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Cell and Extracellular Matrix Interactions in a Dynamic Biomechanical Environment:
Published in Michel R. Labrosse, Cardiovascular Mechanics, 2018
Mechanical forces, both intracellular and extracellular, play crucial roles in focal adhesion maturation. The application of internal or external force on initial adhesions stimulates their transition to focal complexes by recruiting vinculin to stabilize and strengthen the adhesion (Galbraith et al. 2002). Similarly, force generation induces the development of focal complexes into focal adhesions by activating Rho (Riveline et al. 2001). In focal adhesions, Rho regulates cellular contractility through two main mechanisms, which are mediated by two different integrin classes (Schiller et al. 2013). Engagement of αv-class integrins activates Rho and acts through mDia to promote actin stress fiber formation (Schiller et al. 2013). Actin stress fibers not only serve to provide a substrate for myosin to pull on but also serve to cluster integrins together to aid focal adhesion formation (Chrzanowska-Wodnicka and Burridge 1996). In contrast, engagement of α5β1 integrins activates Rho and acts through Rho kinase (ROCK) to stimulate myosin II and force generation (Schiller et al. 2013). Cellular contractility is critical to focal adhesion formation, as inhibiting contractility leads to stress fiber and focal adhesion disassembly (Chrzanowska-Wodnicka and Burridge 1996).
AGE-RAGE Axis in the Aging and Diabetic Heart
Published in Sara C. Zapico, Mechanisms Linking Aging, Diseases and Biological Age Estimation, 2017
Karen M. O’Shea, Ann Marie Schmidt, Ravichandran Ramasamy
The precise consequences of RAGE signaling vary based on cell type, as well as duration of RAGE stimulation. RAGE transduces extracellular signals through ligand binding to its 332-amino acid extracellular component, consisting of 2 “C”-type domains preceded by 1 “V”-type immunoglobulin-like domain (Yan et al. 2003). RAGE also contains a transmembrane domain and a highly charged 43-amino acid cytosolic tail, which is responsible for mediating intracellular signaling (Schmidt et al. 2001). While the precise mechanisms of intracellular RAGE signaling have not been fully elucidated, the cytosolic tail interacts with the formin protein, Diaph1 (also known as mDia1 or Drf1) (Hudson et al. 2008). The cytosolic domain of RAGE is critical for RAGE-dependent signaling and modulation of gene expression. When the cytosolic domain is deleted, this imparts a “dominant negative” effect; although cells may bind ligand, ligands are not able to activate RAGE signaling (Bucciarelli et al. 2008, Harja et al. 2008).
Zearalenone: Insights into New Mechanisms in Human Health
Published in Dongyou Liu, Handbook of Foodborne Diseases, 2018
Cornelia Braicu, Alina Andreea Zimta, Ioana Berindan-Neagoe
The pig ovarian granulosa cells treated with concentrations between 15 and 300 μM of α- and β-zearalenol have a drop in progesterone production stimulated by FSH, forskolin, and pregnenolone, although cellular viability is lost only in the case of FSH [45]. In cows, the insulin-like growth factor 1 (IGF1)+FSH or FSH stimulated granulosa cells, the estradiol quantity has risen, and the progesterone level has dropped after exposure to 0.31–3.1 μM of α-ZOL. The cellular viability exhibited conflicting results: in the case of IGF1 combined with FSH, it was greater, whereas in the case of FSH, it was lower [46]. ZEA alone stimulates the progesterone production only at low dosage [47], although in other studies done on pregnant mice, the level of progesterone after ZEA exposure was raised in the blood [48], or in bovine granulosa cells. In the second case, 31 μM of β-ZEA caused up to 100% increase in estradiol and progesterone in FSH-stimulated granulosa cells, although the viability was reduced. When compared with IGF1, the opposite effect was obtained [49]. This mycotoxin does not bind to the progesterone receptor [47]. ZEA reduced the formation of the first polar body by 29% and caused a drop in granulosa cell proliferation, which led to abnormality of the meiotic spindle. There were no poles, multiple poles, or disintegrated poles; gamma tubulin disruption; and decrease in actin expression or underexpression of the regulatory proteins profilin-1 and mDia1 [50]. Another study tried to explain the loss of granulosa cell viability through increases in intracellular reactive oxygen species (ROS) concentration caused by a disruption of antioxidants activity: Sod1, Cat, Gpx1, and GSH. It was observed that while their transcription is not affected, their activation is decreased in all cases, with the only difference being the concentration: some of them reacted at 30 μM, others at 60 μM [51].
Formin proteins in megakaryocytes and platelets: regulation of actin and microtubule dynamics
Published in Platelets, 2019
Malou Zuidscherwoude, Hannah L.H. Green, Steven G. Thomas
mDia1 function has also been directly investigated in megakaryocytes. Pan et al. (48) used shRNA in human CD34+ derived megakaryocytes to knockdown mDia1 expression to approximately 50–60% of controls. In these cells, proplatelet formation (PPF) was increased, F-actin polymerisation was decreased and the stability of microtubules was increased, as assessed by increased Glu-tubulin (28,29). These data indicate that partial inactivation of mDia1 activity in mature megakaryocytes is required to allow proplatelet formation. This effect is proposed to be mediated through reducing actin-myosin contractile forces in the mature megakaryocyte which allows for the protrusion of proplatelets, an effect also seen in inhibition of myosin IIa (48). However, this effect may also be related to observed changes in microtubule stability which could alter motor protein interaction with microtubules facilitating proplatelet extension (49). Intriguingly, platelet counts are normal in the mDia1 knockout mouse (Thomas, Unpublished data) indicating a possible difference between human and mouse cells, or some compensatory mechanism in the knockout. As indicated above, the mDia1 knockout platelets are increased in size (Thomas, Unpublished data) suggesting that there is a defect in proplatelet formation/release when mDia1 is absent. In addition, the knockdown experiments performed by Pan et al. were done after megakaryocyte differentiation, and so, the effect of reduced mDia1 expression on human megakaryocyte development was not studied.
Loss of mDia1 and Fhod1 impacts platelet formation but not platelet function
Published in Platelets, 2021
Malou Zuidscherwoude, Elizabeth J. Haining, Victoria A. Simms, Stephanie Watson, Beata Grygielska, Alex T. Hardy, Andrea Bacon, Stephen P. Watson, Steven G. Thomas
The clearest defect observed is disrupted platelet production with a decreased platelet count being observed, which is most severe in the DKO mice. The evidence presented here suggests that mDia1 is the major player in this phenotype, as mDia1 KOs show a tendency toward thrombocytopenia, which is exacerbated by the loss of Fhod1 in the DKOs. In contrast, Fhod1 KO mice alone display no change in platelet number strongly suggesting that Fhod1 contributes, but does not play a major role in this process. In addition to the reduced production of platelets in mDia1 KO and DKO mice, there are also disruptions to the process which results in enlarged platelet size, and perturbed surface receptor profiles.
Rho GTPases and their downstream effectors in megakaryocyte biology
Published in Platelets, 2019
Irina Pleines, Deya Cherpokova, Markus Bender
Another group of Rho effectors, the mDia proteins, induce actin assembly. Strikingly, a gain of function variant in mDIA1, encoded by the gene DIAPH1, was shown to result in macrothrombocytopenia in humans (60). Consistently, while DIAPH1 knockdown increased PPF, overexpression of a constitutive active mutant inhibited PPF of human CD34+-derived MKs (61). Together, these results strongly suggest that, besides ROCK, mDIA1 is another critical effector of RhoA in MKs.