Biology subjects

Mohan, J.

Publications and source records attributed to Mohan, J..

5 recordsLinked to original sources

bioRxiv2025

Androgen receptor contributes to radioresistance through DNA repair and autophagy in AR-positive prostate cancer cells

Androgen receptor (AR) is a critical therapeutic target in prostate cancer (PCa), and androgen blockade is known to act synergistically with radiation therapy. However, the mechanisms through which AR modulates radiation response are not yet fully understood. In this study, we aimed to investigate the role of AR in mediating radioresistance in PCa. AR-positive LNCaP and castration-resistant C4-2 cells exhibited significantly higher radioresistance than AR-negative cells, as determined by apoptosis and cell viability assays. Following irradiation, most LNCaP cells were arrested in the G1 phase, accompanied by rapid p53 activation and p21 induction. Consistently, AR silencing significantly increased radiosensitivity and reduced DNA-PKcs expression and phosphorylation, suggesting that AR enhances DNA repair, likely through non-homologous end joining (NHEJ). At the cellular level, irradiation markedly induced macroautophagy in LNCaP and C4-2 cells, as evidenced by increased LC3B-II accumulation and autophagic vacuole formation, and the upregulation of 11 autophagy-related genes was identified by whole-transcriptomic analysis. To assess their functional relevance, we performed siRNA-mediated knockdown of selected autophagy-related genes and assessed cell viability and Annexin V/PI staining. Notably, BECN1 and LC3 knockdown significantly enhanced radiosensitivity, with BECN1 knockdown showing an effect comparable to that observed with AR silencing. These results suggest that radiation-induced autophagy promotes the survival of AR-positive prostate cancer cells. Moreover, immunohistochemical analysis of ex vivo-irradiated, patient-derived PCa tissues from patients with newly diagnosed high-Gleason score prostate cancer undergoing prostatectomy further demonstrated that radiation-induced autophagy supports the survival of high-grade AR-positive tumor cells. Collectively, our findings reveal that AR promotes radioresistance in PCa by enhancing both DNA repair and autophagy. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=138 SRC="FIGDIR/small/690226v1_ufig1.gif" ALT="Figure 1"> View larger version (45K): org.highwire.dtl.DTLVardef@3f713corg.highwire.dtl.DTLVardef@1233a11org.highwire.dtl.DTLVardef@1b94e5eorg.highwire.dtl.DTLVardef@c8338c_HPS_FORMAT_FIGEXP M_FIG C_FIG

cancer biology↗

bioRxiv2024

Cell Maps for Artificial Intelligence: AI-Ready Maps of Human Cell Architecture from Disease-Relevant Cell Lines

This article describes the Cell Maps for Artificial Intelligence (CM4AI) project and its goals, methods, standards, current datasets, software tools, status, and future directions. CM4AI is the Functional Genomics Data Generation Project in the U.S. National Institute of Healths (NIH) Bridge2AI program. Its overarching mission is to produce ethical, AI-ready datasets of cell architecture, inferred from multimodal data collected for human cell lines, to enable transformative biomedical AI research.

systems biology↗

bioRxiv2021

Membrane insertion of Cavin1 facilitates caveolae assembly

Caveolae are small plasma membrane invaginations, important for control of membrane tension, signaling cascades and lipid sorting. The caveolae coat protein Cavin1 is essential for shaping such high curvature membrane structures. Yet, a mechanistic understanding of how Cavin1 assembles at the membrane interface is lacking. Here, we used model membranes combined with biophysical dissection and computational modelling to show that Cavin1 inserts into membranes. We establish that initial PI(4,5)P2-dependent membrane adsorption of the trimeric helical region 1 (HR1) of Cavin1 mediates the subsequent partial separation and membrane insertion of the individual helices. Insertion kinetics of the HR1 is further enhanced by the presence of flanking negatively charged disordered regions, which was found important for the co-assembly of Cavin1 with Caveolin1 in living cells. We propose that this intricate mechanism potentiates membrane curvature generation and facilitates dynamic rounds of assembly and disassembly of Cavin1 at the membrane. Significance statementCaveolae are cholesterol enriched membrane invaginations coupled to severe muscle and lipid disorders. Their formation is dependent on assembly of the protein Cavin1 at the lipid membrane interface driving membrane curvature. In this work, we dissect the mechanism for how Cavin1 binds and inserts into membranes using a combination of biochemical and biophysical characterization as well as computational modelling. The proposed model for membrane assembly potentiates dynamic switching between shielded and exposed hydrophobic helices used for membrane insertion and clarifies how Cavin1 can drive membrane curvature and the formation of caveolae.

cell biology↗

bioRxiv2021

Resident Cardiac Macrophages Mediate Adaptive Myocardial Remodeling

Cardiac macrophages represent a heterogeneous cell population with distinct origins, dynamics, and functions. Recent studies have revealed that C-C Chemokine Receptor 2 positive (CCR2+) macrophages derived from infiltrating monocytes regulate myocardial inflammation and heart failure pathogenesis. Comparatively little is known about the functions of tissue resident (CCR2-) macrophages. Herein, we identify an essential role for CCR2- macrophages in the chronically failing heart. Depletion of CCR2- macrophages in mice with dilated cardiomyopathy accelerated mortality and impaired ventricular remodeling and coronary angiogenesis, adaptive changes necessary to maintain cardiac output in the setting of reduced cardiac contractility. Mechanistically, CCR2- macrophages interacted with neighboring cardiomyocytes via focal adhesion complexes and were activated in response to mechanical stretch through a transient receptor potential vanilloid 4 (TRPV4) dependent pathway that controlled growth factor expression. These findings establish a role for tissue resident macrophages in adaptive cardiac remodeling and introduce a new mechanism of cardiac macrophage activation.

immunology↗

bioRxiv2019

Does Long-Term Selection for Development Time Result in Canalization: A Test Using Drosophila melanogaster

Canalization denotes the robustness of a trait against genetic or environmental perturbation. Plasticity, in contrast indicates the environmental sensitivity of a trait. Stabilizing selection is thought to increase canalization of a trait, whereas directional selection is often thought to lead to decanalization. However, the relationship between selection, canalization and plasticity remains largely unclear. Experimental evolution is a powerful approach for addressing fundamental questions in evolution. Here, we ask whether long-term directional selection for reduced pre-adult development time in Drosophila melanogaster results in the evolution of increased canalization for development time, the trait under primary selection. We additionally investigate whether pre-adult survivorship, a trait only secondarily under selection in this experimental regime, also evolves to become canalized. We examine canalization both in terms of stability of population means and of within population variability across two environmental axes. We used four large outbred populations of D. melanogaster selected for rapid pre-adult development and early reproduction for 295 generations, and four corresponding ancestral control populations that were not under conscious selection for development time or early reproduction. The selected populations had evolved 25% reduction in both development time and pre-adult survivorship at the time of this study. We studied development time and pre-adult survivorship of the selected populations and controls across various combinations ofrearing temperature and larval density. Development time in the selected populations had become more canalized than controls with regard to density, but not temperature. Canalization of development time across density appears to have evolved due to evolutionary changes in the lifehistory and physiology of the selected populations. Pre-adult survivorship, only a secondary correlate of fitness in the selected populations, did not show any clear trend in terms of canalization with regard to either density or temperature, and, overall variation in the trait was greater compared to development time within and across environments. Whether long-term directional selection canalizes or not, therefore, appears to be dependent in a complex way on specific interactions of trait, selection regime and environmental factor in the context of the ecology and physiology of the popualtions under study.

evolutionary biology↗