The glucocorticoid dexamethasone suppresses antigen-induced degranulation, cytokine production, and intermediate signaling events in RBL-2H3 mast cells, although the exact mechanisms are uncertain. By microarray analysis, we discovered that expression of the inhibitory adaptor protein, downstream of tyrosine kinase (Dok)-1, was up-regulated 4-fold in dexamethasone-treated RBL-2H3 cells. The up-regulation was apparent with as little as 1 to 10 nM dexamethasone. Treatment with dexamethasone also enhanced tyrosine phosphorylation of Dok-1, augmented recruitment of Ras GTPase-activating protein (RasGAP) by Dok-1, and inhibited activation of the mitogen-activated protein (MAP) kinase pathway in antigen-stimulated cells. The same effects were obtained by transient overexpression of Dok-1 but not by overexpression of Dok-1 that was mutated in RasGAP-binding domain. The negative regulatory role of Dok-1 was further validated by the expression of small interfering RNA directed against Dok-1, which enhanced activation of MAP kinase and subsequent release of arachidonic acid and tumor necrosis factor-alpha. These findings identify Dok-1 as mediator of the antiallergic actions of dexamethasone and as a negative regulator of the MAP kinase pathway and downstream release of inflammatory mediators.
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http://dx.doi.org/10.1124/mol.104.008607 | DOI Listing |
Cancer Med
February 2025
Centre for Medical Research, Ningbo No.2 Hospital, Ningbo, China.
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View Article and Find Full Text PDFAm J Med Genet A
January 2025
Department of Experimental Medicine, Sapienza University of Rome, Rome, Italy.
TBCK (TBC1 Domain-Containing Kinase) encodes a protein playing a role in actin organization and cell growth/proliferation via the mTOR signaling pathway. Deleterious biallelic TBCK variants cause Hypotonia, infantile, with psychomotor retardation and characteristic facies 3. We report on three affected sibs, also displaying cardiac malformations.
View Article and Find Full Text PDFIUBMB Life
January 2025
Department of Reproductive Medical Center, First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan Province, China.
Abnormality of granulosa cells (GCs) is the critical cause of follicular atresia in premature ovarian failure (POF). RIPK3 is highly expressed in GCs derived from atretic follicles. We focus on uncovering how RIPK3 contributes to ovarian GC senescence.
View Article and Find Full Text PDFJ Transl Med
January 2025
Department of Hematology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, No. 1 Shuaifuyuan, Beijing, 100730, China.
Background: Immunotherapy is a significant risk factor for severe COVID-19 in multiple myeloma (MM) patients. Understanding how immunotherapies lead to severe COVID-19 is crucial for improving patient outcomes.
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Sci Rep
January 2025
Department of Clinical Genetics, National Institute of Genetic Engineering and Biotechnology, Tehran, Iran.
Head and neck squamous cell carcinoma (HNSCC) is an aggressive cancer that is notably associated with a high risk of lymph node metastasis, a major cause of cancer mortality. Current therapeutic options remain limited to surgery supplemented by radio- or chemotherapy; however, these interventions often result in high-grade toxicities. Distant metastasis significantly contributed to the poor prognosis and decreased survival rates.
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