Ramezani-Rad P.,University of California at San Francisco |
Geng H.,University of California at San Francisco |
Hurtz C.,University of California at San Francisco |
Chan L.N.,University of California at San Francisco |
And 8 more authors.
Blood | Year: 2013
The Sox4 transcription factor mediates early B-cell differentiation. Compared with normal pre-B cells, SOX4 promoter regions in Ph+ ALL cells are significantly hypomethylated. Loss and gain-of-function experiments identified Sox4 as a critical activator of PI3K/AKT and MAPK signaling in ALL cells. ChIP experiments confirmed that SOX4 binds to and transcriptionally activates promoters of multiple components within the PI3K/AKT and MAPK signaling pathways. Cre-mediated deletion of Sox4 had little effect on normal pre-B cells but compromised proliferation and viability of leukemia cells, which was rescued by BCL2L1 and constitutively active AKT and p110 PI3K. Consistent with these findings, high levels of SOX4 expression in ALL cells at the time of diagnosis predicted poor outcome in a pediatric clinical trial (COG P9906). Collectively, these studies identify SOX4 as a central mediator of oncogenic PI3K/AKT and MAPK signaling in ALL. © 2013 by The American Society of Hematology.
Hoving J.C.,University of Cape Town |
Kirstein F.,University of Cape Town |
Nieuwenhuizen N.E.,University of Cape Town |
Fick L.C.E.,University of Cape Town |
And 5 more authors.
Gastroenterology | Year: 2012
Induction of colitis in mice by administration of oxazolone is mediated by T-helper (Th) 2 cells and has features of human ulcerative colitis. We investigated whether activation of interleukin (IL)-4Rα on T and B cells determines their effector functions and mediates oxazolone-induced colitis. We studied induction of colitis with oxazolone in wild-type mice and those with CD4 + T cells that did not express IL-4Rα (Lck creIL-4Rα -/lox). We also generated mice with B cells that did not express IL-4Rα (mb1 creIL-4Rα -/lox) and studied induction of colitis. Lck creIL- 4Rα -/lox mice did not develop colitis in response to oxazolone, and their levels of IL-4, IL-13, and immunoglobulin (Ig) E were reduced. Adoptive transfer of nave, wild-type CD4 + Th cells depleted of natural killer T cells to Lck creIL-4Rα -/lox mice restored their susceptibility to colitis. In contrast, Lck creIL- 4Rα -/lox mice maintained their protection against colitis when IL-13deficient CD4 + T cells were transferred. These findings indicate that development of colitis involves not only natural killer T-cell functions, but also requires IL-13 production by CD4 + T helper cells. Mb1 creIL-4Rα -/lox mice, which cannot produce IgE, were also protected against oxazolone-induced colitis. Blocking IgE binding significantly reduced mast cell numbers in colons and protected wild-type BALB/c mice from the onset of colitis. IL-4 appears to induce CD4 + Th2 cells to produce IL-13 and B cells to produce IgE, which together mediate oxazolone-induced colitis in mice. © 2012 AGA Institute.
Grouls S.,University of Heidelberg |
Iglesias D.M.,McGill University |
Wentzensen N.,U.S. National Cancer Institute |
Moeller M.J.,RWTH Aachen |
And 7 more authors.
Journal of the American Society of Nephrology | Year: 2012
β-Catenin/Wnt signaling is essential during early inductive stages of kidney development, but its role during postinductive stages of nephron development and maturation is not well understood. In this study, we used Pax8Cre mice to target β-catenin deficiency to renal epithelial cells at the late S-shaped body stage and the developing collecting ducts. The conditional β-catenin knockout mice formed abnormal kidneys and had reduced renal function. The kidneys were hypoplasticwith a thin cortex; a superficial layer of tubules was missing. A high proportion of glomeruli had small, underdeveloped capillary tufts. In these glomeruli, well differentiated podocytes replaced parietal epithelial cells in Bowman's capsule; capillaries toward the outer aspect of these podocytes mimicked the formation of glomerular capillaries. Tracing nephrogenesis in embryonic conditional β-catenin knockout mice revealed that these "parietal podocytes"derived from precursor cells in the parietal layer of the S-shaped body by direct lineage switch. Taken together, these findings demonstrate that β-catenin/Wnt signaling is important during the late stages of nephrogenesis and for the lineage specification of parietal epithelial cells. Copyright © 2012 by the American Society of Nephrology.
Werner M.,Albert Ludwigs University of Freiburg |
Werner M.,Max Planck Institute for Immunobiology |
Hobeika E.,Max Planck Institute for Immunobiology |
Hobeika E.,Albert Ludwigs University of Freiburg |
And 2 more authors.
Immunological Reviews | Year: 2010
Engagement of the B-cell antigen receptor (BCR) or its precursor, the pre-BCR, induces a cascade of biochemical reactions that regulate the differentiation, selection, survival, and activation of B cells. This cascade is initiated by receptor-associated tyrosine kinases that activate multiple downstream signaling pathways. Since it is required for metabolism, cell growth, development, and survival, the activation of phosphoinositide 3-kinase (PI3K)-dependent pathways represents a crucial event of BCRpre-BCR signaling. The phosphorylated substrates of the PI3K promote specific recruitment of selected signaling proteins to the plasma membrane, where important signaling complexes are formed to mediate the above-mentioned biological processes. Here, we review the principles of PI3K signaling and highlight the role of an important PI3K-driven module in VDJ recombination of immunoglobulin (Ig) genes during early B-cell development as compared with class switch recombination of Ig genes in mature B cells after activation by specific antigens. Furthermore, we discuss the role of PI3K in the survival of mature B cells, which is strictly dependent on BCR expression and basal BCR signaling. © 2010 John Wiley & Sons AS.
Infantino S.,Albert Ludwigs University of Freiburg |
Infantino S.,Max Planck Institute for Immunobiology |
Benz B.,Albert Ludwigs University of Freiburg |
Benz B.,Max Planck Institute for Immunobiology |
And 6 more authors.
Journal of Experimental Medicine | Year: 2010
Signals processed through the B cell antigen receptor (BCR) control both the proliferation and differentiation of B lymphocytes. How these different signaling modes are established at the BCR is poorly understood. We show that a conserved arginine in the tail sequence of the Igα subunit of the BCR is methylated by the protein arginine methyltransferase 1. This modification negatively regulates the calcium and PI-3 kinase pathways of the BCR while promoting signals leading to B cell differentiation. Thus, Igα arginine methylation can play an important role in specifying the outcome of BCR signaling. © 2010 Infantino et al.
Messerschmidt D.M.,Max Planck Institute for Immunobiology |
Messerschmidt D.M.,Singapore Institute of Medical Biology |
Kemler R.,Max Planck Institute for Immunobiology
Developmental Biology | Year: 2010
Early lineage segregation in mouse development results in two, either CDX2- or OCT4/NANOG-positive, cell populations. CDX2-positive cells form the trophectoderm (TE), OCT4/NANOG-positive cells the inner cell mass (ICM). In a second lineage decision ICM cells segregate into Epiblast (EPI) and primitive endoderm (PE). EPI and PE formation depend on the activity of the transcription factors Nanog and Gata4/6. A role for Nanog, a crucial pluripotency factor, in preventing PE differentiation has been proposed, as outgrowths of mutant ICMs result in PE, but not EPI derivatives. We established Nanog-mutant mouse lines and analyzed EPI and PE formation in vivo. Surprisingly, Gata4 expression in mutant ICM cells is absent or strongly decreased, thus loss of Nanog does not result in precocious endoderm differentiation. However, Nanog-deficient embryos retain the capacity to form PE in chimeric embryos and, in contrast to recent reports, in blastocyst outgrowths. Based on our findings we propose a non-cell autonomous requirement of Nanog for proper PE formation in addition to its essential role in EPI determination. © 2010 Elsevier Inc.
Ziegler C.,Helmholtz Center for Infection Research |
Goldmann O.,Helmholtz Center for Infection Research |
Hobeika E.,Max Planck Institute for Immunobiology |
Geffers R.,Helmholtz Center for Infection Research |
And 2 more authors.
EMBO Molecular Medicine | Year: 2011
Staphylococcus aureus is an important human pathogen that can cause long-lasting persistent infections. The mechanisms by which persistent infections are maintained involve both bacterial escape strategies and modulation of the host immune response. So far, the investigations in this area have focused on strategies used by S. aureus to persist within the host. Here, we used an experimental mouse model to investigate the host response to persistent S. aureus infection. Our results demonstrated that T cells, which are critical for controlling S. aureus infection, gradually lost their ability to respond to antigenic stimulation and entered a state of anergy with the progression of infection towards persistence. The T cell hyporesponsiveness was reverted by co-stimulation with the phorbol ester PMA, an activator of protein kinase C, suggesting that a failure in the T cell receptor (TCR)-proximal signalling events underlie the hyporesponsive phenotype. The presence of these anergic antigen-specific T cells may contribute to the failure of the host immune response to promote sterilizing immunity during persistent S. aureus infection and also offers new possibilities for novel immunotherapeutic approaches. © 2011 EMBO Molecular Medicine.
Salomao R.,Federal University of São Paulo |
Brunialti M.K.C.,Federal University of São Paulo |
Rapozo M.M.,Federal University of São Paulo |
Baggio-Zappia G.L.,Federal University of São Paulo |
And 2 more authors.
Shock | Year: 2012
Since the definition of systemic inflammatory response syndrome/sepsis was originally proposed, a large amount of new information has been generated showing a much more complex scenario of inflammatory and counterinflammatory responses during sepsis. Moreover, some fundamental mechanisms of sensing and destroying invading microorganisms have been uncovered, which include the discovery of TLR4 as the lipopolysaccharide (LPS) gene, implications of innate immune cells as drivers of the adaptive response to infection, and the modulation of multiple accessory molecules that stimulate or inhibit monocyte/macrophage and lymphocyte interactions. The complexity of the infection/injury-induced immune response could be better appreciated with the application of genomics and proteomics studies, and LPS was a useful tool in many of these studies. In this review, we discuss aspects of bacterial recognition and induced cellular activation during sepsis. Because of the relevance of endotoxin (LPS) research in the field, we focus on LPS and host interactions as a clue to understand microorganisms sensing and cell signaling, then we discuss how this response is modulated in septic patients. © 2012 by the Shock Society.
Lange U.C.,Max Planck Institute for Immunobiology |
Schneider R.,Max Planck Institute for Immunobiology
BioEssays | Year: 2010
During mammalian development, maintenance of cell fate through mitotic divisions require faithful replication not only of the DNA but also of a particular epigenetic state. Germline cells have the capacity of erasing this epigenetic memory at crucial times during development, thereby resetting their epigenome. Certain marks, however, appear to escape this reprogramming, which allows their transmission to the offspring and potentially guarantees transgenerational epigenetic inheritance. Here we discuss the molecular requirements for faithful transmission of epigenetic information and our current knowledge about the transmission of epigenetic information through generations. © 2010 Wiley Periodicals, Inc.
van Essen D.,Max Planck Institute for Immunobiology |
Zhu Y.,Max Planck Institute for Immunobiology |
Saccani S.,Max Planck Institute for Immunobiology
Molecular Cell | Year: 2010
Activation of transcription from a silenced state is crucial to achieve specific gene expression in many biological contexts. Methylation of lysine 9 on histone H3 (H3K9) is widely associated with transcriptional silencing, and its disappearance is linked to the activation of several inflammatory genes by NF-κB. Here we describe that this event is controlled by a feed-forward circuit catalyzed by the activity of the histone demethylase Aof1 (also known as Lsd2/Kdm1b). We find that Aof1 is required for removal of dimethyl H3K9 at specific promoters, and thereby it controls stimulus-induced recruitment of NF-κB and gene expression. However, Aof1 is itself recruited by interaction with the c-Rel subunit of NF-κB, which is found at low levels associated with promoters in unstimulated cells. Thus, at these tightly regulated genes, NF-κB functions both as a transcriptional activator and as an upstream targeting signal that marks promoters to be derepressed by histone demethylation. © 2010 Elsevier Inc.