Govindaswamy Chinnadurai, Ph.D.
Professor of Molecular Virology
Molecular Microbiology and Immunology
Ph.D. in Molecular Biology, University of Texas, Dallas, 1974
Our current research projects center around two pioneering discoveries made in our laboratory. Our studies exploit adenovirus E1A and E1B genes to investigate functions of cellular genes that control oncogenesis and apoptosis.
Adenovirus E1A has been extensively studied as a model dominant viral oncogene. Studies
on E1A have been instrumental in the discovery of common mechanisms by which the oncogenes
of small DNA tumor viruses promote cell proliferation by subverting the cell cycle.
The oncogenic activities of E1A are controlled by the N-terminal half of E1A (exon
1) through interaction with three major cellular protein complexes such as the pRb
family proteins, p300/CBP transcriptional co-activators and p400 chromatin remodeling
complex (Figure 1). Studies from our laboratory led to the unexpected discovery that
the E1A C-terminal region (exon 2) negatively regulates cell transformation and oncogenesis.
Mutational dissection of the E1A C-terminal region and proteomic analysis of cellular
proteins associated with E1A C-terminal region have revealed that interaction of E1A
with three different cellular protein complexes – CtBP corepressor complex, DYRK1A/1B/HAN11
complex, FOXK1 and K2 transcription factors, contribute to suppression of oncogenic
transformation. We are undertaking genomic approaches to elucidate the molecular
pathways regulated by these cellular protein complexes and to determine the effect
of E1A on the manifestation of cellular processes regulated by various pathways.
We have demonstrated that one of the cellular protein complexes, FOXK1/K2 that is
targeted by E1A C-terminal region is also targeted by the E6 proteins of certain non-oncogenic
cutaneous human papillomaviruses. We are investigating the role of the oncogenesis
restraining activities controlled by E1A and E6 proteins on viral replication in the
respective host cells.
Figure 1. Schematic illustration of interaction of cellular proteins with HAdv5 E1A
proteins. The functional consequences of such protein interactions are indicated. The green
upward arrows indicate activation and the red downward arrows indicate suppression
of various cellular processes.
Figure 2. A. Domain structure of BIK protein. Three domains of human BIK and their homologies to BIK proteins from different animal species are shown. The α3 region (predicted) encompassing the BH3 domain is highly conserved. The C-terminal domain (aa121-135) that is required for maximal pro-apoptotic activity of hBIK is conserved only in mBIK. B. Domain structure of BNIP3. The BH3-like domain , the conserved domain, the trans-membrane domain (TM) and the Cys residues implicated in the stabilization of BNIP3 homodimers are indicated. The amino acid sequences of the TM domain and the sequence elements that mediate detergent-stable homodimerization are shown.
Our work on apoptosis regulation during adenovirus infection led to the discovery of the founding member (BIK) of a class of pro-apoptotic molecules known as ‘BH3-only’ proteins (Figure 2A). The BH3-only protein BIK plays an essential role in adenovirus-induced apoptosis and is targeted by the viral anti-apoptosis protein, E1B-19K to suppress virus-induced apoptosis. Adenovirus induced apoptosis signaling is transmitted through BIK to the multi-domain pro-apoptotic protein BAX. Our current research focuses on the molecular mechanisms of BIK ‘activation’ in virus-infected cells, selective BIK-dependent cell death signaling via BAX and the role of BIK on viral pathogenesis. We have also discovered certain unanticipated activities of the multi-domain pro-apoptotic molecule BAK in adenovirus infected cells. The specific role of BAK in adenovirus replication, viral egress and spread is being investigated. Our laboratory also discovered the BH3-only related molecule BNIP3 (Figure 2B). The BNIP3 subfamily proteins (BNIP3 and BNIP3L) are major effectors of mitochondrial autophagy and they also induce context-dependent apoptosis. These molecules are also targeted by the viral anti-apoptosis protein E1B-19K. We are investigating the role of BNIP3 and BNIP3L in virus-induced autophagy and modulation of their activities by E1B-19K. Paradoxically, BNIP3 which is highly expressed under hypoxic conditions promote the development of solid tumors. We are investigating the role of BNIP3 in tumorigenesis in mouse models.
Labs and Facilities
Select Recent Publications
- Chinnadurai G. Opposing oncogenic activities of small DNA tumor virus transforming
proteins. Trends Microbiol. 2011 Apr;19(4):174-83. Epub 2011 Feb 15. PubMed PMID:
21330137; PubMed Central PMCID: PMC3095844.
- Komorek J, Kuppuswamy M, Subramanian T, Vijayalingam S, Lomonosova E, Zhao LJ, Mymryk
JS, Schmitt K, Chinnadurai G. 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. 2010 Mar;84(6):2719-31. Epub 2010 Jan 6.
PubMed PMID: 20053746; PubMed Central PMCID: PMC2826030.
- Zhao LJ, Kuppuswamy M, Vijayalingam S, Chinnadurai G. Interaction of ZEB and histone
deacetylase with the PLDLS-binding cleft region of monomeric C-terminal binding protein
2. BMC Mol Biol. 2009 Sep 15;10:89. PubMed PMID: 19754958; PubMed Central PMCID: PMC2749851.
- Chinnadurai G, Vijayalingam S, Rashmi R. BIK, the founding member of the BH3-only
family proteins: mechanisms of cell death and role in cancer and pathogenic processes.
Oncogene. 2008 Dec;27 Suppl 1:S20-9. Review. PubMed PMID: 19641504; PubMed Central
- Lomonosova E, Chinnadurai G. BH3-only proteins in apoptosis and beyond: an overview. Oncogene. 2008 Dec;27 Suppl 1:S2-19. Review. PubMed PMID: 19641503; PubMed Central PMCID: PMC2928556.
- Chinnadurai G, Vijayalingam S, Gibson SB. BNIP3 subfamily BH3-only proteins: mitochondrial
stress sensors in normal and pathological functions. Oncogene. 2008 Dec;27 Suppl 1:S114-27.
Review. PubMed PMID: 19641497; PubMed Central PMCID: PMC2925272.
- Chinnadurai G. The transcriptional corepressor CtBP: a foe of multiple tumor suppressors.
Cancer Res. 2009 Feb 1;69(3):731-4. Epub 2009 Jan 20. Review. PubMed PMID: 19155295.
- Kuppuswamy M, Vijayalingam S, Zhao LJ, Zhou Y, Subramanian T, Ryerse J, Chinnadurai
G. Role of the PLDLS-binding cleft region of CtBP1 in recruitment of core and auxiliary
components of the corepressor complex. Mol Cell Biol. 2008 Jan;28(1):269-81. Epub
2007 Oct 29. PubMed PMID: 17967884; PubMed Central PMCID: PMC2223311.
- Subramanian T, Vijayalingam S, Lomonosova E, Zhao LJ, Chinnadurai G. Evidence for
involvement of BH3-only proapoptotic members in adenovirus-induced apoptosis. J Virol.
2007 Oct;81(19):10486-95. Epub 2007 Jul 25. PubMed PMID: 17652400; PubMed Central
- Chinnadurai G. Transcriptional regulation by C-terminal binding proteins. Int J Biochem Cell Biol. 2007;39(9):1593-607. Epub 2007 Feb 4. Review. PubMed PMID: 17336131.
- 5R01-CA084941-09, E1A-CtBP interactions in oncogenic transformations, 09/21/2007-07/31/2012.
- 2R01-CA033616-30, Apoptosis regulation by adenovirus and cellular genes, 07/01/2011-04/30/2016.