Browsing by Author "Pradeep Kumar Bhaskar"

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DLin52 is crucial for dE2F and dRBF mediated transcriptional regulation of pro-apoptotic gene hid
(Elsevier, 2014) Pradeep Kumar Bhaskar; Satya Surabhi; Bipin Kumar Tripathi; Ashim Mukherjee; Mousumi Mutsuddi
Drosophila lin52 (dlin52) is a member of Myb transcription regulator complex and it shows a dynamic pattern of expression in all Drosophila tissues. Myb complex functions to activate or repress transcription in a site-specific manner; however, the detailed mechanism is yet to be clearly understood. Members of the Drosophila melanogaster Myb-MuvB/dREAM complex have been known to regulate expression of a wide range of genes including those involved in regulating apoptosis. E2F and its corepressor RBF also belong to this complex and together they regulate expression of genes involved in cell cycle progression, apoptosis, differentiation, and development. In the present study, we examined whether the depletion of dlin52 in developing photoreceptor neurons results in enhanced apoptosis and disorganisation of the ommatidia. Strikingly, we found that dLin52 is essential for transcriptional repression of the pro-apoptotic gene, hid; decrease in dlin52 levels led to dramatic induction of hid and apoptosis in eye-antennal discs. Reduction of Rpd3 (HDAC1), another member of the dREAM complex, also led to marginal upregulation of Hid. In addition, we also demonstrated that an optimum level of dLin52 is needed for dE2F1/2 activity on the hid promoter. dlin52 cooperates with dRBF and dE2F1/2 for recruitment of repressor complex on the hid promoter. Preliminary data indicate that Rpd3/HDAC1 also contributes to hid repression. Based on the findings, we conclude that dLin52 functions as a co-factor and modulates activity of members of dMyb/dREAM complex at hid promoter, thus regulating apoptosis by repressing this pro-apoptotic gene in the developing Drosophila eye. © 2014 Elsevier B.V.
Dynamic pattern of expression of dlin52, a member of the Myb/MuvB complex, during Drosophila development
(2012) Pradeep Kumar Bhaskar; Ashim Mukherjee; Mousumi Mutsuddi
The DREAM (DP, RB, E2F and MuvB) complex is required in humans to arrest the expression of cell cycle genes during quiescence. One of its members LIN52 has been isolated from the repressor complex but little is known about its molecular function. It has been reported recently that the serine residue 28 of LIN52 is phosphorylated by DYRK1A, and point mutation of this residue or down regulation of DYRK1A (which phosphorylates LIN52) leads to disruption of DREAM complex assembly, which is needed for G 0 arrest. Function of all the members of the dMyb complex (homologue of DREAM complex) in Drosophila melanogaster is not well characterized. We have studied the Drosophila orthologue of LIN52, known as dlin52, which is strongly conserved across various taxa from worms to human. dlin52 is reported to be present in a large protein complex containing important transcriptional regulators of cell proliferation and cell death like dE2F1, dMyb and dRbf. We have examined the expression of dlin52 transcripts and protein during development. Strong nuclear expression of dlin52 is seen in larval eye-antennal discs, brain, fat body, wing discs and salivary glands. dlin52 is abundantly expressed in endoreplicated tissues like salivary glands, fat body, and certain regions of the gut, and the nurse cells from adult ovaries. dlin52 is also expressed in the larval optic lobe, as well as in the developing neurons of ventral ganglion, indicating that this gene has an important role to play in cell cycle regulation and neuronal development. Robust expression of dlin52 protein was observed in quiescent cells like that of the imaginal cells of larval salivary gland, while marginal expression was seen in the germarium of adult ovary. Study of the spatial and temporal pattern of expression of this gene will help in better understanding of the function of this protein during various developmental processes. © 2011 Elsevier B.V. All rights reserved.
Modeling of human parkinson’s disease in fly
(Springer Singapore, 2019) Souradip Chatterjee; Pradeep Kumar Bhaskar; Ashim Mukherjee; Mousumi Mutsuddi
Years of in-depth research have contributed substantially to the understanding of the pathophysiology of Parkinson’s diseases (PD). However, many crucial questions related to the etiology of the disease remain unanswered, which compelled the need for developing more realistic and genetically malleable model systems for modeling the precise neuropathology of the disease in vivo. Ever-expanding genetic toolkit and conservation of implicated signaling pathways and neurological properties have prompted the use of Drosophila melanogaster (fly) as an instrumental model. Humanized fly models have aided in gaining insight into different cellular disturbances (protein aggregation and misfolding), mitochondrial deficits, and oxidative stress toward causation of Parkinson’s disease. The transgenic and humanized Drosophila model provides a decisive platform to assess the pathogenic properties of rare variants and open a window to analyze the cellular processes and signaling pathways that have been disrupted, which is ultimately manifested by the death of dopaminergic neurons in the brain of Parkinson-affected subjects. Apart from gaining molecular insight, toxin-induced models of Drosophila recapitulate multiple symptoms of environmental toxin-induced PD. Environmental toxin-induced models of Drosophila have proven to be an efficient means to study gene-environment interactions, which elevate susceptibility for Parkinsonism. Employment of Drosophila to scrutinize gene-environment interactions has led to the screening of many genetic risk factors. Additionally, the rapid development of genome manipulation technologies have paced up the development of more realistic models, which can precisely replicate all pathological features of the disease. This should be worthwhile to elucidate uncharted genetic and environmental risk factors, which are responsible for the complex pathogenesis associated with Parkinson’s disease. The ease of genetic manipulations that mimic symptoms of PD in Drosophila makes it one of the most favorite model organisms for analyzing the underlying cause of PD, the second most prevalent neurological disorder after Alzheimer’s disease. © Springer Nature Singapore Pte Ltd. 2019.
MTHFR C677T predisposes to poag but not to PACG in a North Indian population: A case control study
(Public Library of Science, 2014) Shashank Gupta; Pradeep Kumar Bhaskar; Ritu Bhardwaj; Abhishek Chandra; Vidya Nair Chaudhry; Prashaant Chaudhry; Akhtar Ali; Ashim Mukherjee; Mousumi Mutsuddi
Hyperhomocysteinemia induced by the C677T genetic variant in MTHFR (methylenetetrahydrofolate reductase) has been implicated in neuronal cell death of retinal ganglion cells (RGC), which is a characteristic feature of glaucoma. However, association of MTHFR C677T with glaucoma has been controversial because of inconsistent results across association studies. Association between MTHFR C677T and glaucoma has not been reported in Indian population. Therefore, with a focus on neurodegenerative death of RGC in glaucoma, the current study aimed to investigate association of MTHFR C677T with Primary Open Angle Glaucoma (POAG) and Primary Angle Closure Glaucoma (PACG) in a North Indian population. A total of 404 participants (231 patients and 173 controls) were included in this study. Genotyping was performed by Polymerase Chain Reaction-Restriction Fragment Length Polymorphism. A few random samples were also tested by direct sequencing. Genotypic and allelic distributions of the POAG and PACG cohorts were compared to that of controls by chisquare test and odds ratios were reported with 95% confidence intervals. Genotypic and allelic distributions between POAG cases and controls were significantly different (p = 0.03 and p = 0.01 respectively). Unlike POAG, we did not find significant difference in the genotypic and allelic distributions of C677T between PACG cases and controls (p>0.05). We also observed a higher proportion of TT associated POAG in females than that in males. However, this is a preliminary indication of gender specific risk of C677T that needs to be replicated in a larger cohort of males and females. The present investigation on MTHFR C677T and glaucoma reveals that the TT genotype and T allele of this polymorphism are significant risk factors for POAG but not for PACG in North Indian population. Ours is the first report demonstrating association of MTHFR C677T with POAG but not PACG in individuals from North India. © 2014 Gupta et al.