H2020Индивидуална стипендия2016–2018

MECHANOCHECK · ATR-mediated mechanotransduction and connections with the actin cytoskeleton

„Хоризонт 2020“ — Действия „Мария Склодовска-Кюри“

Период: 2016-04-01 → 2018-03-31
Финансиране от ЕС: 180 277 €
Участници: 1
Схема: MSCA-IF-EF-ST

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Накратко на български

Протеинът ATR регулира гъвкавостта на клетката и ядрото, като например при неговата липса клетките стават два пъти по-меки. Това помага да се разбере как клетките реагират на механичен стрес и защо дефектите в ATR затрудняват тяхното оцеляване при миграция.

Този кратък обзор е генериран от изкуствен интелект

Кратко обяснение, генерирано от езиков модел по текста на CORDIS. Оригиналът е по-долу.

Резултати накратко

ATR-mediated mechanotransduction and connections with the actin cytoskeleton

ATR is a protein kinase that controls DNA damage response (DDR), together with ATM, Chk1 and Chk2. DDR genes are often mutated in cancer cells and act as an anti-cancer barrier in response to oncogenic stimuli. ATR is essential and protects the integrity of replicating chromosomes, prevents fragile site expression and aberrant condensation events. While the tumour suppressive role of ATR in mediating the DNA damage response has been extensively studied, the recent findings from the Foiani’s laboratory that ATR controls chromatin association to the nuclear envelope and responds to mechanical stress by re-localizing at nuclear membranes, prompted us to propose a novel role for ATR in controlling cellular and nuclear plasticity. Using multidisciplinary techniques and experimental approaches, including AFM, micropattern and innovated cell stretching and cell compression device, we quantitatively studied how ATR acts on cellular and nuclear plasticity. We found that ATR functions control cell plasticity, which sense mechanical stress. Basically, ATR-defective cells become twice softer than normal cells. At spatio-temporal level, the mechano-response occurs primarily through the actin cytoskeleton, which forms the cellular mechanical system linking the extracellular microenvironment to the nucleus. We investigated the connection between ATR and actin and we surprisingly found out that ATR directly controls nuclear plasticity, which in turn controls cell plasticity, rather than play a role in actin organization and dynamics. ATR defective cells have compromised nuclear morphology and organization; these cells are highly susceptive to mechanical stress, and have a lower survive rate during interstitial migration. These results suggest that ATR could play an active role in influencing the metastatic process, thus implying that ATR may possess a tumorigenic function. This line of research contributes to open new directions in the ATR field and to link the control of cellular and nuclear plasticity with the capability of cells in interstitial migration. Thus it might lead to novel target for cancer metastasis and new cancer drug discovery.

Текст от CORDIS, на английски · Данни: CORDIS, © Европейски съюз

Цел на проекта

The ATR protein kinase controls the DNA damage response (DDR), with ATM, Chk1 and Chk2. DDR genes are often mutated in cancer cells and act as an anti-cancer barrier in response to oncogenic stimuli. ATR is essential and protects the integrity of replicating chromosomes, prevents fragile site expression and aberrant condensation events. The Foiani laboratory recently found that ATR associates with the nuclear envelope during S phase and prophase and in response to osmotic or mechanical stress. Moreover, ATR-defective cells exhibit aberrant chromatin condensation and nuclear envelope breakdown. These observations prompted us to suggest that the ATR-mediated mechanical response enables cells to cope with the mechanical stress induced by topological transitions through the modulation of nuclear plasticity and chromatin association to the nuclear envelope. However, the molecular mechanism and functional relevance of ATR-mediated mechanical response remain unclear. Mechanosensing occurs primarily through the actin cytoskeleton, which forms the cellular mechanical system linking the extracellular microenvironment to the nucleus. We aim at understanding the connections between the ATR-mediated mechanotransduction pathway and actin modulation in response to mechanical stress. Our working hypothesis is that ATR may be part of an integrated response to mechanical stress that has a more general role in controlling cell and nuclear plasticity through the modulation of actin cytoskeleton and nuclear events. To address these questions, we will employ and develop various multidisciplinary approaches including state-of-the-art Atomic Force Microscopy (AFM), micropatterned protein substrate, novel microfluidic device and accompanied with advanced molecular biology techniques in order to quantitatively and systematically explore the ATR mediated mechanotransduction.

Оригинален текст от CORDIS (на английски).

Участници

IFOM-ISTITUTO FONDAZIONE DI ONCOLOGIA MOLECOLARE ETS · MilanoКоординаторИталия