Publications by authors named "Rince John"

8 Publications

  • Page 1 of 1

A Fresh Look at the Structure, Regulation, and Functions of Fodrin.

Mol Cell Biol 2020 08 14;40(17). Epub 2020 Aug 14.

Cancer Research Program-III, Rajiv Gandhi Centre for Biotechnology, University of Kerala, Thiruvananthapuram, India

Fodrin and its erythroid cell-specific isoform spectrin are actin-associated fibrous proteins that play crucial roles in the maintenance of structural integrity in mammalian cells, which is necessary for proper cell function. Normal cell morphology is altered in diseases such as various cancers and certain neuronal disorders. Fodrin and spectrin are two-chain (αβ) molecules that are encoded by paralogous genes and share many features but also demonstrate certain differences. Fodrin (in humans, typically a heterodimer of the products of the SPTAN1 and SPTBN1 genes) is expressed in nearly all cell types and is especially abundant in neuronal tissues, whereas spectrin (in humans, a heterodimer of the products of the SPTA1 and SPTB1 genes) is expressed almost exclusively in erythrocytes. To fulfill a role in such a variety of different cell types, it was anticipated that fodrin would need to be a more versatile scaffold than spectrin. Indeed, as summarized here, domains unique to fodrin and its regulation by Ca, calmodulin, and a variety of posttranslational modifications (PTMs) endow fodrin with additional specific functions. However, how fodrin structural variations and misregulated PTMs may contribute to the etiology of various cancers and neurodegenerative diseases needs to be further investigated.
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http://dx.doi.org/10.1128/MCB.00133-20DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7431051PMC
August 2020

α-Fodrin is required for the organization of functional microtubules during mitosis.

Cell Cycle 2019 Oct 27;18(20):2713-2726. Epub 2019 Aug 27.

Cancer Research Program-III, Rajiv Gandhi Centre for Biotechnology, University of Kerala , Thiruvananthapuram , India.

The cytoskeleton protein α-fodrin plays a major role in maintaining structural stability of membranes. It was also identified as part of the brain γ-tubulin ring complex, the major microtubule nucleator. Here, we investigated the requirement of α-fodrin for microtubule spindle assembly during mitotic progression. We found that α-fodrin depletion results in abnormal mitosis with uncongressed chromosomes, leading to prolonged activation of the spindle assembly checkpoint and a severe mitotic delay. Further, α-fodrin repression led to the formation of shortened spindles with unstable kinetochore-microtubule attachments. We also found that the mitotic kinesin CENP-E had reduced levels at kinetochores to likely account for the chromosome misalignment defects in α-fodrin-depleted cells. Importantly, we showed these cells to exhibit reduced levels of detyrosinated α-tubulin, which primarily drives CENP-E localization. Since proper microtubule dynamics and chromosome alignment are required for completion of normal mitosis, this study reveals an unforeseen role of α-fodrin in regulating mitotic progression. Future studies on these lines of observations should reveal important mechanistic insight for fodrin's involvement in cancer.
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http://dx.doi.org/10.1080/15384101.2019.1656476DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6773225PMC
October 2019

Binding of alpha-fodrin to gamma-tubulin accounts for its role in the inhibition of microtubule nucleation.

FEBS Lett 2019 06 17;593(11):1154-1165. Epub 2019 May 17.

Cancer Research Programme, Rajiv Gandhi Centre for Biotechnology, Trivandrum, India.

Non-erythroid spectrin or fodrin is present as part of the γ-tubulin ring complex (γ-TuRC) in brain tissue and brain derived cells. Here, we show that fodrin, which is otherwise known for providing structural support to the cell membrane, interacts directly with γ-tubulin within the γ-TuRC through a GRIP2-like motif. Turbidometric analysis of microtubule polymerization with nucleation-potent γ-TuRC isolated from HEK-293 cells that lack fodrin and the γ-TuRC from goat brain that contains fodrin shows inefficiency of the latter to promote nucleation. The involvement of fodrin was confirmed by the reduction in the microtubule polymerization efficiency of HEK-293 derived γ-TuRCs upon addition of purified brain fodrin. Thus, the interaction of fodrin with gamma-tubulin is responsible for its inhibitory effect on γ-tubulin mediated microtubule nucleation.
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http://dx.doi.org/10.1002/1873-3468.13425DOI Listing
June 2019

Cell cycle-dependent regulation of cytoglobin by Skp2.

FEBS Lett 2017 11 23;591(21):3507-3522. Epub 2017 Oct 23.

Department of Biochemistry, University of Delhi South Campus, New Delhi, India.

Cytoglobin (Cygb) is a cellular haemoprotein belonging to the globin family with ambiguous biological functions. Downregulation of Cygb in many cancers is indicative of its tumour-suppressive role. This is the first report showing the cell cycle regulation of Cygb, which was found to peak at G1 and rapidly decline in S phase. Importantly, Skp2-mediated degradation of Cygb was identified as the key mechanism for controlling its oscillating levels during the cell cycle. Moreover, overexpression of Cygb stimulates hypophosphorylation of Rb causing delayed cell cycle progression. Overall, the study reveals a novel mechanism for the regulated expression of Cygb and also assigns a new role to Cygb in cell cycle control.
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http://dx.doi.org/10.1002/1873-3468.12864DOI Listing
November 2017

Oncogenic Human Papillomavirus 16E7 modulates SUMOylation of FoxM1b.

Int J Biochem Cell Biol 2015 Jan 11;58:28-36. Epub 2014 Nov 11.

Department of Biochemistry, University of Delhi South Campus, Benito Juarez Road, New Delhi 110021, India. Electronic address:

The oncogenic transcription factor Forkhead box M1b (FoxM1b), a key regulator of cell cycle, is often overexpressed in many human cancers. Interestingly, posttranslational modifications are known to play important role in regulating the levels and activity of FoxM1b. The purpose of the present study was to characterize the SUMOylation of FoxM1b and identify the functional consequences including viral pathogenesis. Here, we report that FoxM1b interacts with SUMOylating enzymes Ubc9 and PIAS1 and acts as a substrate for SUMOylation. We also show that SUMOylation facilitates FoxM1b protein destabilization and nucleocytoplasmic shuttling. More importantly, we provide the first evidence for a role of E7 oncoprotein in high risk human papillomavirus (HPV) mediated upregulation of FoxM1b. The elevated expression of FoxM1 was determined to be posttranscriptional and was attributed to decreased SUMOylation of FoxM1b in the E7-expressing cells. Moreover, we demonstrate the involvement of SUMOylation in regulation of FoxM1 and present biochemical evidence that HPV16 E7 oncoprotein can modulate SUMOylation of FoxM1b by impairing its interaction with Ubc9. Together, these results provide a novel connection between SUMOylation of FoxM1b and HPV carcinogenesis. The findings may have important implications in the discovery of future anti-cancer therapeutics.
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http://dx.doi.org/10.1016/j.biocel.2014.11.002DOI Listing
January 2015

DNA damage induced activation of Cygb stabilizes p53 and mediates G1 arrest.

DNA Repair (Amst) 2014 Dec 27;24:107-112. Epub 2014 Sep 27.

Department of Biochemistry, University of Delhi South Campus, Benito Juarez Road, Dhaula Kuan, New Delhi 110021, India. Electronic address:

Cytoglobin (Cygb) is an emerging tumor suppressor gene silenced by promoter hypermethylation in many human tumors. So far, the precise molecular mechanism underlying its tumor suppressive function remains poorly understood. Here, we identified Cygb as a genotoxic stress-responsive hemoprotein upregulated upon sensing cellular DNA damage. Our studies demonstrated that Cygb physically associates with and stabilizes p53, a key cellular DNA damage signaling factor. We provide evidence that Cygb extends the half-life of p53 by blocking its ubiquitination and subsequent degradation. We show that, upon DNA damage, cells overexpressing Cygb displayed proliferation defect by rapid accumulation of p53 and its target gene p21, while Cygb knockdown cells failed to efficiently arrest in G1 phase in response to DNA insult. These results suggest a possible involvement of Cygb in mediating cellular response to DNA damage and thereby contributing in the maintenance of genomic integrity. Our study thus presents a novel insight into the mechanistic role of Cygb in tumor suppression.
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http://dx.doi.org/10.1016/j.dnarep.2014.09.003DOI Listing
December 2014

Cytoglobin in tumor hypoxia: novel insights into cancer suppression.

Tumour Biol 2014 Jul 10;35(7):6207-19. Epub 2014 May 10.

Department of Biochemistry, University of Delhi South Campus, Benito Juarez Marg, New Delhi, 110021, India.

Emerging new and intriguing roles of cytoglobin (Cygb) have attracted considerable attention of cancer researchers in recent years. Hypoxic upregulation of Cygb as well as its altered expression in various human cancers suggest another possible role of this newly discovered globin in tumor cell response under low oxygen tension. Since tumor hypoxia is strongly associated with malignant progression of disease and poor treatment response, it constitutes an area of paramount importance for rational design of cancer selective therapies. However, the mechanisms involved during this process are still elusive. This review outlines the current understanding of Cygb's involvement in tumor hypoxia and discusses its role in tumorigenesis. A better perception of Cygb in tumor hypoxia response is likely to open novel perspectives for future tumor therapy.
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http://dx.doi.org/10.1007/s13277-014-1992-zDOI Listing
July 2014

High-risk HPV16E6 stimulates hADA3 degradation by enhancing its SUMOylation.

Carcinogenesis 2014 Aug 2;35(8):1830-9. Epub 2014 May 2.

Department of Biochemistry, University of Delhi South Campus, New Delhi 110021, India

Despite significant research, our understanding of the molecular mechanisms of Human Papilloma Virus (HPV) induced cancers remains incomplete. Majority of invasive cervical cancers are caused by high-risk HPV 16 and 18. Two potent HPV oncoproteins, E6 and E7, promote human malignancies by disrupting the activities of key regulators of cell proliferation and apoptosis. Recent investigations have identified hADA3, a transcriptional coactivator protein as a target of high-risk HPV16E6. However, the mechanism of degradation of hADA3 by E6 and its contribution in HPV induced carcinogenesis is poorly understood. Here, we showed that E6-mediated proteolysis of hADA3 is responsible for maintaining low levels of hADA3 in HPV-positive cervical cancer cell lines. We demonstrate that HPV16E6 targets hADA3 for ubiquitin-mediated degradation via E6AP ubiquitin ligase. We also show that hADA3 undergoes accelerated SUMOylation in the presence of HPV16E6. Our data represent the first evidence that hADA3 is posttranslationally modified by SUMOylation, which makes it unstable and establishes a link between SUMOylation and E6-mediated ubiquitination of hADA3. Furthermore, depletion of Ubc9 prevented rapid degradation of hADA3 in E6 expressing cervical cancer cells and overexpression of hADA3 resulted in suppression of proliferation and migration abilities of SiHa cells. Overall, this study underscores the importance of posttranslational modifications in HPV16E6-mediated downregulation of hADA3 thereby unveiling a novel mechanism by which HPV induces oncogenesis.
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http://dx.doi.org/10.1093/carcin/bgu104DOI Listing
August 2014
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