Rapid alterations of cell cycle control proteins in human T lymphocytes in microgravity
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RESEARCH
Open Access
Rapid alterations of cell cycle control proteins in human T lymphocytes in microgravity Cora S Thiel1,2†, Katrin Paulsen1†, Gesine Bradacs1,3†, Karolin Lust3,4, Svantje Tauber1, Claudia Dumrese1,5, Andre Hilliger6, Kathrin Schoppmann1,3, Josefine Biskup1, Nadine Gölz1, Chen Sang7, Urs Ziegler5, Karl-Heinrich Grote3, Frauke Zipp8, Fengyuan Zhuang7, Frank Engelmann6,9, Ruth Hemmersbach10, Augusto Cogoli11 and Oliver Ullrich1,3,12*
Abstract In our study we aimed to identify rapidly reacting gravity-responsive mechanisms in mammalian cells in order to understand if and how altered gravity is translated into a cellular response. In a combination of experiments using “functional weightlessness” provided by 2D-clinostats and real microgravity provided by several parabolic flight campaigns and compared to in-flight-1g-controls, we identified rapid gravity-responsive reactions inside the cell cycle regulatory machinery of human T lymphocytes. In response to 2D clinorotation, we detected an enhanced expression of p21 Waf1/Cip1 protein within minutes, less cdc25C protein expression and enhanced Ser147phosphorylation of cyclinB1 after CD3/CD28 stimulation. Additionally, during 2D clinorotation, Tyr-15phosphorylation occurred later and was shorter than in the 1 g controls. In CD3/CD28-stimulated primary human T cells, mRNA expression of the cell cycle arrest protein p21 increased 4.1-fold after 20s real microgravity in primary CD4+ T cells and 2.9-fold in Jurkat T cells, compared to 1 g in-flight controls after CD3/CD28 stimulation. The histone acetyltransferase (HAT) inhibitor curcumin was able to abrogate microgravity-induced p21 mRNA expression, whereas expression was enhanced by a histone deacetylase (HDAC) inhibitor. Therefore, we suppose that cell cycle progression in human T lymphocytes requires Earth gravity and that the disturbed expression of cell cycle regulatory proteins could contribute to the breakdown of the human immune system in space. Keywords: Adaptive immunity, spaceflight, signal transduction, gravisensitivity
Introduction Gravity has been a constant force throughout evolutionary history on Earth. Thus, it is one of the fundamental biological questions, if and how life on Earth requires and responds to gravity at the functional cellular and molecular level. In unicellular organisms, such as Paramecium and Loxodes, gravity can be perceived rapidly by gravireceptors, which are gravi-sensitive ion channels in the cell membrane or statocyst-like organelles [1]. In mammalian cells, rapid gravi-responsive elements are unknown. The sensitivity of human cells exposed to reduced gravity has already been suspected for cells of the * Correspondence: [email protected] † Contributed equally 1 Institute of Anatomy, Faculty of Medicine, University of Zurich, Winterthurerstrasse 190, 8057 Zurich, Switzerland Full list of author information is available at the end of the article
immune system since the first Apollo missions, where more than half of the astronauts suffered from bacterial
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