Metastatic cancer patients experience a severe loss of skeletal muscle mass and function known as cachexia. Cachexia is associated with poor prognosis and accelerated death in cancer patients, yet its underlying mechanisms remain poorly understood. Here, we identify the metal transporter ZIP14 as a critical mediator of cancer-induced cachexia. ZIP14 is upregulated in cachectic muscles from mice and patients with metastatic cancer and can be induced by TNF-α and TGF-β cytokines.Strikingly, in vivo manipulation of Zip14 expression has profound impact on muscle atrophy in experimental models of metastasis.We find that ZIP14-mediated zinc uptake in muscle progenitor cells represses the expression of the key myogenic factors MyoD and Mef2c, and blocks muscle-cell differentiation. Importantly, ZIP14-mediated zinc accumulation in differentiated muscle cells induces myosin heavy chain loss. These results highlight a previously unrecognized role for altered zinc homeostasis in muscle during metastatic-cancer-induced cachexia, and implicate ZIP14 as a therapeutic target for its treatment.
SummaryPrimary cilia, which emanate from the cell surface, exhibit assembly and disassembly dynamics along the progression of the cell cycle. However, the mechanism that links ciliary dynamics and cell cycle regulation remains elusive. In the present study, we report that Pololike kinase 1 (Plk1), one of the key cell cycle regulators, which regulate centrosome maturation, bipolar spindle assembly and cytokinesis, acts as a pivotal player that connects ciliary dynamics and cell cycle regulation. We found that the kinase activity of centrosome enriched Plk1 is required for primary cilia disassembly before mitotic entry, wherein Plk1 interacts with and activates histone deacetylase 6 (HDAC6) to promote ciliary deacetylation and resorption. Furthermore, we showed that pericentriolar material 1 (PCM1) acts upstream of Plk1 and recruits the kinase to pericentriolar matrix (PCM) in a dynein-dynactin complex-dependent manner. This process coincides with the primary cilia disassembly dynamics at the onset of mitosis, as depletion of PCM1 by shRNA dramatically disrupted the pericentriolar accumulation of Plk1. Notably, the interaction between PCM1 and Plk1 is phosphorylation dependent, and CDK1 functions as the priming kinase to facilitate the interaction. Our data suggest a mechanism whereby the recruitment of Plk1 to pericentriolar matrix by PCM1 plays a pivotal role in the regulation of primary cilia disassembly before mitotic entry. Thus, the regulation of ciliary dynamics and cell proliferation share some common regulators.
The centrosome acts as the major microtubule-organizing center (MTOC) for cytoskeleton maintenance in interphase and mitotic spindle assembly in vertebrate cells. It duplicates only once per cell cycle in a highly spatiotemporally regulated manner. When the cell undergoes mitosis, the duplicated centrosomes separate to define spindle poles and monitor the assembly of the bipolar mitotic spindle for accurate chromosome separation and the maintenance of genomic stability. However, centrosome abnormalities occur frequently and often lead to monopolar or multipolar spindle formation, which results in chromosome instability and possibly tumorigenesis. A number of studies have begun to dissect the role of mitotic kinases, including NIMA-related kinases (Neks), cyclindependent kinases (CDKs), Polo-like kinases (Plks) and Aurora kinases, in regulating centrosome duplication, separation and maturation and subsequent mitotic spindle assembly during cell cycle progression. In this Commentary, we review the recent research progress on how these mitotic kinases are coordinated to couple the centrosome cycle with the cell cycle, thus ensuring bipolar mitotic spindle fidelity. Understanding this process will help to delineate the relationship between centrosomal abnormalities and spindle defects.
Background: Aurora kinases show different localizations and play distinct roles, yet the mechanisms remain largely unknown. Results: Different localization leads to functional divergence of the Auroras and their N termini also contribute to the localization. Conclusion: Both N/C termini of Aurora A/B contribute to their spatial compartmentalization and function. Significance: Functional divergence of Aurora kinases is largely determined by their localizations through binding with partners/substrates.
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