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  1. The effect of Plasmodium vivax infection on SOCS gene expression in Anopheles dirus (Diptera: Culicidae)
    Kittiwattanawong K, Ponlawat A, Boonrotpong S, Nanakorn N, Kongchouy N, Moonmake S, et al.
    Trop Biomed, 2020 Jun 01;37(2):397-408.
    PMID: 33612809
    The Anopheles dirus mosquito is a primary malaria vector that transmits many species of Plasmodium parasites in Thailand and is widely spread across its geographic area. In the current study, the levels of expression of the suppressor of cytokine signaling (SOCS) gene in An. dirus mosquitoes infected with P. vivax were examined. The level of the gene's expression determined by mRNA extraction in An. dirus females (n=2,400) was studied at different times (0, 12, 24, 36, and 48 h after feeding), with different types of blood feeding (non-feeding, parasite-negative blood feeding, parasite-positive blood feeding) and in different parts of the body of mosquito samples (thorax and abdomen). The datasets were analyzed based on their relative expression ratio by the 2-ΔΔCT method and were tested for significant differences with ANOVA. The results showed that the An. dirus SOCS gene was stimulated in the abdomen 12 h and 24 h after blood feeding about three times more highly than in unfed females, with the difference being significant. At 24 h after P. vivax-infected blood feeding, the SOCS gene in the abdomen was expressed more highly than 24 h after parasite-negative blood feeding and expression was almost 36 times higher than in the control group who were not fed blood. However, in the thorax at all times after feeding and non-feeding, there was no expression of the SOCS gene. Therefore, the SOCS gene in An. dirus was most highly expressed 24 h post-feeding with a P. vivax-infected bloodmeal, which indicates that the SOCS gene in the major malaria vector in Thailand plays an important role in its immune system and its response to P. vivax infection.
    Matched MeSH terms: Suppressor of Cytokine Signaling Proteins/genetics*
  2. Fulltext Regulation of embryonic hematopoiesis by a cytokine-inducible SH2 domain homolog in zebrafish
    Lewis RS, Noor SM, Fraser FW, Sertori R, Liongue C, Ward AC
    J Immunol, 2014 Jun 15;192(12):5739-48.
    PMID: 24835394 DOI: 10.4049/jimmunol.1301376
    Cytokine-inducible SH2 domain-containing protein (CISH), a member of the suppressor of cytokine signaling family of negative feedback regulators, is induced by cytokines that activate STAT5 and can inhibit STAT5 signaling in vitro. However, demonstration of a definitive in vivo role for CISH during development has remained elusive. This study employed expression analysis and morpholino-mediated knockdown in zebrafish in concert with bioinformatics and biochemical approaches to investigate CISH function. Two zebrafish CISH paralogs were identified, cish.a and cish.b, with high overall conservation (43-46% identity) with their mammalian counterparts. The cish.a gene was maternally derived, with transcripts present throughout embryogenesis, and increasing at 4-5 d after fertilization, whereas cish.b expression commenced at 8 h after fertilization. Expression of cish.a was regulated by the JAK2/STAT5 pathway via conserved tetrameric STAT5 binding sites (TTCN3GAA) in its promoter. Injection of morpholinos targeting cish.a, but not cish.b or control morpholinos, resulted in enhanced embryonic erythropoiesis, myelopoiesis, and lymphopoiesis, including a 2- 3-fold increase in erythrocytic markers. This occurred concomitantly with increased activation of STAT5. This study indicates that CISH functions as a conserved in vivo target and regulator of STAT5 in the control of embryonic hematopoiesis.
    Matched MeSH terms: Suppressor of Cytokine Signaling Proteins/genetics
  3. Silencing of suppressor of cytokine signaling-3 due to methylation results in phosphorylation of STAT3 in imatinib resistant BCR-ABL positive chronic myeloid leukemia cells
    Al-Jamal HA, Jusoh SA, Yong AC, Asan JM, Hassan R, Johan MF
    Asian Pac J Cancer Prev, 2014;15(11):4555-61.
    PMID: 24969884
    BACKGROUND: Silencing due to methylation of suppressor of cytokine signaling-3 (SOCS-3), a negative regulator gene for the JAK/STAT signaling pathway has been reported to play important roles in leukemogenesis. Imatinib mesylate is a tyrosine kinase inhibitor that specifically targets the BCR-ABL protein and induces hematological remission in patients with chronic myeloid leukemia (CML). Unfortunately, the majority of CML patients treated with imatinib develop resistance under prolonged therapy. We here investigated the methylation profile of SOCS-3 gene and its downstream effects in a BCR-ABL positive CML cells resistant to imatinib.

    MATERIALS AND METHODS: BCR-ABL positive CML cells resistant to imatinib (K562-R) were developed by overexposure of K562 cell lines to the drug. Cytotoxicity was determined by MTS assays and IC50 values calculated. Apoptosis assays were performed using annexin V-FITC binding assays and analyzed by flow cytometry. Methylation profiles were investigated using methylation specific PCR and sequencing analysis of SOCS-1 and SOCS-3 genes. Gene expression was assessed by quantitative real-time PCR, and protein expression and phosphorylation of STAT1, 2 and 3 were examined by Western blotting.

    RESULTS: The IC50 for imatinib on K562 was 362 nM compared to 3,952 nM for K562-R (p=0.001). Percentage of apoptotic cells in K562 increased upto 50% by increasing the concentration of imatinib, in contrast to only 20% in K562-R (p<0.001). A change from non-methylation of the SOCS-3 gene in K562 to complete methylation in K562-R was observed. Gene expression revealed down- regulation of both SOCS-1 and SOCS-3 genes in resistant cells. STAT3 was phosphorylated in K562-R but not K562.

    CONCLUSIONS: Development of cells resistant to imatinib is feasible by overexposure of the drug to the cells. Activation of STAT3 protein leads to uncontrolled cell proliferation in imatinib resistant BCR-ABL due to DNA methylation of the SOCS-3 gene. Thus SOCS-3 provides a suitable candidate for mechanisms underlying the development of imatinib resistant in CML patients.

    Matched MeSH terms: Suppressor of Cytokine Signaling Proteins/genetics*
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