Biology subjects

S, M.

Publications and source records attributed to S, M..

4 recordsLinked to original sources

bioRxiv2024

Co-lethality of LEU2 and BAP2 is carbon source dependent and is overcome by BUL1 deletion in Saccharomyces cerevisiae

In a leucine requiring Saccharomyces cerevisiae strain, deletion of BAP2, a high affinity leucine permease confers lethality in presence of fermentable sugars, but not other carbon sources. Deletion of BUL1, an adaptor overcomes this lethality. BUL1 deletion augments leucine import through accumulation of Bap3 and Bap2 in the plasma membrane and reduces their turnover. We suspect BUL1 as a cognate adaptor for ubiquitylation of these permeases.

genetics↗

bioRxiv2024

Ovarian cancer cells exhibit diverse migration strategies on stiff collagenous substrata

In homoeostasis, the shape of epithelial cells and their sessility, i.e. lack of movement are intricately linked together. Alterations in this relationship as a result of malignant transformation and variations, thereof by the mechanical microenvironments that cancer cells encounter as they migrate are as yet ill-understood. Here we explore the interdependency of such traits in two morphologically distinct but invasive ovarian cancer cell lines (OVCAR-3 and SK-OV-3) under mechanically variant contexts. To do so, we came up with a minimal metric toolkit consisting of velocity, local and global turning angles, persistence of migration, major axis dynamics, morphomigrational angle, and elongation dynamics, and rigorously measured their variation using a Shannon entropic distribution to map heterogeneity in behavior between, and across, trajectories of migration. Two stiffness conditions on polymerized Collagen I with Youngs moduli of 0.5 (soft) and 20 (stiff) kPa were chosen. Both the epithelioid OVCAR-3 and mesenchymal SK-OV-3 cells on soft substrata migrated slowly and in an undirected manner. On stiff substrata, SK-OV-3 showed a persistent directed motion with higher velocity. Surprisingly, OVCAR-3 cells on higher stiffness moved at a velocity higher than SK-OV-3 cells and showed a distinct angular motion. The polarity of SK-OV-3 cells on stiff substrata was well-correlated with their movement, whereas for OVCAR-3, we observed an unusual slip behavior, where the axes of cell shape and movement were poorly correlated. An examination of their deformability showed that OVCAR-3 and SKOV-3 on softer substrata were relatively rigid but showed greater shape variation (especially OVCAR-3) on stiffer substrata. Therefore, a rigorous quantification using the above metric toolkit reveals how an interplay between intrinsic deformability and the mechanical microenvironment on pathotypic matrix substrata allow distinct migratory dynamics of epithelioid and mesenchymal ovarian cancer cells.

cancer biology↗

bioRxiv2021

Invariant Differential Expression Analysis Reveals Mechanism of Cancer Resistance to Cell Cycle Inhibitors

Retinoblastoma (RB) is a good model to study drug resistance to cell-cycle inhibitors because it is driven by mutations in the core components of cell-cycle, i.e, Rb gene. However, there is limited gene expression dataset in RB which has major reproducibility issues. We have developed invariant differential expression analysis (iDEA) that improves the state of the art in differential expression analysis (DEA). iDEA uses strong Boolean implication relationships in a large diverse human dataset GSE119087 (n = 25,955) to filter the noisy differentially expressed genes (DEGs). iDEA was applied to RB datasets and a gene signature was computed that led to prediction and mechanism of drug sensitivity. The prediction was confirmed using drugs-sensitive/resistant RB cell-lines and mouse xenograft models using CDC25 inhibitor NSC663284. iDEA improved reproducibility of differential expression across diverse retina/RB cohorts and RB cell-lines with different drug sensitivity (Y79/Weri vs NCC). Pathway analysis revealed WNT/{beta}-catenin involved in distinguishing drug sensitivity to CDC25 inhibitor NSC663284. NSC663284 inhibited tumour cell proliferation in mouse xenograft model containing Y79 cells indicating novel therapeutic option in RB. Invariant differentially expressed genes (iDEGs) are robustly associated with outcome in diverse cancer datasets and supports for a fundamental mechanism of drug resistance.

systems biology↗

bioRxiv2020

Membrane localization of paralogous leucine permeases Bap2 and Bap3 is regulated by Bul1

Timeliness in expression and degradation of the nutrient permeases is crucial for any organism. In Saccharomyces cerevisiae, post translational regulation of nutrient permeases such as trafficking and turnover are poorly understood. We found that loss of a leucine permease BAP2, but not other permeases lead to severe growth retardation when the carbon source is glucose or galactose but not glycerol and lactate. Leucine prototrophy suppressed the retardation, showing BAP2 and LEU2 are synthetically lethal. We discovered that loss of BUL1, an arrestin involved in trafficking of diverse permeases suppressed this lethality. The suppression required another leucine permease, BAP3. Our results suggest that BUL1 downregulate permeases BAP2 and BAP3 present in plasma membrane through Rsp5 dependent endocytosis. We speculate that by regulating leucine import BUL1 regulates the activity of TORC1.

genetics↗