Abstract 32: EBP50 and NF-κB: A Feed-Forward Regulation of Vascular Inflammation

2012 ◽  
Vol 32 (suppl_1) ◽  
Author(s):  
Kristen Leslie ◽  
GyunJee Song ◽  
Stacey Barrick ◽  
Alessandro Bisello
Keyword(s):  
Macrophage Activation ◽  
Nuclear Translocation ◽  
Vascular Inflammation ◽  
Cell Types ◽  
Dominant Negative ◽  
Scaffolding Protein ◽  
Vsmc Proliferation ◽  
Multiple Cell ◽  
Low Levels

Inflammation plays a fundamental role in the development of cardiovascular diseases such as atherosclerosis and restenosis. The vascular response to inflammation in these diseases requires communication between multiple cell types such as vascular smooth muscle cells (VSMC) and macrophages. We have identified a scaffolding protein, Ezrin Binding Protein 50 (EBP50, also known as NHERF-1), which is expressed at very low levels in normal vessels but is up-regulated following vascular injury. EBP50 promotes VSMC proliferation and neointima formation after wire injury in mouse femoral arteries. In the current study, we hypothesized that EBP50 functions as a central mediator linking macrophage activation and the response of vessels to inflammation. Similar to the observations in vessels, treatment of primary VSMC and macrophages with LPS or TNFα increased EBP50 expression. This increase was dependent on NF-κB signaling because pharmacological inhibition of NF-κB and expression of a dominant negative IκBα abolished the induction of EBP50. Interestingly, LPS-induced activation of NF-κB (determined by phosphorylation of IKKα/β, degradation of IκBα, and p65 phosphorylation) was impaired in EBP50 null VSMC and macrophages. Moreover, nuclear translocation of the p65 subunit of NF-κB was also reduced in EBP50 -/- VSMC. Consistent with the role of EBP50 on NF-κB, LPS- and TNFα-induced macrophage activation (determined by the expression of the inflammatory markers iNOS, TNFα, and IL-1β) was reduced in EBP50 -/- macrophages and mice. Similarly, the expression of iNOS, VCAM-1, and ICAM-1 in VSMC was decreased in EBP50 -/- VSMC and mice. Collectively, these observations indicate that EBP50 and NF-κB participate in a positive feedback loop leading to increased macrophage activation and enhanced response of VSMC to inflammation, suggesting its involvement in vascular remodeling.

scholarly journals Microtubule–microtubule sliding by kinesin-1 is essential for normal cytoplasmic streaming in Drosophila oocytes

2016 ◽  
Vol 113 (34) ◽  
pp. E4995-E5004 ◽  
Author(s):  
Wen Lu ◽  
Michael Winding ◽  
Margot Lakonishok ◽  
Jill Wildonger ◽  
Vladimir I. Gelfand
Keyword(s):  
Cytoplasmic Streaming ◽  
Cell Types ◽  
Nurse Cells ◽  
Wild Type ◽  
Actin Cortex ◽  
Microtubule Motor ◽  
Multiple Cell ◽  
Cytoplasmic Microtubules ◽  
Two Populations

Cytoplasmic streaming in Drosophila oocytes is a microtubule-based bulk cytoplasmic movement. Streaming efficiently circulates and localizes mRNAs and proteins deposited by the nurse cells across the oocyte. This movement is driven by kinesin-1, a major microtubule motor. Recently, we have shown that kinesin-1 heavy chain (KHC) can transport one microtubule on another microtubule, thus driving microtubule–microtubule sliding in multiple cell types. To study the role of microtubule sliding in oocyte cytoplasmic streaming, we used a Khc mutant that is deficient in microtubule sliding but able to transport a majority of cargoes. We demonstrated that streaming is reduced by genomic replacement of wild-type Khc with this sliding-deficient mutant. Streaming can be fully rescued by wild-type KHC and partially rescued by a chimeric motor that cannot move organelles but is active in microtubule sliding. Consistent with these data, we identified two populations of microtubules in fast-streaming oocytes: a network of stable microtubules anchored to the actin cortex and free cytoplasmic microtubules that moved in the ooplasm. We further demonstrated that the reduced streaming in sliding-deficient oocytes resulted in posterior determination defects. Together, we propose that kinesin-1 slides free cytoplasmic microtubules against cortically immobilized microtubules, generating forces that contribute to cytoplasmic streaming and are essential for the refinement of posterior determinants.

scholarly journals Platelet and Erythrocyte Extravasation across Inflamed Corneal Venules Depend on CD18, Neutrophils and Mast Cell Degranulation

2021 ◽  
Vol 22 (14) ◽  
pp. 7360
Author(s):  
Angie De La Cruz ◽  
Aubrey Hargrave ◽  
Sri Magadi ◽  
Justin A. Courson ◽  
Paul T. Landry ◽  
...  
Keyword(s):  
Mast Cell ◽  
Cell Types ◽  
Mast Cell Degranulation ◽  
Wild Type ◽  
Delayed Wound Healing ◽  
Corneal Epithelial ◽  
Corneal Abrasion ◽  
Low Levels ◽  
Endothelial Pores

Platelet extravasation during inflammation is under-appreciated. In wild-type (WT) mice, a central corneal epithelial abrasion initiates neutrophil (PMN) and platelet extravasation from peripheral limbal venules. The same injury in mice expressing low levels of the β2-integrin, CD18 (CD18hypo mice) shows reduced platelet extravasation with PMN extravasation apparently unaffected. To better define the role of CD18 on platelet extravasation, we focused on two relevant cell types expressing CD18: PMNs and mast cells. Following corneal abrasion in WT mice, we observed not only extravasated PMNs and platelets but also extravasated erythrocytes (RBCs). Ultrastructural observations of engorged limbal venules showed platelets and RBCs passing through endothelial pores. In contrast, injured CD18hypo mice showed significantly less venule engorgement and markedly reduced platelet and RBC extravasation; mast cell degranulation was also reduced compared to WT mice. Corneal abrasion in mast cell-deficient (KitW-sh/W-sh) mice showed less venule engorgement, delayed PMN extravasation, reduced platelet and RBC extravasation and delayed wound healing compared to WT mice. Finally, antibody-induced depletion of circulating PMNs prior to corneal abrasion reduced mast cell degranulation, venule engorgement, and extravasation of PMNs, platelets, and RBCs. In summary, in the injured cornea, platelet and RBC extravasation depends on CD18, PMNs, and mast cell degranulation.

scholarly journals Phospholipase D2 Localizes to the Plasma Membrane and Regulates Angiotensin II Receptor Endocytosis

2004 ◽  
Vol 15 (3) ◽  
pp. 1024-1030 ◽  
Author(s):  
Guangwei Du ◽  
Ping Huang ◽  
Bruce T. Liang ◽  
Michael A. Frohman
Keyword(s):  
Plasma Membrane ◽  
Angiotensin Ii ◽  
Membrane Vesicle ◽  
Membrane Vesicles ◽  
Cell Types ◽  
Dominant Negative ◽  
Secretory Cells ◽  
Resting Cells ◽  
Angiotensin Ii Receptor ◽  
Multiple Cell

Phospholipase D (PLD) is a key facilitator of multiple types of membrane vesicle trafficking events. Two PLD isoforms, PLD1 and PLD2, exist in mammals. Initial studies based on overexpression studies suggested that in resting cells, human PLD1 localized primarily to the Golgi and perinuclear vesicles in multiple cell types. In contrast, overexpressed mouse PLD2 was observed to localize primarily to the plasma membrane, although internalization on membrane vesicles was observed subsequent to serum stimulation. A recent report has suggested that the assignment of PLD2 to the plasma membrane is in error, because the endogenous isoform in rat secretory cells was imaged and found to be present primarily in the Golgi apparatus. We have reexamined this issue by using a monoclonal antibody specific for mouse PLD2, and find, as reported initially using overexpression studies, that endogenous mouse PLD2 is detected most readily at the plasma membrane in multiple cell types. In addition, we report that mouse, rat, and human PLD2 when overexpressed all similarly localize to the plasma membrane in cell lines from all three species. Finally, studies conducted using overexpression of wild-type active or dominant-negative isoforms of PLD2 and RNA interference-mediated targeting of PLD2 suggest that PLD2 functions at the plasma membrane to facilitate endocytosis of the angiotensin II type 1 receptor.

scholarly journals Generation of a Quantitative Luciferase Reporter for Sox9 SUMOylation

2020 ◽  
Vol 21 (4) ◽  
pp. 1274
Author(s):  
Hideka Saotome ◽  
Atsumi Ito ◽  
Atsushi Kubo ◽  
Masafumi Inui
Keyword(s):  
Cell Types ◽  
Live Cells ◽  
Luciferase Reporter ◽  
Dependent Manner ◽  
Post Translational Modifications ◽  
Extracellular Signal ◽  
Multiple Cell ◽  
Sox9 Activity ◽  
Reporter Signal

Sox9 is a master transcription factor for chondrogenesis, which is essential for chondrocyte proliferation, differentiation, and maintenance. Sox9 activity is regulated by multiple layers, including post-translational modifications, such as SUMOylation. A detection method for visualizing the SUMOylation in live cells is required to fully understand the role of Sox9 SUMOylation. In this study, we generated a quantitative reporter for Sox9 SUMOylation that is based on the NanoBiT system. The simultaneous expression of Sox9 and SUMO1 constructs that are conjugated with NanoBiT fragments in HEK293T cells induced luciferase activity in SUMOylation target residue of Sox9-dependent manner. Furthermore, the reporter signal could be detected from both cell lysates and live cells. The signal level of our reporter responded to the co-expression of SUMOylation or deSUMOylation enzymes by several fold, showing dynamic potency of the reporter. The reporter was active in multiple cell types, including ATDC5 cells, which have chondrogenic potential. Finally, using this reporter, we revealed a extracellular signal conditions that can increase the amount of SUMOylated Sox9. In summary, we generated a novel reporter that was capable of quantitatively visualizing the Sox9-SUMOylation level in live cells. This reporter will be useful for understanding the dynamism of Sox9 regulation during chondrogenesis.

scholarly journals Nitric Oxide Transiently Converts Synaptic Inhibition to Excitation in Retinal Amacrine Cells

2006 ◽  
Vol 95 (5) ◽  
pp. 2866-2877 ◽  
Author(s):  
Brian Hoffpauir ◽  
Emily McMains ◽  
Evanna Gleason
Keyword(s):  
Nitric Oxide ◽  
Hippocampal Neurons ◽  
Reversal Potential ◽  
Amacrine Cells ◽  
Cell Types ◽  
Synaptic Function ◽  
Positive Shift ◽  
Gabaergic Synapses ◽  
Multiple Cell

Nitric oxide (NO) is generated by multiple cell types in the vertebrate retina, including amacrine cells. We investigate the role of NO in the modulation of synaptic function using a culture system containing identified retinal amacrine cells. We find that moderate concentrations of NO alter GABAA receptor function to produce an enhancement of the GABA-gated current. Higher concentrations of NO also enhance GABA-gated currents, but this enhancement is primarily due to a substantial positive shift in the reversal potential of the current. Several pieces of evidence, including a similar effect on glycine-gated currents, indicate that the positive shift is due to an increase in cytosolic Cl−. This change in the chloride distribution is especially significant because it can invert the sign of GABA- and glycine-gated voltage responses. Furthermore, current- and voltage-clamp recordings from synaptic pairs of GABAergic amacrine cells demonstrate that NO transiently converts signaling at GABAergic synapses from inhibition to excitation. Persistence of the NO-induced shift in ECl− in the absence of extracellular Cl− indicates that the increase in cytosolic Cl− is due to release of Cl− from an internal store. An NO-dependent release of Cl− from an internal store is also demonstrated for rat hippocampal neurons indicating that this mechanism is not restricted to the avian retina. Thus signaling in the CNS can be fundamentally altered by an NO-dependent mobilization of an internal Cl− store.

scholarly journals Atypical Cristae Morphology of Human Syncytiotrophoblast Mitochondria

2011 ◽  
Vol 286 (27) ◽  
pp. 23911-23919 ◽  
Author(s):  
Daniela De Los Rios Castillo ◽  
Mariel Zarco-Zavala ◽  
Sofia Olvera-Sanchez ◽  
Juan Pablo Pardo ◽  
Oscar Juarez ◽  
...  
Keyword(s):  
Atp Synthase ◽  
Physiological Function ◽  
Cell Types ◽  
Dimeric Complex ◽  
Inhibitory Protein ◽  
Low Levels ◽  
Mitochondrial Complexes

Mitochondrial complexes I, III2, and IV from human cytotrophoblast and syncytiotrophoblast associate to form supercomplexes or respirasomes, with the following stoichiometries: I1:(III2)1 and I1:(III2)1–2:IV1–4. The content of respirasomes was similar in both cell types after isolating mitochondria. However, syncytiotrophoblast mitochondria possess low levels of dimeric complex V and do not have orthodox cristae morphology. In contrast, cytotrophoblast mitochondria show normal cristae morphology and a higher content of ATP synthase dimer. Consistent with the dimerizing role of the ATPase inhibitory protein (IF1) (García, J. J., Morales-Ríos, E., Cortés-Hernandez, P., and Rodríguez-Zavala, J. S. (2006) Biochemistry 45, 12695–12703), higher relative amounts of IF1 were observed in cytotrophoblast when compared with syncytiotrophoblast mitochondria. Therefore, there is a correlation between dimerization of complex V, IF1 expression, and the morphology of mitochondrial cristae in human placental mitochondria. The possible relationship between cristae architecture and the physiological function of the syncytiotrophoblast mitochondria is discussed.

Hdm2 Is an Ubiquitin Ligase for the Anti-Apoptotic Protein Ku70.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 3347-3347
Author(s):  
Vivian Gama ◽  
Jose A. Gomez ◽  
Lindsey D. Mayo ◽  
Arthur L. Haas ◽  
Shigemi Matsuyama
Keyword(s):  
Dna Damage ◽  
Endothelial Cells ◽  
Ubiquitin Ligase ◽  
Nuclear Translocation ◽  
Umbilical Vein ◽  
Resistant Mutant ◽  
Genotoxic Stress ◽  
Cell Types ◽  
Dominant Negative ◽  
Akt Phosphorylation

Abstract Protection of endothelial cells (ECs) from inappropriate apoptosis induced by various stresses (e.g. drugs, parasites, and reactive oxygen species) is necessary to maintain homeostasis. On the other hand, blockade of angiogenesis in malignant tissue is a promising strategy to fight against cancer. However, the molecular mechanism of survival control of ECs is not well understood. Bax is a key mediator of apoptosis in various cell types including ECs. Ku70 is a subunit of the Ku complex involved in DNA repair and is ubiquitously expressed. Recently, we found that the cytosolic form of Ku70 binds Bax and inhibits Bax-mediated apoptosis, and that the decrease of cytosolic Ku70 is necessary to activate Bax. Furthermore, we reported that ubiquitin-dependent Ku70 proteolysis is involved in Ku70 decrease in ECs treated by genotoxic stresses. The remaining important problem was the identification of Ku70 ubiquitin ligase decreasing Ku70 to activate Bax in ECs. Here we report evidences showing that Hdm2 is an ubiquitin ligase of Ku70. It is known that Hdm2 ubiquitinylates p53, a tumor suppressor protein, and that Hdm2 level increases in response to DNA damage. Using purified recombinant proteins, we confirmed that Hdm2 conjugates ubiquitin chains to Ku70. Hdm2 overexpression in human umbilical vein endothelial cells (HUVECs) induced Ku70 decrease. Genotoxic stress (i.e. etoposide treatment) induced Ku70 decrease in Mdm2 (mouse version of Hdm2)-proficient mouse embryonic fibroblasts (MEFs) whereas Ku70 decrease was significantly suppressed in Mdm2-deficient MEFs. We verified Ku70-Hdm2 association by immunoprecipitation and GST pull-downs. Nutlin-3, a well-characterized inhibitor of Hdm2-p53 interaction, effectively disrupted Hdm2-Ku70 interaction, suggesting that Hdm2 uses the same domain to bind both p53 and Ku70. In cancer cells, it has been reported that the survival kinase Akt phosphorylates Hdm2, and that this phosphorylation stimulates nuclear translocation of Hdm2 to ubiquitinylate and inactivate p53 in the nucleus. We investigated whether Akt-dependent phosphorylation of Hdm2 influences its activity to regulate Ku70 level in HUVECs. Vascular endothelial growth factor (VEGF) is known to increase ECs survival through Akt activation. Thus, VEGF was employed as a physiological activator of Akt. VEGF inhibited etoposide-induced Ku70 degradation in HUVECs. Importantly, VEGF stimulated nuclear localization of Hdm2. Constitutively active AKT, which has been reported to induce Hdm2 nuclear translocation, but not the dominant negative AKT, efficiently inhibited Ku70 degradation. Moreover, an Akt phosphorylation resistant mutant of Hdm2 was able to down-regulate Ku70 but not p53 in HUVECs, suggesting a differential mechanism of regulation for these two substrates. In addition, Hdm2 mutant without ubiquitin ligase activity did not decrease Ku70 or p53, supporting the hypothesis that Hdm2 directly modulates these proteins. Taken together, we propose that Hdm2 acts as a Ku70 ubiquitin ligase, and that VEGF-mediated activation of Akt prevents cytosolic Ku70 ubiquitinylation by Hdm2 probably by inducing Hdm2 translocation into the nucleus. Our results suggest that Ku70 level in ECs is controlled by the balance of DNA damage-induced factor (Hdm2 and p53) and survival kinase (Akt), and that Ku70 plays an important role in the decision making process of apoptosis induction in ECs.

Unraveling a Novel Mechanism of Stat5 Regulation by FAK and Rac1 in Flt3ITD Induced Leukemogenesis

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 858-858
Author(s):  
Anindya Chatterjee ◽  
Joydeep Ghosh ◽  
Baskar Ramdas ◽  
Sasidhar Vemula ◽  
Holly Martin ◽  
...  
Keyword(s):  
Tyrosine Kinase ◽  
Essential Role ◽  
Nuclear Translocation ◽  
Conflicts Of Interest ◽  
Myeloproliferative Neoplasms ◽  
Dominant Negative ◽  
Post Transplantation ◽  
Pharmacological Inhibition ◽  
F 14

Abstract Abstract 858 Multiple genetic checks and balances regulate the complex process of hematopoiesis. Despite these measures, mutations in crucial regulatory genes are still known to occur, which in some cases results in abnormal hematopoiesis, including leukemogenesis and/or myeloproliferative neoplasms (MPN). An example of a mutated gene that contributes to leukemogenesis is the FMS- like tyrosine kinase 3 (Flt3) that encodes a receptor tyrosine kinase, which plays an essential role in normal hematopoiesis. Interestingly, Flt3 is one of the most frequently mutated genes (∼30%) in acute myeloid leukemia (AML). Although various pathways downstream of Flt3 activation that lead to leukemic transformation have been extensively studied, effective treatment options for Flt3ITD mediated leukemogenesis is still warranted. In this study we used genetic, pharmacological and biochemical approaches to identify a novel role of Focal adhesion kinase (FAK) in Flt3ITD induced leukemogenesis. We observed hyperactivation of FAK in Flt3ITD expressing human and mouse cell. Treatment with FAK specific small molecule inhibitors F-14 and Y-11, inhibited proliferation and induced cell death of Flt3ITD expressing cells. Similarly, treatment of primary AML patient samples (n=9) expressing Flt3ITD mutations with F-14 inhibited their proliferation. Consistently expression of a dominant negative domain of FAK (FRNK) inhibited hyperproliferation and induced death of Flt3ITD bearing cells. Further, low-density bone marrow (LDBM) cells derived from FAK−/− mice transduced with Flt3ITD showed significantly reduced growth compared to wild-type (WT) LDBM cells transduced with Flt3ITD. We also observed hyperactivation of Rac1 in Flt3ITD expressing cells downstream of FAK, which was downregulated upon treatment with FAK inhibitor F-14 and Y11. Moreover, expression of dominant negative Rac1N17, or treatment with Rac1 inhibitor NSC23766 inhibited hyperproliferation of ITD bearing cells. We next wanted to ascertain the underlying mechanism of FAK mediated activation of Rac1 in Flt3ITD expressing cells. Toward this end, we found RacGEF Tiam1 to be hyperactive in Flt3ITD expressing cells, which was downregulated upon pharmacological inhibition of FAK. A Tiam1-Rac1 complex was also co-immunoprecipitated from Flt3ITD bearing cells, and this association was perturbed upon pharmacological inhibition of FAK. While, Stat5 a key molecule in Flt3ITD mediated leukemic progression, is activated and recruited to the nucleus to express Stat5 responsive genes; however the mechanism of Stat5 translocation to the nucleus is unknown. We observed a novel mechanism involving FAK and Rac1GTPase, in regulating the nuclear translocation of active Stat5. Pharmacological inhibition of FAK and Rac1 resulted in reduced Rac1 and STAT5 translocation into the nucleus, indicating a role of FAK-Rac-STAT5 signaling in Flt3ITD induced leukemogenesis. More importantly, expression of Flt3ITD in Rac1−/− or FAK−/− LDBM cells, showed inhibition of Stat5 activation and its failure to translocate into the nucleus when compared to Flt3ITD expression in WT-LDBM cells. We also observed association between active Rac1 and active Stat5 in the nucleus and in whole cell lysates of Flt3ITD bearing cells, and also in human AML patient samples (n=3), which was attenuated upon pharmacological inhibition of FAK. To determine the effect of FAK inhibition in vivo on Flt3ITD induced MPN, syngeneic transplantation was performed, and mice were treated with vehicle or with FAK inhibitor F-14. While vehicle treated mice developed MPN within 30 days, mice treated with F-14 showed significant overall survival (*p<0.02) and over 50% F-14 treated mice survived till 60 days post transplantation. Inhibition of kinases, and other signaling molecules, that are deregulated in cancer is an exciting new therapeutic strategy. This study indicate an essential role of FAK and Rac1 molecules in Flt3ITD mediated proliferation, survival and leukemogenesis, and demonstrates a novel mechanistic role of FAK/Rac1 in translocating active Stat5 into the nucleus and regulates transformation. To our knowledge, this is also the first time a role of RacGEF Tiam1 is observed in Flt3ITD induced leukemogenesis. Overall, this study demonstrates inhibition of FAK and Rac1 as potentially novel targets, and provides an alternative approach in treating humans suffering from Flt3-ITD induced AML. Disclosures: No relevant conflicts of interest to declare.

Essential roles of IκB kinases α and β in serum- and IL-1-induced human VSMC proliferation

2000 ◽  
Vol 278 (6) ◽  
pp. H1823-H1831 ◽  
Author(s):  
Sebastian Sasu ◽  
Debbie Beasley
Keyword(s):  
Smooth Muscle ◽  
Fluorescent Protein ◽  
Interleukin 1 ◽  
Fold Increase ◽  
Dominant Negative ◽  
Dominant Negative Mutant ◽  
Mutant Form ◽  
Mobility Shift ◽  
Vsmc Proliferation

Interleukin-1 (IL-1) is a potent vascular smooth muscle cell (VSMC) mitogen, which can stimulate cells via activation of nuclear factor-κB (NF-κB) following phosphorylation of its inhibitory subunit (IκB). Because the proliferative effect of IL-1 is additive with that of serum, the present studies assessed the role of IκB kinases (IKKs) and NF-κB in both IL-1- and serum-induced VSMC proliferation. IL-1β (1 ng/ml) induced marked and persistent NF-κB activation in VSMC that was maximal at 1 h and persisted for 3 days. There was a 3-fold increase in DNA synthesis after acute IL-1 exposure (24–96 h) and a 12-fold increase after chronic IL-1 exposure (>7 days). Electrophoretic mobility shift assay and supershift analysis indicated that IL-1-induced NF-κB complexes consisted of p65/p50 heterodimers and p50 homodimers. Human saphenous vein smooth muscle cells (HSVSMC) were transiently cotransfected with expression plasmids encoding a dominant negative mutant form of either IKKα or IKKβ, in which K44 was mutated to A (K44A), and a green fluorescent protein expression plasmid that allows identification of transfected cells. IL-1 induced nuclear localization of p65 in 95% of cells transfected with vector alone but in only 69% and 26% of cells expressing IKKα (K44A) or IKKβ (K44A), respectively. Likewise, proliferation increased 3.2-fold in IL-1-treated HSVSMC which had been transfected with vector alone, but only 2.2- and 1.5-fold proliferation in HSVSMC expressing IKKα (K44A) or IKKβ (K44A), respectively. Although serum activated NF-κB transiently, serum-induced proliferation was markedly attenuated in HSVSMC expressing IKKα (K44A) and IKKβ (K44A) compared with HSVSMC transfected with vector alone. The results support an essential role of IKKs in the proliferative response of HSVSMC to IL-1 and to serum.

scholarly journals Tribbles in normal and malignant haematopoiesis

2015 ◽  
Vol 43 (5) ◽  
pp. 1112-1115 ◽  
Author(s):  
Sarah J. Stein ◽  
Ethan A. Mack ◽  
Kelly S. Rome ◽  
Warren S. Pear
Keyword(s):  
E3 Ligase ◽  
Cell Types ◽  
Protein Family ◽  
Conserved Motifs ◽  
Tissue Specific ◽  
Cellular Events ◽  
Haematopoietic Cells ◽  
Evolutionarily Conserved ◽  
Multiple Cell

The tribbles protein family, an evolutionarily conserved group of pseudokinases, have been shown to regulate multiple cellular events including those involved in normal and malignant haematopoiesis. The three mammalian Tribbles homologues, Trib1, Trib2 and Trib3 are characterized by conserved motifs, including a pseudokinase domain and a C-terminal E3 ligase-binding domain. In this review, we focus on the role of Trib (mammalian Tribbles homologues) proteins in mammalian haematopoiesis and leukaemia. The Trib proteins show divergent expression in haematopoietic cells, probably indicating cell-specific functions. The roles of the Trib proteins in oncogenesis are also varied and appear to be tissue-specific. Finally, we discuss the potential mechanisms by which the Trib proteins preferentially regulate these processes in multiple cell types.

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