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Quantitative Microtubule Fractionation Technique to Separate Stable Microtubules, Labile Microtubules, and Free Tubulin in Mouse Tissues
Published on: November 17, 2023
Modelling the microtubule: towards a better understanding of short-chain fatty acid molecular pharmacology
Josephine Kilner1, Bernard M Corfe, Stephen J Wilkinson
1Department of Chemical and Biological Engineering, ChELSI Institute, The University of Sheffield, Sheffield, UK.
Abstract:
Systems biology combines experimental data with computational modelling to describe complex biological mechanisms and pathways. Short-chain fatty acids (SCFAs-chemopreventive compounds produced in the colon lumen) impair microtubule (MT) function in colon cancer cells by altering the relative expression of β-tubulin isotypes. The β-tubulin isotype composition along MT fibres is believed to contribute to a "tubulin code" defining which microtubule-associated proteins (MAPs) and kinesins are recruited and the arrangement of tubulin post-transcriptional modifications (PTMs) along the fibre, which in turn dictate many critical cellular functions. SCFAs drive acetylation of many proteins by virtue of being histone deacetylase inhibitors (HDACi's). Known acetyl-proteins include transcription factors and cytoplasmic cytoskeletal keratins as well as histones. Disruption of the MT cytoskeleton is a prime target of many cancer therapies including anti-microtubule drugs (AMD). This review focuses on SCFAs as HDACi's and how they might affect tubulin dynamics, modifications and isotypes. It discusses the evolution of mechanistic models that have helped improve understanding of tubulin-MT structure and dynamics and how to develop these models, combined with those describing transcription and the cell cycle, could provide hypotheses for how SCFAs disrupt cytoskeletal function. The review demonstrates how systems biology could offer potentially novel ideas for therapies in the prevention and treatment of cancers through the continued development and elaboration of such models.
Insights
Short-chain fatty acids (SCFAs), acting as histone deacetylase inhibitors, disrupt microtubule (MT) function in colon cancer cells by altering tubulin isotypes. Systems biology models can reveal novel therapeutic strategies for cancer prevention and treatment.
Area of Science:
- Systems biology
- Cancer research
- Molecular biology
Background:
- Short-chain fatty acids (SCFAs) are chemopreventive compounds produced in the colon.
- SCFAs impair microtubule (MT) function in colon cancer cells by altering β-tubulin isotype expression.
- The "tubulin code" influences MT-associated proteins, kinesins, and post-transcriptional modifications (PTMs), affecting cellular functions.
Purpose of the Study:
- To review how SCFAs, as histone deacetylase inhibitors (HDACi's), affect tubulin dynamics, modifications, and isotypes.
- To explore the role of systems biology in understanding SCFA-mediated disruption of cytoskeletal function.
- To propose novel therapeutic strategies for cancer prevention and treatment.
Main Methods:
- Review of existing literature on SCFAs, tubulin, MT dynamics, and systems biology.
- Analysis of mechanistic models describing tubulin-MT structure and dynamics.
- Integration of models for transcription and cell cycle regulation.
Main Results:
- SCFAs, functioning as HDACi's, promote protein acetylation, including histones and cytoskeletal proteins.
- Alterations in β-tubulin isotype composition by SCFAs impact MT function and the "tubulin code".
- Disruption of the MT cytoskeleton is a key target for cancer therapies.
Conclusions:
- Systems biology approaches, integrating experimental data and computational models, are crucial for understanding SCFA effects on cytoskeletal function.
- Mechanistic models can generate hypotheses for how SCFAs disrupt cellular processes in colon cancer.
- Developing and elaborating these models offers potential for novel cancer therapies.
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