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T-cell activation decreases miRNA-15a/16 levels to promote MEK1-ERK1/2-Elk1 signaling and proliferative capacity.
Urena, Frank; Ma, Chi; Hoffmann, FuKun W; Nunes, Lance G A; Urschitz, Johann; Moisyadi, Stefan; Khadka, Vedbar S; Deng, Youping; Hoffmann, Peter R.
Afiliación
  • Urena F; Department of Cell and Molecular Biology, John A. Burns School of Medicine, University of Hawaii, Honolulu, Hawaii, USA; Department of Molecular Biosciences and Bioengineering, University of Hawaii at Manoa, Honolulu, Hawaii, USA.
  • Ma C; Department of Cell and Molecular Biology, John A. Burns School of Medicine, University of Hawaii, Honolulu, Hawaii, USA.
  • Hoffmann FW; Department of Cell and Molecular Biology, John A. Burns School of Medicine, University of Hawaii, Honolulu, Hawaii, USA.
  • Nunes LGA; Department of Anatomy, Physiology and Biochemistry, John A. Burns School of Medicine, University of Hawaii, Honolulu, Hawaii, USA.
  • Urschitz J; Department of Anatomy, Physiology and Biochemistry, John A. Burns School of Medicine, University of Hawaii, Honolulu, Hawaii, USA.
  • Moisyadi S; Department of Anatomy, Physiology and Biochemistry, John A. Burns School of Medicine, University of Hawaii, Honolulu, Hawaii, USA.
  • Khadka VS; Department of Quantitative Health Sciences, John A. Burns School of Medicine, University of Hawaii, Honolulu, Hawaii, USA.
  • Deng Y; Department of Quantitative Health Sciences, John A. Burns School of Medicine, University of Hawaii, Honolulu, Hawaii, USA.
  • Hoffmann PR; Department of Cell and Molecular Biology, John A. Burns School of Medicine, University of Hawaii, Honolulu, Hawaii, USA. Electronic address: peterrh@hawaii.edu.
J Biol Chem ; 298(3): 101634, 2022 03.
Article en En | MEDLINE | ID: mdl-35085550
While miRs have been extensively studied in the context of malignancy and tumor progression, their functions in regulating T-cell activation are less clear. In initial studies, we found reduced levels of miR-15a/16 at 3 to 18 h post-T-cell receptor (TCR) stimulation, suggesting a role for decreased levels of this miR pair in shaping T-cell activation. To further explore this, we developed an inducible miR15a/16 transgenic mouse model to determine how elevating miR-15a/16 levels during early stages of activation would affect T-cell proliferation and to identify TCR signaling pathways regulated by this miR pair. Doxycycline (DOX)-induced expression of miR-15a/16 from 0 to 18 h post-TCR stimulation decreased ex vivo T-cell proliferation as well as in vivo antigen-specific T-cell proliferation. We also combined bioinformatics and proteomics approaches to identify the mitogen-activated protein kinase kinase 1 (MEK1) (Map2k1) as a target of miR-15a/16. MEK1 targeting by miR-15a/16 was confirmed using miR mimics that decreased Map2k1 mRNA containing the 3'-UTR target nucleotide sequence (UGCUGCUA) but did not decrease Map2k1 containing a mutated control sequence (AAAAAAAA). Phosphorylation of downstream signaling molecules, extracellular signal-regulated protein kinase 1/2 (ERK1/2) and Elk1, was also decreased by DOX-induced miR-15a/16 expression. In addition to MEK1, ERK1 was subsequently found to be targeted by miR-15a/16, with DOX-induced miR-15a/16 reducing total ERK1 levels in T cells. These findings show that TCR stimulation reduces miR-15a/16 levels at early stages of T-cell activation to facilitate increased MEK1 and ERK1, which promotes the sustained MEK1-ERK1/2-Elk1 signaling required for optimal proliferation.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Linfocitos T / Sistema de Señalización de MAP Quinasas / MicroARNs Tipo de estudio: Prognostic_studies Límite: Animals Idioma: En Revista: J Biol Chem Año: 2022 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Estados Unidos
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Linfocitos T / Sistema de Señalización de MAP Quinasas / MicroARNs Tipo de estudio: Prognostic_studies Límite: Animals Idioma: En Revista: J Biol Chem Año: 2022 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Estados Unidos