Govindaswamy Chinnadurai, PhD
- Email: firstname.lastname@example.org
Saint Louis University (SLU)
One of our research interests center around deregulation of cell proliferation by viral oncoproteins leading to oncogenic transformation of differentiated epithelial cells and deregulation of apoptosis pathways. We use human adenovirus E1A and E1B genes to study these cellular processes. Our group discovered that the E1A oncoprotein possesses an oncogenesis restraining activity in addition to its well-known oncogenic function. This activity of E1A is mediated through interaction with three different cellular protein complexes – CtBP1/2, DYRK1A/1B/HAN11 and FOXK1/K2. The molecular pathways deregulated through these interactions are investigated using engineered E1A mutants that are individually deficient in interaction with different cellular protein complexes and cellular genomic approaches. Our research also established that one of the viral proteins, E1B-19K, functions as a viral homolog of cellular BCL-2 family anti-apoptosis proteins. We identified the founding member of the BH3-only family pro-apoptotic proteins, BIK, that is targeted by viral and cellular anti-apoptosis proteins. We are investigating how BIK signals cell death in response to different apoptotic stimuli through a second class of pro-apoptotic proteins, BAK and BAK.
The second area of our focus is the role of CtBP1 (C-terminal binding protein 1) in human development and disease. CtBP1) is the founding member of the CtBP family proteins (comprising of CtBP1 and CtBP2, and their splice forms). We discovered CtBP1 as a cellular protein that interacted with a specific motif (PLDLS) at the C-terminal region of adenovirus E1A. CtBP1 and CtBP2 genes play overlapping and unique transcriptional roles during development. The long splice forms (nuclear) of CtBP proteins function as transcriptional corepressors in association with sequence specific DNA-binding repressors as well as various chromatin modifying repression effector molecules. Recently it was reported by David Beck and Wendy Chung that in several patients who exhibited neurodevelopmental delays such as intellectual disability, ataxia, hypotonia and tooth enamel defects, the CtBP1 gene contained a recurrent de novo mutation R342W (CtBP1-L)/R331W (CtBP1-S). We (in collaboration with Drs. Beck and Chung) are developing cell and animal models to elucidate the mechanism by which the CtBP1 mutation leads to neurodevelopmental delays. These models will be valuable to accurately diagnose the disorder and to unravel the mechanism by which the mutant allele contributes to the neurodevelopmental disorder. Studies on cell and animal models may suggest valuable strategies to ameliorate the effects of the disorder which has devastating consequences for the young patients and their families.