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Identification of Intracellular Signaling Events Induced in Viable Cells by Interaction with Neighboring Cells Undergoing Apoptotic Cell Death
Published on: December 27, 2016
Lethal weight loss: the focus shifts to signal transduction
1North Shore-Long Island Jewish Research Institute, Manhasset, NY 11020, USA. kjtracey@sprynet.com
Abstract:
A hallmark of life-threatening disease in vertebrates is cachexia, a syndrome of weight loss with progressive erosion of body protein. Tumor necrosis factor (TNF) and other endogenously derived factors are sufficient to mediate the pathophysiology of cachexia in vivo, but the downstream signaling pathways have remained a mystery until recently. Tracey describes the involvement of the stress-activated protein kinase p38 and the transcriptional regulators nuclear factor kappa B and peroxisome proliferator-activated receptor gamma coactivator-1 in causing alterations in myocytes and skeletal muscle physiology. Furthermore, soluble factors including TNF and proteolysis-inducing factor may enhance protein degradation through the ubiquitin-proteosome pathway.
Insights
Cachexia, a wasting disease, involves body protein loss. New research reveals stress-activated protein kinase p38 and other factors contribute to muscle changes and protein breakdown via the ubiquitin-proteasome pathway.
Area of Science:
- Biochemistry
- Molecular Biology
- Physiology
Background:
- Cachexia is a critical condition in severe diseases, characterized by significant weight and muscle loss.
- The molecular mechanisms driving cachexia have been largely unknown, despite identifying factors like tumor necrosis factor (TNF).
Purpose of the Study:
- To elucidate the downstream signaling pathways involved in the pathophysiology of cachexia.
- To identify key molecular players and pathways responsible for muscle wasting in cachexia.
Main Methods:
- Investigated the role of stress-activated protein kinase p38.
- Examined the involvement of transcriptional regulators nuclear factor kappa B (NF-κB) and peroxisome proliferator-activated receptor gamma coactivator-1 (PGC-1).
- Explored the contribution of soluble factors like TNF and proteolysis-inducing factor (PIF) to protein degradation.
Main Results:
- Identified the involvement of stress-activated protein kinase p38 in cachexia.
- Demonstrated the role of nuclear factor kappa B and PGC-1 in altering myocyte and skeletal muscle physiology.
- Showed that TNF and PIF can enhance protein degradation through the ubiquitin-proteasome pathway.
Conclusions:
- The stress-activated protein kinase p38 pathway is implicated in cachexia.
- NF-κB and PGC-1 are key regulators of skeletal muscle alterations in cachexia.
- The ubiquitin-proteasome pathway is a significant target for protein degradation in cachexia, influenced by factors like TNF and PIF.
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