The role of Trib1 in myeloid leukaemogenesis and differentiation

2015 ◽  
Vol 43 (5) ◽  
pp. 1104-1107 ◽  
Author(s):  
Takuro Nakamura
Keyword(s):  
Integration Site ◽  
Myeloid Cell ◽  
Mouse Bone Marrow ◽  
Erk Activation ◽  
Extracellular Signal ◽  
Enhancer Binding Protein ◽  
Transforming Activity ◽  
Virus Integration ◽  
Ecotropic Virus

Tribbles homolog 1 (Trib1) was identified as a common integration site of the Homeobox a9 (Hoxa9)/murine ecotropic virus integration site 1 (Meis1) retrovirus in acute myeloid leukaemia (AML). Trib1 is by itself a transforming gene for myeloid cells but also significantly accelerates progression of Hoxa9/Meis1-induced AML. The strong transforming activity of Trib1 depends on its bi-directional function in CCAAT/enhancer-binding protein (C/EBPα) degradation and MAPK/ERK kinase (MEK)/extracellular-signal-regulated kinase (ERK) activation. TRIB1 is also involved in a certain type of human AML and a TRIB1 somatic point mutation R107L was identified in a case of Down syndrome (DS)-related acute megakaryocytic leukaemia. Although Trib1 knockout (KO) did not suppress haematopoiesis in mouse bone marrow significantly, increase in mature granulocytes was observed and promotion of myeloid differentiation was associated with the increased C/EBPα protein. Trib1 thus plays an important role in myeloid cell development and transformation.

Association of a region of bovine chromosome 1 (BTA1) with age at puberty in Angus bulls

2016 ◽  
Vol 28 (10) ◽  
pp. 1618 ◽  
Author(s):  
María E. Fernández ◽  
Alberto Prando ◽  
Andrés Rogberg-Muñoz ◽  
Pilar Peral-García ◽  
Andrés Baldo ◽  
...  
Keyword(s):  
Integration Site ◽  
Bovine Genome ◽  
Chromosome 1 ◽  
Nucleotide Polymorphisms ◽  
Single Nucleotide ◽  
Complex Locus ◽  
Age At Puberty ◽  
Virus Integration ◽  
Ecotropic Virus ◽  
Larger Sample

Age at puberty is an important component of reproductive performance in cattle, so it is important to identify genes that contribute to the regulation of the onset of puberty and polymorphisms that explain differences between bulls. In a previous study, we found putative associations between age at puberty in Angus bulls and single-nucleotide polymorphisms (SNPs) in Chromosomes 1 and X. In the present work we aimed to confirm these findings in a larger sample of Angus bulls (n = 276). Four SNPs located in these regions were genotyped using SEQUENOM technology and the genotypes obtained were tested for association with age at puberty. The results showed that SNPs rs135953349 and rs110604205 on BTA1 were still significantly associated with age of puberty estimated at progressive sperm motility of 10% (P < 0.05). The association previously found on Chromosome X could not be confirmed. Analysis of the bovine genome revealed that the associated region (99.17–99.99 Mb) contained four predicted loci: myelodysplasia syndrome 1 (MDS1) and ecotropic virus integration site 1 (EVI1) complex locus (MECOM), eGF-like and EMI domain-containing 1 pseudogene-like (LOC100337483), microRNA mir-551b (MIR551B) and mCG140927-like (LOC100139843). The results obtained could contribute to the understanding of puberty regulation and could be useful for further identification and annotation of gene function in the context of reproduction.

Extracellular signal-regulated kinase activation by parathyroid hormone in distal tubule cells

2007 ◽  
Vol 292 (3) ◽  
pp. F1028-F1034 ◽  
Author(s):  
W. Bruce Sneddon ◽  
Yanmei Yang ◽  
Jianming Ba ◽  
Lisa M. Harinstein ◽  
Peter A. Friedman
Keyword(s):  
Conditioned Media ◽  
Kidney Cells ◽  
Wild Type ◽  
Egfr Transactivation ◽  
Hek 293 ◽  
Erk Activation ◽  
Hek 293 Cells ◽  
293 Cells ◽  
Extracellular Signal

The PTH receptor (PTH1R) activates multiple signaling pathways, including extracellular signal-regulated kinases 1 and 2 (ERK1/2). The role of epidermal growth factor receptor (EGFR) transactivation in ERK1/2 activation by PTH in distal kidney cells, a primary site of PTH action, was characterized. ERK1/2 phosphorylation was stimulated by PTH and blocked by the EGFR inhibitor, AG1478. Upon PTH stimulation, metalloprotease cleavage of membrane-bound heparin-binding fragment (HB-EGF) induced EGFR transactivation of ERK. Conditioned media from PTH-treated distal kidney cells activated ERK in HEK-293 cells. AG1478 added to HEK-293 cells ablated transactivation by conditioned media. HB-EGF directly activated ERK1/2 in HEK-293 cells. Pretreatment of distal kidney cells with the metalloprotease inhibitor GM-6001 abolished transactivation of ERK1/2 by PTH. The role of the PTH1R COOH terminus in PTX-sensitive ERK1/2 activation was characterized in HEK-293 cells transfected with wild-type PTH1R, with a PTH1R mutated at its COOH terminus, or with PTH1R truncated at position 480. PTH stimulated ERK by wild-type, mutated and truncated PTH1Rs 21-, 27- and 57-fold, respectively. Thus, the PTH1R COOH terminus exerts an inhibitory effect on ERK activation. EBP50, a scaffolding protein that binds to the PDZ recognition domain of the PTH1R, impaired PTH but not isoproterenol or calcitonin-induced ERK activation. Pertussis toxin inhibited PTH-stimulated ERK1/2 by mutated and truncated PTH1Rs and abolished ERK1/2 activation by wild-type PTH1R. We conclude that ERK phosphorylation in distal kidney cells by PTH requires PTH1R activation of Gi, which leads to stimulation of metalloprotease-mediated cleavage of HB-EGF and transactivation of the EGFR and is regulated by EBP50.

scholarly journals Ecotropic virus integration site-1 gene preferentially expressed in post-myelodysplasia acute myeloid leukemia: possible association with GATA-1, GATA-2, and stem cell leukemia gene expression

Blood ◽  
1995 ◽  
Vol 85 (12) ◽  
pp. 3713-3718 ◽  
Author(s):  
JH Ohyashiki ◽  
K Ohyashiki ◽  
T Shimamoto ◽  
K Kawakubo ◽  
T Fujimura ◽  
...  
Keyword(s):  
Gene Expression ◽  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Integration Site ◽  
Cell Leukemia ◽  
Virus Integration ◽  
Ecotropic Virus ◽  
Stem Cell Leukemia ◽  
Acute Myeloid ◽  
Virus Integration Site

We investigated expression of the human ecotropic virus integration site-1 (EVI1) gene in patients with leukemia and myelodysplastic syndrome (MDS) using the reverse transcriptase-polymerase chain reaction (RT-PCR) method. The EVI1 transcripts were detected in 5 (10.0%) of 50 patients with de novo acute myeloid leukemia (AML), including two AML patients with trilineage myelodysplasia, and in 8 (34.8%) of 23 patients with post-myelodysplastic syndrome AML (post-MDS AML). EVI1 expression was also detected in 6 (35.3%) of 17 MDS patients and three of six patients with chronic myeloid leukemia (CML) in myelomegakaryoblast crisis. No EVI1 transcripts were detected in patients with acute lymphoid leukemia (n = 15) or CML in lymphoid blast crisis (n = 4). Chromosomal abnormalities at the 3q26 region, where the EVI1 gene is located, were found in one patient with MDS and two patients with CML myelomegakaryoblast crisis who had EVI1 expression. Our results showed that EVI1 expression was frequent in patients with post-MDS AML and AML with trilineage myelodysplasia, regardless of the presence or absence of 3q26 abnormalities. EVI1 expression was accompanied by expression of GATA-1 and GATA-2, and often by stem cell leukemia (SCL) gene expression. In patients with post-MDS AML, EVI1 expression was not always associated with a 3q26 abnormality, whereas EVI1 expression in CML myelomegakaryoblast crisis was often linked to a 3q26 abnormality. Our results suggest that the leukemogenic role of EVI1 expression may differ between post-MDS AML and leukemia, with EVI1 expression associated with a 3q26 abnormality.

Congenital Duplication of the Palm in a Patient with Multiple Anomalies

2003 ◽  
Vol 28 (3) ◽  
pp. 276-279 ◽  
Author(s):  
M. M. AL-QATTAN
Keyword(s):  
Family Member ◽  
Integration Site ◽  
Mammary Tumour ◽  
Mouse Mammary Tumour Virus ◽  
Virus Integration ◽  
Virus Integration Site

In 1995, Parr and McMahon described a syndrome of congenital duplication of footpads in mice which lacked a protein called ‘Wingless-type mouse mammary tumour virus integration site family member 7a” (Wnt-7a). This syndrome has not been described in humans and the following report describes a similar syndrome in a Saudi girl. The role of Wnt-7a in the development of the limb along the dorso-ventral axis is discussed, along with interaction between the Wnt-7a and other axes of limb growth.

Role of CaM kinase II and ERK activation in thrombin-induced endothelial cell barrier dysfunction

2003 ◽  
Vol 285 (1) ◽  
pp. L43-L54 ◽  
Author(s):  
Talaibek Borbiev ◽  
Alexander D. Verin ◽  
Anna Birukova ◽  
Feng Liu ◽  
Michael T. Crow ◽  
...  
Keyword(s):  
Endothelial Cell ◽  
Cam Kinase Ii ◽  
Cam Kinase ◽  
Barrier Dysfunction ◽  
Erk Activation ◽  
Cytoskeletal Rearrangement ◽  
Myosin Binding Protein ◽  
Extracellular Signal ◽  
Barrier Regulation

We have previously shown that thrombin-induced endothelial cell barrier dysfunction involves cytoskeletal rearrangement and contraction, and we have elucidated the important role of endothelial cell myosin light chain kinase and the actin- and myosin-binding protein caldesmon. We evaluated the contribution of calmodulin (CaM) kinase II and extracellular signal-regulated kinase (ERK) activation in thrombin-mediated bovine pulmonary artery endothelial cell contraction and barrier dysfunction. Similar to thrombin, infection with a constitutively active adenoviral α-CaM kinase II construct induced significant ERK activation, indicating that CaM kinase II activation lies upstream of ERK. Thrombin-induced ERK-dependent caldesmon phosphorylation (Ser789) was inhibited by either KN-93, a specific CaM kinase II inhibitor, or U0126, an inhibitor of MEK activation. Immunofluorescence microscopy studies revealed phosphocaldesmon colocalization within thrombin-induced actin stress fibers. Pretreatment with either U0126 or KN-93 attenuated thrombin-mediated cytoskeletal rearrangement and evoked declines in transendothelial electrical resistance while reversing thrombin-induced dissociation of myosin from nondenaturing caldesmon immunoprecipitates. These results strongly suggest the involvement of CaM kinase II and ERK activities in thrombin-mediated caldesmon phosphorylation and both contractile and barrier regulation.

Constitutive Activation of Extracellular Signal-Regulated Kinase in Human Acute Leukemias: Combined Role of Activation of MEK, Hyperexpression of Extracellular Signal-Regulated Kinase, and Downregulation of a Phosphatase, PAC1

Blood ◽  
1999 ◽  
Vol 93 (11) ◽  
pp. 3893-3899 ◽  
Author(s):  
Seong-Cheol Kim ◽  
Jee-Sook Hahn ◽  
Yoo-Hong Min ◽  
Nae-Choon Yoo ◽  
Yun-Woong Ko ◽  
...  
Keyword(s):  
Acute Leukemia ◽  
Immunoblot Analysis ◽  
Kinase Assay ◽  
Hematopoietic Tissue ◽  
Acute Leukemias ◽  
Erk Activation ◽  
Extracellular Signal Regulated Kinase ◽  
Constitutive Activation ◽  
Extracellular Signal

Abstract Extracellular signal-regulated kinase (ERK) is an important intermediate in signal transduction pathways that are initiated by many types of cell surface receptors. It is thought to play a pivotal role in integrating and transmitting transmembrane signals required for growth and differentiation. Constitutive activation of ERK in fibroblasts elicits oncogenic transformation, and recently, constitutive activation of ERK has been observed in some human malignancies, including acute leukemia. However, mechanisms underlying constitutive activation of ERK have not been well characterized. In this study, we examined the activation of ERK in 79 human acute leukemia samples and attempted to find factors contributing to constitutive ERK activation. First, we showed that ERK and MEK were constitutively activated in acute leukemias by in vitro kinase assay and immunoblot analysis. However, in only one half of the studied samples, the pattern of ERK activation was similar to that of MEK activation. Next, by semiquantitative reverse transcriptase-polymerase chain reaction (RT-PCR) and immunoblot analysis, we showed hyperexpression of ERK in a majority of acute leukemias. In 17 of 26 cases (65.4%) analyzed by immunoblot, the pattern of ERK expression was similar to that of ERK activation. The fact of constitutive activation of ERK in acute leukemias suggested to us the possibility of an abnormal downregulation mechanism of ERK. Therefore, we examined PAC1, a specific ERK phosphatase predominantly expressed in hematopoietic tissue and known to be upregulated at the transcription level in response to ERK activation. Interestingly, in our study, PAC1 gene expression in acute leukemias showing constitutive ERK activation was significantly lower than that in unstimulated, normal bone marrow (BM) samples showing minimal or no ERK activation (P = .002). Also, a significant correlation was observed between PAC1 downregulation and phosphorylation of ERK in acute leukemias (P= .002). Finally, by further analysis of 26 cases, we showed that a complementary role of MEK activation, ERK hyperexpression, and PAC1 downregulation could contribute to determining the constitutive activation of ERK in acute leukemia. Our results suggest that ERK is constitutively activated in a majority of acute leukemias, and in addition to the activation of MEK, the hyperexpression of ERK and downregulation of PAC1 also contribute to constitutive ERK activation in acute leukemias.

scholarly journals Kinetic and biochemical correlation between sustained p44ERK1 (44 kDa extracellular signal-regulated kinase 1) activation and lysophosphatidic acid-stimulated DNA synthesis in Rat-1 cells

1996 ◽  
Vol 320 (1) ◽  
pp. 237-245 ◽  
Author(s):  
Simon J. COOKOnyx ◽  
Frank McCORMICK
Keyword(s):  
Dna Synthesis ◽  
Pertussis Toxin ◽  
Lysophosphatidic Acid ◽  
Peak Response ◽  
Erk Activation ◽  
Extracellular Signal Regulated Kinase ◽  
Herbimycin A ◽  
Extracellular Signal ◽  
Sustained Activation

Rat-1 fibroblasts were used to study the role of the sustained activation of extracellular signal-regulated kinase 1 (ERK1) in lysophosphatidic acid (LPA)-stimulated mitogenic signalling. Mitogenic doses of LPA, like serum, stimulated biphasic, sustained, ERK activation that persisted towards the G1/S boundary. The EC50 for LPA-stimulated ERK activation after 10 min, the time of peak response, was 2 orders of magnitude to the left of that for the sustained response after 3 h or that for DNA synthesis after 22 h, with the result that non-mitogenic doses stimulated a maximal peak response but no second phase. To complement these studies, we examined the role of different signal pathways in regulating the sustained and acute phases of ERK activation using defined biochemical inhibitors and mimetics. Activation of protein kinase C and Ca2+ fluxes played a minor and transient role in regulation of ERK1 activity by LPA in Rat-1 cells. Sustained ERK1 activation stimulated by LPA was completely inhibited by pertussis toxin, whereas the early peak response was only partly affected; this is correlated with the specific inhibition of LPA-stimulated DNA synthesis by pertussis toxin. The selective tyrosine kinase inhibitor herbimycin A completely inhibited sustained ERK1 activation by LPA but, again, the early phase of the response was only partially inhibited. In addition, low doses of staurosporine inhibited ERK1 activation by LPA. The effects of herbimycin A and staurosporine were selective for the response to LPA but did not affect that to epidermal growth factor. The results suggest a strong correlation between sustained ERK1 activation and DNA synthesis in LPA-stimulated Rat-1 cells. Furthermore, the two discrete phases of ERK activation by LPA are regulated by a combination of at least two different signalling pathways; the sustained activation of ERK1 in Rat-1 cells proceeds via a Gi- or Go-mediated pathway which may also involve a tyrosine kinase.

scholarly journals Phosphorylation of the C-Raf N Region Promotes Raf Dimerization

2017 ◽  
Vol 37 (19) ◽  
Author(s):  
Maho Takahashi ◽  
Yanping Li ◽  
Tara J. Dillon ◽  
Yumi Kariya ◽  
Philip J. S. Stork
Keyword(s):  
Drug Targets ◽  
Small Gtpase ◽  
Potential Candidate ◽  
Erk Activation ◽  
Extracellular Signal ◽  
Candidate Drug ◽  
Mitogen Activated Protein

ABSTRACT The activation of Raf kinases by the small GTPase Ras requires two major sets of phosphorylations. One set lies within the activation loop, and the other lies within the N-terminal acidic region (N region). In the most abundant isoform of Raf, C-Raf, N-region phosphorylations occur on serine 338 (S338) and tyrosine 341 (Y341) and are thought to provide allosteric activation of the Raf dimer. We show that the phosphorylations of these N-region sites does not require C-Raf dimerization, but rather, they precede dimerization. One of these phosphorylations (phospho-Y341) is required for C-Raf dimerization, and this action can be replicated by phosphomimetic mutants both in vivo and in vitro. The role of the phosphorylation of Y341 in promoting Raf dimerization is distinct from its well-known function in facilitating S338 phosphorylation. In Ras mutant pancreatic cancer cell lines, the phosphorylation and dimerization of C-Raf are basally elevated. Dimerization is thought to contribute to their elevated growth rate through their activation of the mitogen-activated protein (MAP) kinase (extracellular signal-regulated kinase [ERK]) signaling cascade. Blocking the tyrosine phosphorylation of C-Raf with Src family inhibitors blocks growth, basal dimerization, and ERK activation in these cells. We suggest that the kinases mediating C-Raf Y341 phosphorylation are potential candidate drug targets in selected Ras-dependent cancers.

Role of reactive oxygen species in IL-1β-stimulated sustained ERK activation and MMP-9 induction

2001 ◽  
Vol 281 (6) ◽  
pp. H2568-H2574 ◽  
Author(s):  
Milind V. Gurjar ◽  
Jason Deleon ◽  
Ram V. Sharma ◽  
Ramesh C. Bhalla
Keyword(s):  
Reactive Oxygen Species ◽  
Manganese Superoxide Dismutase ◽  
Reactive Oxygen ◽  
Second Phase ◽  
Oxygen Species ◽  
Erk Activation ◽  
Transient Activation ◽  
Gene Treatment ◽  
Extracellular Signal

We have recently demonstrated that interleukin-1β (IL-1β) stimulates matrix metalloproteinase-9 (MMP-9) induction. In this study we have investigated the roles of superoxide and extracellular signal-regulated kinase (ERK) activation in MMP-9 induction following exposure to IL-1β. IL-1β stimulated biphasic ERK activation in vascular smooth muscle (VSM) cells, a transient activation that reached a maximum at 15 min and declined to baseline levels within 1 h, and a second phase of sustained ERK activation lasting up to 8 h. To determine the role of ERK in IL-1β-stimulated MMP-9 induction, we treated cells with the specific ERK pathway inhibitor PD-98059 at different time intervals after IL-1β stimulation. Addition of PD-98059 up to 4 h after IL-1β stimulation significantly inhibited MMP-9 induction, suggesting a role for sustained ERK activation in MMP-9 induction. IL-1β treatment stimulated superoxide production in VSM cells that was inhibited by pretreatment of cells with the superoxide scavenger N-acetyl-l-cysteine (NAC) and also by overexpression of the human manganese superoxide dismutase (MnSOD) gene. Treatment of VSM cells with NAC selectively inhibited the sustained phase of ERK activation without influencing the transient phase, suggesting a role for reactive oxygen species in sustained ERK activation. In addition, both NAC treatment and MnSOD overexpression significantly inhibited IL-1β-stimulated MMP-9 induction ( P < 0.05). The results demonstrate that IL-1β-dependent MMP-9 induction is mediated by superoxide-stimulated ERK activation.

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