57,500 research outputs found
C/EBPalpha downregualtes c-jun expression
No full textThe transcription factor C/EBPa is crucial for the differentiation of granulocytes. Conditional expression of C/EBPa triggers neutrophilic differentiation and C/EBPa can block TPA induced monocytic differentiation of bipotential myeloid cells. In C/EBPa knockout mice, no mature granulocytes are present. A dramatic increase of c-jun mRNA in C/EBPa knockout mice fetal liver was observed. c-jun, a component of the AP-1 transcription factor complex and a co-activator of the transcription factor PU.1, is important for monocytic differentiation. Here we report that C/EBPa downregulates c-jun expression to drive granulocytic differentiation. Ectopic increase of C/EBPa expression decreases c-jun mRNA level, and the human c-jun promoter activity is downregulated 8 fold in presence of C/EBPa. C/EBPa and c-jun interact through their leucine zipper domains and this interaction prevents c-jun from binding to DNA. This results in downregulation of c-jun’s capacity to autoregulate its own promoter through the proximal AP-1 site. Overexpression of c-jun prevents C/EBPa induced granulocytic differentiation. c-jun expression was higher in AML M2 patients with dominant negative C/EBPa mutations in comparison to AML M2 patients without C/EBPa mutations. Thus, we propose a model in which C/EBPa needs to downregulate c-jun expression and transactivation capacity for promoting granulocytic differentiation.Der Transkriptionsfaktor C/EBPa ist essentiell für die Differenzierung von Granulozyten. Die konditionelle Expression von C/EBPa induziert die neutrophile Differenzierung. Überdies kann C/EBPa die TPA-induzierte Differenzierung von myeloiden Vorläuferzellen zu Monozyten blockieren. In C/EBPa knockout Mäusen gibt es keine reifen Granulozyten. In der fötalen Leber von C/EBPa knockout Mäusen konnte eine stark erhöhte Expression der c-jun mRNA beobachtet werden. c-jun ist eine Komponente des AP-1 Transkriptionsfaktorkomplexes, ein Koaktivator des Transkriptionsfaktors PU.1 und ist wichtig für die Differenzierung von Monozyten. In dieser Arbeit zeigen wir, dass C/EBPa die c-jun Expression herunterreguliert und somit die Differenzierung von Granulozyten induziert. Die Überexpression von C/EBPa reduzierte die c-jun mRNA Menge und die Aktivität des humanen c-jun Promotors war in der Gegenwart von C/EBPa 8-fach herunterreguliert. C/EBPa und c-jun interagieren über ihre Leucin-Zipper Domänen und diese Interaktion verhindert die DNA-Bindung von c-jun. Dies resultiert in einer verminderten Kapazität von c-jun, den eigenen Promotor über die proximale AP-1 Stelle zu regulieren. Die Überexpression von c-jun blockiert die durch C/EBPa induzierte granulozytäre Differenzierung. Die c-jun Expression war in AML-M2 Patienten mit dominant-negativen Mutationen in C/EBPa im Vergleich zu AML-M2 Patienten ohne Mutationen in C/EBPa erhöht. Aufgrund dieser Daten schlagen wir ein Modell vor, in dem C/EBPa die Expression und Transaktivierungskapazität von c-jun herunterregulieren muß, um die granulozytäre Differenzierung zu induzieren
Signaling through CD44 affects cell cycle progression and c-Jun expression in acute myeloid leukemia cells
No full textWe present here the first evidence linking CD44 signaling to c-Jun expression and cell cycle progression in myeloid cell line models. CD44 ligation with the anti-CD44 monoclonal antibodies have been shown to induce differentiation and inhibit the proliferation of human acute myeloid leukemia (AML) cells, and c-Jun is involved in the regulation of these processes. The effects of anti-CD44 monoclonal antibody A3D8, on myeloid cells were associated with specific disruption of cell cycle events and induction of G0/G1 arrest. Induction of G0/G1 arrest was accompanied by an increase in the expression of p21, attenuation of pRb phosphorylation and associated with decreased CDK2 and CDK4 kinase activities. We observed that A3D8 treatment of AML patient blasts and HL60/U937 cells led to the downregulation of c-Jun expression at mRNA and protein level. Transient transfection studies showed the inhibition of c-jun promoter activity by A3D8, involving both AP-1 sites. Furthermore, A3D8 treatment caused a decrease in JNK protein expression and a decrease in the level of phosphorylated c-Jun. Ectopic overexpression of c-Jun in HL60 cells was able to induce proliferation and prevent the anti-proliferative effects of A3D8. Targeting of G1 regulatory proteins and the resulting induction of G1 arrest by A3D8 may provide new insights into anti-proliferative and differentiation therapy of AML
Portrait of Jun Gun, N.W. Australian Aboriginal [picture] /
No full textCondition: Fair, very yellowed.; Title from inscription.; Inscriptions: "Jun Gun, N. W. Australian Aboriginal" --Printed lower left corner. "J. W. Lindt, Melbourne" --Printed lower right corner
Proto-oncogene c-jun expression is induced by AML1-ETO in a JNK dependent manner:possible role in the pathogenesis of acute myeloid leukemia
No full textOverexpression of proto-oncogene c-jun and constitutive activation of the Jun NH2-terminal kinase (JNK) signaling pathway have been implicated in the leukemic transformation process. However, c-jun expression has not been investigated in acute myeloid leukemia (AML) cells containing the most common chromosomal translocations. t(8;21) is one of the most common AML-associated translocation and results in the AML1-ETO fusion protein. Overexpression of AML1-ETO in NIH3T3 cells leads to increased phosphorylation of Ser63 in c-Jun, which is generally JNK dependent. The role of the JNK signaling pathway for the functional properties of AML1-ETO is, however, unknown.
In the present study we found high expression levels of c-jun mRNA in t(8;21), t(15;17) or inv(16) positive patient cells by microarray analysis. Within t(8;21) positive patient samples, there was a correlation between AML1-ETO and c-jun mRNA expression levels. In myeloid U937 cells, c-jun mRNA and c-Jun protein expression levels increased upon induction of AML1-ETO. AML1-ETO transactivated the human c-jun promoter through the proximal AP-1 site via activating the JNK signaling pathway. JNK targets c-Jun and ATF-2, which also bind to the proximal AP-1 site in U937 cells, were also phosphorylated upon AML1-ETO induction. Furthermore, AML1-ETO induction increased the DNA binding capacity of c-Jun and ATF-2 to the proximal AP-1 site of the c-jun promoter, which might result in their enhanced transactivation capacities.
Interference with JNK and c-Jun activation by using JIP-1 or a JNK inhibitor reduced the transactivation capacity of AML1-ETO on the c-jun promoter and the pro-apoptotic function of AML1-ETO in U937 cells. AML1-ETO seems to activate the JNK signaling pathway by inducing the expression of a cytoplasmic factor, possibly G-CSF, because supernatant of AML1-ETO expressing cells was sufficient to induce phosphorylation of JNK and c-Jun in wildtype U937 cells.
This data demonstrates a novel mechanism of how AML1-ETO might exert positive effects on target gene expression and identifies the proto-oncogene c-jun as a common target gene in AML patient cells.Überexpression des Proto-Onkogens c-jun und konstitutive Aktivierung des Jun NH2-terminalen Kinase (JNK)-Signaltransduktionsweges sind wichtig für die leukämische Transformation in der Chronischen Myeloischen Leukämie. Die Expression von c-jun bei Akuter Myeloischer Leukämie (AML) mit den häufigsten reziproken Translokationen ist jedoch unbekannt. Bei einer der häufigsten AML Translokation t(8;21) wurde in Fibroblastenzellen gezeigt, daß das AML1-ETO-Fusionsgen die Phosphorylierung des Serin 63 in c-Jun erhöht. Die Rolle des JNK-Signalweges, der c-Jun am Serin 63 phosphorylieren kann, für die Funktion von AML1-ETO wurde bisher jedoch nicht untersucht. Weiterhin kann aktiviertes c-Jun durch eine positive Rückkoppelungsschleife über den c-jun Promotor zur Erhöhung der c-Jun Expression führen.
In der vorliegenden Arbeit konnten wir zeigen, daß AML Patientenzellen mit den häufigen Translokationen: t(8;21), t(15;17) oder inv(16) mehr c-jun mRNA besitzen im Vergleich zu Knochenmarkszellen gesunder Probanden. Weiterhin fanden wir eine hohe Korrelation zwischen der AML1-ETO und der c-jun mRNA bei t(8;21) positiven Patientenzellen. Induktion von AML1-ETO in der myeloischen U937 Zellinie erhöhte sowohl c-jun mRNA als auch c-Jun Proteinexpression. Damit konnten wir zeigen, daß AML1-ETO die Erhöhung der c-jun Expression bewirkt. Wir untersuchten den molekularen Mechanismus in U937 Zellen mittels transienter Transfektionen und fanden, daß AML1-ETO den c-jun Promotor durch die proximale AP-1 Seite transaktiviert. Diese Transaktivierung erfolgte indirekt über Aktivierung des JNK-Signaltransduktionsweges durch AML1-ETO. AML1-ETO-Induktion führte auch zur Phosphorylierung der JNK-Zielproteine c-Jun und ATF-2. Diese konnten im Gelretardierungsassay an die proximale AP-1 Seite des c-jun Promotors binden und wurden durch AML1-ETO-Induktion in ihrer Bindungsfähigkeit verstärkt. Deshalb nehmen wir an, daß die Transaktivierungskapazität des c-jun Promotors durch AML1-ETO über die Aktivierung des JNK-Signalweges läuft
Crosstalk between c-Jun and TAp73alpha/beta contributes to the apoptosis–survival balance
No full textThe p53-family member p73 plays a role in various cellular signaling pathways during development and growth control and it can have tumor suppressor properties. Several isoforms of p73 exist with considerable differences in their function. Whereas the functions of the N-terminal isoforms (TA and delta Np73) and their opposing pro- and antiapoptotic roles have become evident, the functional differences of the distinct C-terminal splice forms of TAp73 have remained unclear. Here, we characterized the global genomic binding sites for TAp73alpha and TAp73beta by chromatin immunoprecipitation sequencing as well as the transcriptional responses by performing RNA sequencing. We identified a specific p73 consensus binding motif and found a strong enrichment of AP1 motifs in close proximity to binding sites for TAp73alpha. These AP1 motif-containing target genes are selectively upregulated by TAp73alpha, while their mRNA expression is repressed upon TAp73beta induction. We show that their expression is dependent on endogenous c-Jun and that recruitment of c-Jun to the respective AP1 sites was impaired upon TAp73beta expression, in part due to downregulation of c-Jun. Several of these AP1-site containing TAp73alpha-induced genes impinge on apoptosis induction, suggesting an underlying molecular mechanism for the observed functional differences between TAp73alpha and TAp73beta
Erbb4 (Jm-B/Cyt-1)-Induced Expression and Phosphorylation of C-Jun Is Abrogated by Human Papillomavirus Type 16 E5 Protein
No full textHuman papillomavirus type 16 E5 (HPV-16 E5) is a highly hydrophobic membrane protein with weak-transforming activity , which is associated with ErbB4 receptor in HPV-16-infected cervical lesions. Presently, we investigated the transforming mechanisms of E5 involving ErbB4 signaling. Firstly, we report a role for ErbB4 (JM-b/CYT-1) receptor that activates c -jun gene expression and phosphorylating at Ser63 and Ser73 of the c-Jun protein in ligand-independent and Ras-c-jun NH2-terminal kinase-dependent pathway. Secondly, we show that HPV-16 E5 protein can form a complex with ErbB4 via binding to the extracellular and transmembrane domains of ErbB4 (JM-b/CYT-1). When co- expressing HPV-16 E5 and ErbB4 in cells, E5 can abrogate ErbB4-induced c-Jun protein expression and phosphorylation resulted in increasing cell proliferation compared to ErbB4- expressing cells. The interaction between of HPV-16 E5 and ErbB4 provides more insight into the mechanisms of HPV-16 E5 transformation induction
Einige Worte am Grabe des verewigten W. Mardorf, Kantors zu Spangenberg am 12. Jun. 1823
No full textEINIGE WORTE AM GRABE DES VEREWIGTEN W. MARDORF, KANTORS ZU SPANGENBERG AM 12. JUN. 1823
Einige Worte am Grabe des verewigten W. Mardorf, Kantors zu Spangenberg am 12. Jun. 1823 ( - )
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Trauernde und Leidtragende! (10)
Epilogue (20
Proline-rich tyrosine kinase 2 mediates gonadotropin-releasing hormone signaling to a specific extracellularly regulated kinase-sensitive transcriptional locus in the luteinizing hormone beta-subunit gene
No full textG protein-coupled receptor regulation of gene transcription primarily occurs through the phosphorylation of transcription factors by MAPKs. This requires transduction of an activating signal via scaffold proteins that can ultimately determine the outcome by binding signaling kinases and adapter proteins with effects on the target transcription factor and locus of activation. By investigating these mechanisms, we have elucidated how pituitary gonadotrope cells decode an input GnRH signal into coherent transcriptional output from the LH beta-subunit gene promoter. We show that GnRH activates c-Src and multiple members of the MAPK family, c-Jun NH2-terminal kinase 1/2, p38MAPK, and ERK1/2. Using dominant-negative point mutations and chemical inhibitors, we identified that calcium-dependent proline-rich tyrosine kinase 2 specifically acts as a scaffold for a focal adhesion/cytoskeleton-dependent complex comprised of c-Src, Grb2, and mSos that translocates an ERK-activating signal to the nucleus. The locus of action of ERK was specifically mapped to early growth response-1 (Egr-1) DNA binding sites within the LH beta-subunit gene proximal promoter, which was also activated by p38MAPK, but not c-Jun NH2-terminal kinase 1/2. Egr-1 was confirmed as the transcription factor target of ERK and p38MAPK by blockade of protein expression, transcriptional activity, and DNA binding. We have identified a novel GnRH-activated proline-rich tyrosine kinase 2-dependent ERK-mediated signal transduction pathway that specifically regulates Egr-1 activation of the LH beta-subunit proximal gene promoter, and thus provide insight into the molecular mechanisms required for differential regulation of gonadotropin gene expression
c-Jun reprograms Schwann cells of injured nerves to generate a repair cell essential for regeneration.
No full textThe radical response of peripheral nerves to injury (Wallerian degeneration) is the cornerstone of nerve repair. We show that activation of the transcription factor c-Jun in Schwann cells is a global regulator of Wallerian degeneration. c-Jun governs major aspects of the injury response, determines the expression of trophic factors, adhesion molecules, the formation of regeneration tracks and myelin clearance and controls the distinctive regenerative potential of peripheral nerves. A key function of c-Jun is the activation of a repair program in Schwann cells and the creation of a cell specialized to support regeneration. We show that absence of c-Jun results in the formation of a dysfunctional repair cell, striking failure of functional recovery, and neuronal death. We conclude that a single glial transcription factor is essential for restoration of damaged nerves, acting to control the transdifferentiation of myelin and Remak Schwann cells to dedicated repair cells in damaged tissue
Transforming growth factor beta (TGF beta) mediates schwann cell death in vitro and in vivo: Examination of c-jun activation, interactions with survival signals, and the relationship of TGF beta-mediated death to schwann cell differentiation
No full textIn some situations, cell death in the nervous system is controlled by an interplay between survival factors and negative survival signals that actively induce apoptosis. The present work indicates that the survival of Schwann cells is regulated by such a dual mechanism involving the negative survival signal transforming growth factor beta (TGF beta), a family of growth factors that is present in the Schwann cells themselves. We analyze the interactions between this putative autocrine death signal and previously defined paracrine and autocrine survival signals and show that expression of a dominant negative c-Jun inhibits TGF beta -induced apoptosis. This and other findings pinpoint activation of c-Jun as a key downstream event in TGF beta -induced Schwann cell death. The ability of TGF beta to kill Schwann cells, like normal Schwann cell death in vivo, is under a strong developmental regulation, and we show that the decreasing ability of TGF beta to kill older cells is attributable to a decreasing ability of TGF beta to phosphorylate c-Jun in more differentiated cells
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