruses (Adv), the proteins coded by the early region E1A play a central role in inducing apoptosis and the process is actively suppressed by E1B-19K which is a viral homolog of BCL-2. Studies on Adv- induced apoptosis have served as the model for apoptosis induced by other viral infections. Adv also serves as a valuable tool to dissect the normal and pathological functions of apoptosis regulators. During Adv-induced apoptosis, the BH3-only protein BIK functions as the apical effector. BIK-mediated apoptosis signaling results in the activation of multi-domain (BH1-3) pro-apoptotic members BAX and BAK. The present renewal application will focus on unraveling the functions of two E1B-19K target BH3-only molecules BIK and BNIP3, and the BH1-3 molecules BAK and BAX in virus-induced apoptosis and apoptotic injury in an animal model and in cancer development.
In Aim 1, we will investigate the mode of transcriptional activation of Bik through an E2F-1 dependent pathway, a novel post- transcriptional mode of activation of BIK by viral oncogenes that interact with pRB. The role of virus- induced apoptosis in Adv-induced apoptotic liver damage will be investigated in the Bik-null mouse model. We will also use an immunodeficient mouse model to evaluate anti-apoptosis therapeutics to inhibit virus-induced hepatic injury. We have postulated that viruses may exploit apoptosis for intercellular spread during late stages of viral infection. Our results suggest that BAX and BAK may have novel functions in viral egress and spread.
In Aim 2, we will use Adv to elucidate novel functions of BAX and BAK by which they promote or restrict viral spread. Clinical results and experimental evidence suggest that the E1B-19K target molecule BNIP3 plays a fundamental role in the development of solid tumors such as lung and breast carcinomas.
In Aim 3, we will investigate the role of BNIP3 in tumor development and progression using Bnip3 knockout mouse and a conditional p53-Rb1 KO lung cancer mouse model. In this Aim, we will also investigate the roles of BNIP3 in regulating Adv-induced autophagy and autophagic cell death. Our proposed studies on these critical cellular apoptosis regulators may provide important new insights on their role in virus-induced apoptosis, viral spread and pathogenesis. These results will have broad relevance to other virus and pathogen infections. The proposed studies on the E1B-19K target molecules BNIP3 and BIK may illuminate their roles in the development and progression of lung, breast and colon cancers and may suggest strategies to inhibit tumorigenesis and tumor progression.

Public Health Relevance

Our proposed studies on the critical cellular apoptosis regulators will illuminate their roles in virus-induced apoptosis, viral spread and apoptotic organ damage and these results will have broad relevance to other virus and pathogen infections and may provide insights to suppress their pathogenic activity. Our studies on the E1B-19K target molecule BNIP3 will reveal its role in the development and progression of lung cancer and may suggest strategies to inhibit tumorigenesis and tumor progression. Our studies will also illuminate the role of BNIP3 in virus-induced autophagy.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA033616-33
Application #
8657981
Study Section
Special Emphasis Panel (ZRG1-IDM-P (02))
Program Officer
Daschner, Phillip J
Project Start
1999-08-01
Project End
2016-04-30
Budget Start
2014-05-01
Budget End
2015-04-30
Support Year
33
Fiscal Year
2014
Total Cost
$279,371
Indirect Cost
$93,124
Name
Saint Louis University
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
050220722
City
Saint Louis
State
MO
Country
United States
Zip Code
63103
Vijayalingam, S; Kuppuswamy, M; Subramanian, T et al. (2014) Evaluation of apoptogenic adenovirus type 5 oncolytic vectors in a Syrian hamster head and neck cancer model. Cancer Gene Ther 21:228-37
Vijayalingam, S; Chinnadurai, G (2013) Adenovirus L-E1A activates transcription through mediator complex-dependent recruitment of the super elongation complex. J Virol 87:3425-34
Kuppuswamy, Mohan; Subramanian, T; Kostas-Polston, Elizabeth et al. (2013) Functional similarity between E6 proteins of cutaneous human papillomaviruses and the adenovirus E1A tumor-restraining module. J Virol 87:7781-6
Subramanian, T; Zhao, Ling-Jun; Chinnadurai, G (2013) Interaction of CtBP with adenovirus E1A suppresses immortalization of primary epithelial cells and enhances virus replication during productive infection. Virology 443:313-20
Chinnadurai, G (2011) Opposing oncogenic activities of small DNA tumor virus transforming proteins. Trends Microbiol 19:174-83
Komorek, Jessica; Kuppuswamy, Mohan; Subramanian, T et al. (2010) Adenovirus type 5 E1A and E6 proteins of low-risk cutaneous beta-human papillomaviruses suppress cell transformation through interaction with FOXK1/K2 transcription factors. J Virol 84:2719-31
Lomonosova, Elena; Ryerse, Jan; Chinnadurai, G (2009) BAX/BAK-independent mitoptosis during cell death induced by proteasome inhibition? Mol Cancer Res 7:1268-84
Zhao, Ling-Jun; Kuppuswamy, M; Vijayalingam, S et al. (2009) Interaction of ZEB and histone deacetylase with the PLDLS-binding cleft region of monomeric C-terminal binding protein 2. BMC Mol Biol 10:89
Vijayalingam, S; Subramanian, T; Ryerse, Jan et al. (2009) Down-regulation of multiple cell survival proteins in head and neck cancer cells by an apoptogenic mutant of adenovirus type 5. Virology 392:62-72
Chinnadurai, G; Vijayalingam, S; Rashmi, R (2008) BIK, the founding member of the BH3-only family proteins: mechanisms of cell death and role in cancer and pathogenic processes. Oncogene 27 Suppl 1:S20-9

Showing the most recent 10 out of 64 publications