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  • 1
    Publication Date: 2016-01-30
    Description: Dietary antigens are normally rendered nonimmunogenic through a poorly understood "oral tolerance" mechanism that involves immunosuppressive regulatory T (Treg) cells, especially Treg cells induced from conventional T cells in the periphery (pTreg cells). Although orally introducing nominal protein antigens is known to induce such pTreg cells, whether a typical diet induces a population of pTreg cells under normal conditions thus far has been unknown. By using germ-free mice raised and bred on an elemental diet devoid of dietary antigens, we demonstrated that under normal conditions, the vast majority of the small intestinal pTreg cells are induced by dietary antigens from solid foods. Moreover, these pTreg cells have a limited life span, are distinguishable from microbiota-induced pTreg cells, and repress underlying strong immunity to ingested protein antigens.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Kim, Kwang Soon -- Hong, Sung-Wook -- Han, Daehee -- Yi, Jaeu -- Jung, Jisun -- Yang, Bo-Gie -- Lee, Jun Young -- Lee, Minji -- Surh, Charles D -- New York, N.Y. -- Science. 2016 Feb 19;351(6275):858-63. doi: 10.1126/science.aac5560. Epub 2016 Jan 28.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Academy of Immunology and Microbiology, Institute for Basic Science, Pohang, Republic of Korea. Department of Integrative Biosciences and Biotechnology, Pohang University of Science and Technology, Pohang, Republic of Korea. ; Academy of Immunology and Microbiology, Institute for Basic Science, Pohang, Republic of Korea. Department of Integrative Biosciences and Biotechnology, Pohang University of Science and Technology, Pohang, Republic of Korea. Division of Developmental Immunology, La Jolla Institute for Allergy and Immunology, La Jolla, CA 92037, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26822607" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Antigens/immunology ; Diet ; Dietary Proteins/*immunology ; Dyspepsia/*immunology ; Gastrointestinal Microbiome/*immunology ; Germ-Free Life ; Immune Tolerance ; Immunity, Mucosal ; Intestine, Small/*immunology/*microbiology ; Lymphocyte Activation ; Mice ; Mice, Inbred C57BL ; T-Lymphocytes, Regulatory/*immunology
    Print ISSN: 0036-8075
    Electronic ISSN: 1095-9203
    Topics: Biology , Chemistry and Pharmacology , Computer Science , Medicine , Natural Sciences in General , Physics
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  • 2
    Publication Date: 2018-06-15
    Description: A distinct hallmark of acute myeloid leukemia (AML) is the arrest of leukemic myeloblasts at an immature stage of development. Therapies that overcome differentiation arrest have emerged as a powerful strategy for treating AML, but targeting leukemia differentiation remains challenging, mainly because of an incomplete mechanistic understanding of the process. Here, we unveil a new role for cyclin-dependent kinase 2 (CDK2) in blocking myeloid differentiation in AML. We show that among several interphase CDK, only CDK2 undergoes ubiquitin-dependent proteasome degradation, which is accompanied by AML cell differentiation. By using the yeast 2-hybrid system and functional analyses, KLHL6 was identified as a specific E3 ubiquitin ligase regulating the degradation of CDK2. Importantly, inhibiting CDK2, but not other cyclin-dependent kinases CDK1/4/6, effectively induced granulocytic differentiation in AML cell lines and 5 major subtypes of primary patient-derived AML samples. Mechanistically, CDK2 depletion led to the reactivation of differentiation pathway translation, and the differentiation blockade function of CDK2 may be achieved directly by maintaining the activity of PRDX2. Finally, CDK2 depletion arrested tumor growth of AML cells in nude mice and extended survival in both AML cell line and PDX-AML cells derived xenograft mouse models. Thus, our work not only provides experimental evidence for validating CDK2 as a potential therapeutic target for differentiation, but also uncovers the biological function of the CDK2-PRDX2 axis in blocking AML differentiation.
    Keywords: Myeloid Neoplasia
    Print ISSN: 0006-4971
    Electronic ISSN: 1528-0020
    Topics: Biology , Medicine
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