https://www.seas.upenn.edu/%7Edischer/pdfs/Cell_on_Gel-CELLpaper.pdf

Matrix elasticity directs stem cell lineage specification.

At high concentrations, free radicals and radical-derived, nonradical reactive species are hazardous for living organisms and damage all major cellular constituents. At moderate concentrations, how...

/pdf/free-radicals-in-the-physiological-control-of-cell-function-g3w3iyr0ph.pdf

Free Radicals in the Physiological Control of Cell Function

Living in an oxygenated environment has required the evolution of effective cellular strategies to detect and detoxify metabolites of molecular oxygen known as reactive oxygen species. Here we review evidence that the appropriate and inappropriate production of oxidants, together with the ability of organisms to respond to oxidative stress, is intricately connected to ageing and life span.

Oxidants, oxidative stress and the biology of ageing.

Normal tissue cells are generally not viable when suspended in a fluid and are therefore said to be anchorage dependent. Such cells must adhere to a solid, but a solid can be as rigid as glass or softer than a baby's skin. The behavior of some cells on soft materials is characteristic of important phenotypes; for example, cell growth on soft agar gels is used to identify cancer cells. However, an understanding of how tissue cells-including fibroblasts, myocytes, neurons, and other cell types-sense matrix stiffness is just emerging with quantitative studies of cells adhering to gels (or to other cells) with which elasticity can be tuned to approximate that of tissues. Key roles in molecular pathways are played by adhesion complexes and the actinmyosin cytoskeleton, whose contractile forces are transmitted through transcellular structures. The feedback of local matrix stiffness on cell state likely has important implications for development, differentiation, disease, and regeneration.

/pdf/tissue-cells-feel-and-respond-to-the-stiffness-of-their-6dx0rumap6.pdf

Tissue Cells Feel and Respond to the Stiffness of Their Substrate

http://basicmed.med.ncku.edu.tw/admin/up_img/990319-2.pdf

Matrix Crosslinking Forces Tumor Progression by Enhancing Integrin Signaling

Apoptosis signal‐regulating kinase (ASK) 1 was recently identified as a mitogen‐activated protein (MAP) kinase kinase kinase which activates the c‐Jun N‐terminal kinase (JNK) and p38 MAP kinase pathways and is required for tumor necrosis factor (TNF)‐α‐induced apoptosis; however, the mechanism regulating ASK1 activity is unknown. Through genetic screening for ASK1‐binding proteins, thioredoxin (Trx), a reduction/oxidation (redox)‐regulatory protein thought to have anti‐apoptotic effects, was identified as an interacting partner of ASK1. Trx associated with the N‐terminal portion of ASK1 in vitro and in vivo . Expression of Trx inhibited ASK1 kinase activity and the subsequent ASK1‐dependent apoptosis. Treatment of cells with N ‐acetyl‐l‐cysteine also inhibited serum withdrawal‐, TNF‐α‐ and hydrogen peroxide‐induced activation of ASK1 as well as apoptosis. The interaction between Trx and ASK1 was found to be highly dependent on the redox status of Trx. Moreover, inhibition of Trx resulted in activation of endogenous ASK1 activity, suggesting that Trx is a physiological inhibitor of ASK1. The evidence that Trx is a negative regulator of ASK1 suggests possible mechanisms for redox regulation of the apoptosis signal transduction pathway as well as the effects of antioxidants against cytokine‐ and stress‐induced apoptosis.

Mammalian thioredoxin is a direct inhibitor of apoptosis signal-regulating kinase (ASK) 1.

https://www.cell.com/cell/pdf/S0092-8674(06)01405-X.pdf

Force Sensing by Mechanical Extension of the Src Family Kinase Substrate p130Cas

To examine the role of mitogen-activated protein kinase and nuclear factor kappa B (NF-κB) pathways on osteoclast survival and activation, we constructed adenovirus vectors carrying various mutants of signaling molecules: dominant negative Ras (RasDN), constitutively active MEK1 (MEKCA), dominant negative IκB kinase 2 (IKKDN), and constitutively active IKK2 (IKKCA). Inhibiting ERK activity by RasDN overexpression rapidly induced the apoptosis of osteoclast-like cells (OCLs) formed in vitro, whereas ERK activation after the introduction of MEKCA remarkably lengthened their survival by preventing spontaneous apoptosis. Neither inhibition nor activation of ERK affected the bone-resorbing activity of OCLs. Inhibition of NF-κB pathway with IKKDN virus suppressed the pit-forming activity of OCLs and NF-κB activation by IKKCA expression upregulated it without affecting their survival. Interleukin 1α (IL-1α) strongly induced ERK activation as well as NF-κB activation. RasDN virus partially inhibited ERK activation, and OCL survival promoted by IL-1α. Inhibiting NF-κB activation by IKKDN virus significantly suppressed the pit-forming activity enhanced by IL-1α. These results indicate that ERK and NF-κB regulate different aspects of osteoclast activation: ERK is responsible for osteoclast survival, whereas NF-κB regulates osteoclast activation for bone resorption.

/pdf/reciprocal-role-of-erk-and-nf-kb-pathways-in-survival-and-2d3505gxne.pdf

Reciprocal Role of ERK and Nf-κb Pathways in Survival and Activation of Osteoclasts

Activation of a Signaling Cascade by Cytoskeleton Stretch

Force-initiated signal transduction can occur either via membrane-based ionic mechanisms or through changes in cytoskeletal-matrix linkages We report here the stretch-dependent binding of cytoplasmic proteins to Triton X-100 cytoskeletons of L-929 cells grown on collagen-coated silicone Triton X-100-insoluble cytoskeletons were stretched by 10% and incubated with biotinylated cytoplasmic proteins Analysis with two-dimensional gel electrophoresis showed stretch-dependent binding of more than 10 cytoplasmic protein spots Bound cytoplasmic proteins were purified by a photocleavable biotin tag and stretch-dependent binding of paxillin, focal adhesion kinase, and p130Cas was found, whereas the binding of vinculin was unchanged and actin binding decreased with stretch Paxillin binding upon stretch was morphologically and biochemically similar in vitro and in vivo, that is, enhanced in the periphery and inhibited by the tyrosine phosphatase inhibitor, phenylarsine oxide Thus, we suggest that transduction of matrix forces occurs through force-dependent conformation changes in the integrated cytoskeleton

/pdf/force-transduction-by-triton-cytoskeletons-3uhcaf9c9u.pdf

Yasuhiro Sawada

Papers

Mammalian thioredoxin is a direct inhibitor of apoptosis signal-regulating kinase (ASK) 1.

Force Sensing by Mechanical Extension of the Src Family Kinase Substrate p130Cas

Reciprocal Role of ERK and Nf-κb Pathways in Survival and Activation of Osteoclasts

Activation of a Signaling Cascade by Cytoskeleton Stretch

Force transduction by Triton cytoskeletons