COP1 targets C/EBPα for degradation and induces acute myeloid leukemia via Trib1

Yoshida, Akihiro; Kato, Jun; Nakamae, Ikuko; Yoneda-Kato, Noriko

doi:10.1182/blood-2012-12-476101

Cited by 75 publications

(88 citation statements)

References 32 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…15,16,20) In contrast, in adipocytes, TRB1 is a nuclear transcriptional co-activator for the nuclear factor κB (NF-κB) subunit RelA, thereby promoting induction of proinflammatory cytokines in these cells. 45) TRB1 is also a target of inflammatory signals, which provides a molecular rationale for the amplification of proinflammatory responses in white adipose tissue.…”

Section: Discussionmentioning

confidence: 99%

“…13) TRB1 also has a role in the ubiquitin-proteasome pathway as an adaptor protein for constitutive photomorphogenic protein 1 (COP1), thereby promoting ubiquitination and degradation of acetyl coenzyme A carboxylase (ACC) 14) and CCA AT/enhancer-binding protein (C/EBPα, C/EBPβ). 15,16) TRB1 is implicated in diseases such as cancer and myocardial infarction, and high TRB1 expression with gene amplifications is associated with acute myeloid leukemia (AML) and myelodysplastic syndrome through promotion of ERK phosphorylation and degradation of C/EBPα. 14,17,18) There is also evidence linking TRB1 to control of plasma lipid homeostasis, which suggests that this molecule may be linked to risk factors for myocardial infarction.…”

mentioning

confidence: 99%

See 1 more Smart Citation

Positive Regulation of Interleukin-2 Expression by a Pseudokinase, Tribbles 1, in Activated T Cells

Miyajima

Itoh

Inoue

et al. 2015

Biological & Pharmaceutical Bulletin

View full text Add to dashboard Cite

Tribbles 1 (TRB1), a member of the Tribbles family, is a pseudokinase that is conserved among species and implicated in various human diseases including leukemia, cardiovascular diseases, and metabolic disorders. However, the role of TRB1 in the immune response is not understood. To evaluate this role, we examined regulation of TRB1 expression and the function of TRB1 in interleukin-2 (IL-2) induction in Jurkat cells, a human acute T cell leukemia cell line. We found that TRB1 was strongly induced by phorbol 12-myristate 13-acetate (PMA) and ionomycin in these cells. IL-2 expression was induced in Jurkat cells activated by PMA and ionomycin; however, knockdown of TRB1 resulted in decreased induction of IL-2. TRB1 null Jurkat cells established using the CRISPR/Cas9 system also showed reduction of IL-2 expression on PMA/ ionomycin stimulation. TRB1 knockdown also markedly inhibited IL-2 promoter activation. To determine the mechanism of the stimulatory effect on IL-2 induction, we focused on histone deacetylases (HDACs), and found that HDAC1 preferentially interacts with TRB1. TRB1 suppressed the interaction of HDAC1 with nuclear factor of activated T cells 2 (NFAT2), which is a crucial transcription factor for IL-2 induction. These results indicate that TRB1 is a positive regulator of IL-2 induction in activated T cells. Key words Tribbles 1 (TRB1); interleukin-2 (IL-2); histone deacetylase (HDAC); nuclear factor of activated T cells (NFAT)Interleukin-2 (IL-2) is a central factor in the immune system that affects various lymphocyte subsets during differentiation and in immune responses and homeostasis. 1) IL-2 is crucial for differentiation of CD4 + T cells into defined effector T cell subsets following antigen-mediated activation and for development and peripheral expansion of regulatory T (Treg) cells, which promote self-tolerance by suppressing T cell responses. For CD8 + T cells, IL-2 signaling optimizes effector T cell generation and differentiation into memory cells. 2) IL-2 is produced primarily in activated CD4+ T cells and is regulated at the mRNA level by signals from the T cell receptor (TCR) and CD28.3) Regulation of IL-2 transcription has been well characterized, and the nuclear factor of activated T cells (NFAT) and activator protein-1 (AP-1) transcription factors have been shown to be essential for inducible IL-2 expression in activated T cells. [4][5][6] Activation of NFATs is mainly regulated by calcium and calcineurin, while that of AP-1 is regulated by other pathways, including the protein kinase C (PKC) and Ras-mitogen-activated protein kinase (MAPK) pathways. In response to TCR stimulation, phospholipase C γ1 (PLCγ1) is phosphorylated and activated, and subsequent hydrolysis of phosphatidylinositol 4,5-bisphosphate (PIP2) by PLCγ1 produces inositol trisphosphate (IP3) and diacylglycerol (DAG) as second messengers. IP3 mediated Ca 2+ release from the endoplasmic reticulum (ER) and sequential entry of extracellular Ca 2+ through calcium release-activated Ca 2+ (CRAC) channels activates calcineu...

show abstract

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Positive Regulation of Interleukin-2 Expression by a Pseudokinase, Tribbles 1, in Activated T Cells

Miyajima

Itoh

Inoue

et al. 2015

Biological & Pharmaceutical Bulletin

View full text Add to dashboard Cite

show abstract

“…It is thought TRIB1 acts to negatively regulate C/EBP proteins by acting as adaptors to recruit COP1 to C/EBP family members thereby promoting ubiquitination and degradation. Studies have shown that COP1 requires TRIB1 for its action of C/EBPα (Yoshida, et al 2013).…”

Section: Localisationmentioning

confidence: 99%

“…The G-S-P motif is present in human SNIP1 (Smad nuclear interacting protein) which functionally associates with BGR1, which interacts with the Drosophila homologue of Slbo, C/EBP transcription factors (Beausoleil, et al 2004, Kadam, et al 2000. C/EBP transcription factors have been shown to functionally and physically interact with TRIB1 promoting their degradation (Yoshida, et al 2013). Kinase-like domain TRIB1 contains a Ser/Thr kinase-like domain that is composed of some of the motifs present in catalytically active kinases such as a Lysine crucial for ATP binding whilst others are missing.…”

Section: Descriptionmentioning

confidence: 99%

TRIB1 (tribbles pseudokinase 1)

Johnston¹,

Kiss-Tóth²

2017

Atlas of Genetics and Cytogenetics in Oncology and Haematology

View full text Add to dashboard Cite

show abstract

“…11 In mammals, putative substrates of COP1 include transcription factors (c-Jun, ETV1, p53, C/EBPa, TORC2, and FOXO1) and enzymes (acetyl-CoA carboxylase) that are involved in tumorigenesis and metabolism. 7,[12][13][14][15][16][17][18] Because COP1 functions in many biological responses in mammalian cells, the tribbles family appears to be an adaptor protein that recruits COP1 to a specific substrate for proteasome-mediated degradation. The Trib1-COP1 ligase complex specifically targets C/EBPa for degradation in hematopoiesis, and its overexpression causes AML in mouse models.…”

Section: Introductionmentioning

confidence: 99%

Myeloid leukemia factor 1 stabilizes tumor suppressor C/EBPα to prevent Trib1-driven acute myeloid leukemia

et al. 2017

Self Cite

View full text Add to dashboard Cite

Key Points• MLF1 suppresses C/EBPa degradation and AML development induced by the Trib1-COP1 complex.• MLF1 binds to COP1to prevent the interaction between Trib1 and COP1, thereby inhibiting COP1's ubiquitin ligase activity for C/EBPa.C/EBPa is a key transcription factor regulating myeloid differentiation and leukemogenesis.The Trib1-COP1 complex is an E3 ubiquitin ligase that targets C/EBPa for degradation, and its overexpression specifically induces acute myeloid leukemia (AML). Here we show that myeloid leukemia factor 1 (MLF1) stabilizes C/EBPa protein levels by inhibiting the ligase activity of the Trib1-COP1 complex. MLF1 directly interacts with COP1 in the nucleus and interferes with the formation of the Trib1-COP1 complex, thereby blocking its ability to polyubiquitinate C/EBPa for degradation. MLF1 overexpression suppressed the Trib1-induced growth advantage in a murine bone marrow (BM) culture and Trib1-induced AML development in BM-transplanted mouse models. MLF1 was expressed in hematopoietic stem cells and myeloid progenitors (common myeloid progenitors and granulocytemacrophage progenitors) in normal hematopoiesis, which is consistent with the distribution of C/EBPa. An MLF1 deficiency conferred a more immature phenotype on Trib1-induced AML development. A higher expression ratio of Trib1 to MLF1 was a key determinant for AML development in mouse models, which was also confirmed in human patient samples with acute leukemia. These results indicate that MLF1 is a positive regulator that is critical for C/EBPa stability in the early phases of hematopoiesis and leukemogenesis.

show abstract

COP1 targets C/EBPα for degradation and induces acute myeloid leukemia via Trib1

Cited by 75 publications

References 32 publications

Positive Regulation of Interleukin-2 Expression by a Pseudokinase, Tribbles 1, in Activated T Cells

Positive Regulation of Interleukin-2 Expression by a Pseudokinase, Tribbles 1, in Activated T Cells

TRIB1 (tribbles pseudokinase 1)

Myeloid leukemia factor 1 stabilizes tumor suppressor C/EBPα to prevent Trib1-driven acute myeloid leukemia

Contact Info

Product

Resources

About