Sci Signal
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This Podcast features a conversation with Science Signaling's Chief Scientific Editor Michael Yaffe about opportunities for signaling researchers to contribute to the Cancer Moonshot, a federally funded initiative to accelerate cancer research. Administered by the National Cancer Institute (NCI), the goal of the program is to improve the prevention, diagnosis, and treatment of cancer. ⋯ In addition to developing new therapies, there are many other opportunities for signaling researchers to advance the goals of the Cancer Moonshot, such as improving methods of diagnosis and prevention. Listen to Podcast.
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Genetic loss of the voltage-gated sodium channel Nav1.7 (Nav1.7-/-) results in lifelong insensitivity to pain in mice and humans. One underlying cause is an increase in the production of endogenous opioids in sensory neurons. We analyzed whether Nav1.7 deficiency altered nociceptive heterotrimeric guanine nucleotide-binding protein-coupled receptor (GPCR) signaling, such as initiated by GPCRs that respond to serotonin (pronociceptive) or opioids (antinociceptive), in sensory neurons. ⋯ Simultaneously, the efficacy of antinociceptive opioid signaling mediated by the Gαi-coupled mu opioid receptors was increased. Consequently, opioids inhibited more efficiently tetrodotoxin-resistant sodium currents, which are important for pain-initiating neuronal activity in nociceptive neurons. Thus, Nav1.7 controls the efficacy and balance of GPCR-mediated pro- and antinociceptive intracellular signaling, such that without Nav1.7, the balance is shifted toward antinociception, resulting in lifelong endogenous analgesia.
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Comparative Study
Large-scale functional analysis of the roles of phosphorylation in yeast metabolic pathways.
Protein phosphorylation is a widespread posttranslational modification that regulates almost all cellular functions. To investigate the large number of phosphorylation events with unknown functions, we monitored the concentrations of several hundred intracellular metabolites in Saccharomyces cerevisiae yeast strains with deletions of 118 kinases or phosphatases. Whereas most deletion strains had no detectable difference in growth compared to wild-type yeast, two-thirds of deletion strains had alterations in metabolic profiles. ⋯ We demonstrated that the phosphatase Ppq1 was required for metal homeostasis. Combining metabolomic data with published phosphoproteomic data in a stoichiometric model enabled us to predict functions for phosphorylation in the regulation of 47 enzymes. Overall, we provided insights and testable predictions covering greater than twice the number of known phosphorylated enzymes in yeast, suggesting extensive phosphorylation-dependent regulation of yeast metabolism.
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Clinical Trial
Exosomes from bone marrow mesenchymal stem cells contain a microRNA that promotes dormancy in metastatic breast cancer cells.
Breast cancer patients often develop metastatic disease years after resection of the primary tumor. The patients are asymptomatic because the disseminated cells appear to become dormant and are undetectable. Because the proliferation of these cells is slowed, dormant cells are often unresponsive to traditional chemotherapies that exploit the rapid cell cycling of most cancer cells. ⋯ Among various microRNAs (miRNAs) increased in BM-MSC-derived exosomes compared with those from adult fibroblasts, overexpression of miR-23b in BM2 cells induced dormant phenotypes through the suppression of a target gene, MARCKS, which encodes a protein that promotes cell cycling and motility. Metastatic breast cancer cells in patient bone marrow had increased miR-23b and decreased MARCKS expression. Together, these findings suggest that exosomal transfer of miRNAs from the bone marrow may promote breast cancer cell dormancy in a metastatic niche.
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Changes in the actin cytoskeleton in neurons are associated with synaptic plasticity and may also be involved in mechanisms of nociception. We found that the LIM motif-containing protein kinases (LIMKs), which regulate actin dynamics, promoted the development of inflammatory hyperalgesia (excessive sensitivity to painful stimuli). Pain is sensed by the primary sensory neurons of dorsal root ganglion (DRG). ⋯ Inflammatory stimuli stimulated actin polymerization and enhanced the response of the cation channel TRPV1 (transient receptor potential V1) to capsaicin in DRG neurons, effects that were reversed by the knockdown of LIMK or preventing cofilin phosphorylation. Furthermore, inflammatory stimuli caused the serine phosphorylation of TRPV1, which was abolished by preventing cofilin phosphorylation in DRG neurons. We conclude that LIMK-dependent actin rearrangement in primary sensory neurons, leading to altered TRPV1 sensitivity, is involved in the development of inflammatory hyperalgesia.