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PubMed2003

Lymphoid enhancer factor-1 links two hereditary leukemia syndromes through core-binding factor alpha regulation of ELA2.

Two hereditary human leukemia syndromes are severe congenital neutropenia (SCN), caused by mutations in the gene ELA2, encoding the protease neutrophil elastase, and familial platelet disorder with acute myelogenous leukemia (AML), caused by mutations in the gene AML1, encoding the transcription factor core-binding factor alpha (CBFalpha). In mice, CBFalpha regulates the expression of ELA2, suggesting a common link for both diseases. However, gene-targeted mouse models have failed to reproduce either human disease, thus prohibiting further in vivo studies in mice. Here we investigate CBFalpha regulation of the human ELA2 promoter, taking advantage of bone marrow obtained from patients with either illness. In particular, we have identified novel ELA2 promoter substitutions (-199 C to A) within a potential motif for lymphoid enhancer factor-1 (LEF-1), a transcriptional mediator of Wnt/beta-catenin signaling, in SCN patients. The LEF-1 motif lies adjacent to a potential CBFalpha binding site that is in a different position in human compared with mouse ELA2. We find that LEF-1 and CBFalpha co-activate ELA2 expression. In vitro, the high mobility group domain of LEF-1 interacts with the runt DNA binding and proline-, serine-, threonine-rich activation domains of CBFalpha. ELA2 transcript levels are up-regulated in bone marrow of an SCN patient with the -199 C to A substitution. Conversely, a mutation of the CBFalpha activation domain, found in a patient with familial platelet disorder with AML, fails to stimulate the ELA2 promoter in vitro, and bone marrow correspondingly demonstrates reduced ELA2 transcript. Observations in these complementary patients indicate that LEF-1 cooperates with CBFalpha to activate ELA2 in vivo and also suggest the possibility that up-regulating promoter mutations can contribute to SCN. Two hereditary AML predisposition syndromes may therefore intersect via LEF-1, potentially linking them to more generalized cancer mechanisms.

Animals↗
PubMed2007

RUN-CBFbeta interaction in C. elegans: computational prediction and experimental verification.

The Runt domain proteins are eukaryotic transcription factors that regulate major developmental pathways. All members of this family contain a highly-conserved sequence-specific DNA binding domain: the Runt domain (RD). Structural and biochemical studies have shown that the Runt domain undergoes a conformational transition upon binding to DNA and that this process is regulated by an unrelated partner protein CBFbeta that enhances the DNA binding affinity of RD. Most of the reported studies on the Runt domain transcription factors were performed on proteins from mammals and Drosophila whereas very little has been known about the C. elegans RD protein, RUN, which provides the simplest model system for understanding the function of this class of transcription factors. We performed computational studies on RD domains from various species including C. elegans, Drosophila, and human, using the atom-atom contact surface area scoring method. The scoring analysis indicates that the DNA binding regulation of the C. elegans RD protein (CeRD) occurs via its interaction with a CBFbeta-like partner, as found for the human proteins, whereas a different mode of regulation may occur in the Drosophila system. Sequence, secondary structure and fold analyses of a putative CBFbeta protein identified in the C. elegans genome, CeCBFbeta, sharing a 22% identity with the human protein, predict a similar structure of this protein to that of the human CBFbeta protein. We produced the C. elegans proteins CeRD and CeCBFbeta in bacteria and confirmed their physical interaction as well as cross interactions with the corresponding human proteins. We also confirmed the structural similarity of CBFbeta and CeCBFbeta by circular dichroism analysis. The combined results suggest that a similar mechanism of regulation operates for the human and the C. elegans RD proteins despite the low sequence identity between their CBFbeta proteins and the evolutionary distance between the two systems.

Amino Acid Sequence↗
PubMed2006

Functional redundancy of transcription factor-binding sites in the killer cell Ig-like receptor (KIR) gene promoter.

Variegated expression of inhibitory killer cell Ig-like receptors (KIRs) for MHC class I molecules helps NK cells distinguish normal from aberrant self and avoid autoreactivity. Prior studies of KIR promoters have produced conflicting results and no cis-acting sites have been independently confirmed. We took a comprehensive linker-scanning mutagenesis approach and substituted 24 consecutive 10-bp segments in the human KIR3DL1 promoter. Our analysis revealed eight segments that activated and three segments that repressed KIR transcription. Site-directed mutagenesis and electrophoretic mobility shift assays indicated that optimal KIR transcription requires a proximal Ets site that binds several Ets family members, a cAMP response element (CRE), a Runx site and a site that mediates complex interactions between Ets family members, signal transducer and activator of transcription 5 (STAT5) and YY1; Sp1 also contributes to KIR transcription. KIR transcription was greatly reduced by several compound mutations and was abrogated by a combination of mutations that affected the proximal Ets site, and the CRE, Runx, Sp1 and Ets/STAT sites. The many transcription factors that contribute to KIR transcription are partially redundant in the setting of transient transfection assays, helping to explain why only 0-2 activating sites had been reported in each of three prior studies. We propose that the multiplicity of transcription factors enables NK cells to sustain continuous KIR expression in diverse cellular and cytokine milieus, thus preventing NK autoreactivity.

Base Sequence↗
PubMed1997

ALY, a context-dependent coactivator of LEF-1 and AML-1, is required for TCRalpha enhancer function.

LEF-1 is a transcription factor that participates in the regulation of the T-cell receptor alpha (TCR alpha) enhancer by facilitating the assembly of multiple proteins into a higher order nucleoprotein complex. The function of LEF-1 is dependent, in part, on the HMG domain that induces a sharp bend in the DNA helix, and on an activation domain that stimulates transcription only in a specific context of other enhancer-binding proteins. With the aim of gaining insight into the function of context-dependent activation domains, we cloned ALY, a novel LEF-1-interacting protein. ALY is a ubiquitously expressed, nuclear protein that specifically associates with the activation domains of LEF-1 and AML-1 (CBF alpha2, PEBP2 alpha(B), which is another protein component of the TCR alpha enhancer complex. In addition, ALY can increase DNA binding by both LEF-1 and AML proteins. Overexpression of ALY stimulates the activity of the TCR alpha enhancer complex reconstituted in transfected nonlymphoid HeLa cells, whereas down-regulation of ALY by anti-sense oligonucleotides virtually eliminates TCR alpha enhancer activity in T cells. Similar to LEF-1, ALY can stimulate transcription in the context of the TCR alpha enhancer but apparently not when tethered to DNA through an heterologous DNA-binding domain. We propose that ALY mediates context-dependent transcriptional activation by facilitating the functional collaboration of multiple proteins in the TCR alpha enhancer complex.

Amino Acid Sequence↗
PubMed1995

Assembly and function of a TCR alpha enhancer complex is dependent on LEF-1-induced DNA bending and multiple protein-protein interactions.

In this study we examine the molecular basis for the synergistic regulation of the minimal TCR alpha enhancer by multiple proteins. We find that reconstitution of TCR alpha enhancer function in nonlymphoid cells requires expression of the lymphoid-specific proteins LEF-1, Ets-1 and PEBP2 alpha (CBF alpha), and a specific arrangement of their binding sites in the enhancer. We show that Ets-1 cooperates with PEBP2 alpha to bind adjacent sites at one end of the enhancer, forming a ternary complex that is unstable by itself. Stable occupancy of the Ets-1- and PEBP2 alpha-binding sites in a DNase I protection assay was found to depend on both a specific helical phasing relationship with a nonadjacent ATF/CREB-binding site at the other end of the enhancer and on LEF-1. The HMG domain of LEF-1 was found previously to bend the DNA helix in the center of the TCR alpha enhancer. We now show that the HMG domain of the distantly related SRY protein, which also bends DNA, can partially replace LEF-1 in stimulating enhancer function in transfection assays. Taken together with the observation that Ets-1 and members of the ATF/CREB family have the potential to associate in vitro, these data suggest that LEF-1 can coordinate the assembly of a specific higher-order enhancer complex by facilitating interactions between proteins bound at nonadjacent sites.

Activating Transcription Factors↗
PubMed2006

Progression of regulatory gene expression states in fetal and adult pro-T-cell development.

Precursors entering the T-cell developmental pathway traverse a progression of states characterized by distinctive patterns of gene expression. Of particular interest are regulatory genes, which ultimately control the dwell time of cells in each state and establish the mechanisms that propel them forward to subsequent states. Under particular genetic and developmental circumstances, the transitions between these states occur with different timing, and environmental feedbacks may shift the steady-state accumulations of cells in each state. The fetal transit through pro-T-cell stages is faster than in the adult and subject to somewhat different genetic requirements. To explore causes of such variation, this review presents previously unpublished data on differentiation gene activation in pro-T cells of pre-T-cell receptor-deficient mutant mice and a quantitative comparison of the profiles of transcription factor gene expression in pro-T-cell subsets of fetal and adult wildtype mice. Against a background of consistent gene expression, several regulatory genes show marked differences between fetal and adult expression profiles, including those encoding two basic helix-loop-helix antagonist Id factors, the Ets family factor SpiB and the Notch target gene Deltex1. The results also reveal global differences in regulatory alterations triggered by the first T-cell receptor-dependent selection events in fetal and adult thymopoiesis.

Aging↗
PubMed2001

A murine osteosarcoma cell line with a potential to develop ossification upon transplantation.

An osteosarcoma cell line has been established from a soft tissue tumor that occurred spontaneously in a BALB / c mouse. This cell line showed ossification when transplanted into syngeneic mice. To examine the mechanism of bone formation, the expression of mRNAs for osteoblastic and chondroblastic markers and factors associated with ossification has been investigated. In culture, the cells exhibited a spindle shape in the growth phase, but had a polygonal shape in the stationary phase. Reverse transcription-polymerase chain reaction analysis showed that the cells expressed mRNAs for pro-alpha1(I) chain of type I collagen, alkaline phosphatase, osteopontin, osteocalcin, and core binding factor alpha1, suggesting differentiation into the stage of osteoblasts during the stationary phase. After transplantation, histological examination revealed small foci of pale blue material and basophilic networks that were scattered in the tumor tissues at one week. The former stained positive with alcian blue, suggesting a chondroid matrix. Pro-alpha1(II) chain of type II collagen mRNA was expressed at one week. A large part of tumors at two and three weeks consisted of basophilic networks, which stained positive via von Kossa's method, indicating a calcified woven bone. In situ hybridization analysis showed strong expression of osteopontin and osteocalcin mRNAs in tumor cells surrounding the bone matrix. Bone morphogenetic protein-6 and -7 mRNAs were detected in transplanted tumors, but not in cultured cells. These results suggest that the cell line has the properties of an osteoblastic lineage when cultured in vitro and has an ossifying ability through endochondral bone formation processes when transplanted in vivo.

Alkaline Phosphatase↗
PubMed2005

Three-dimensional composites manufactured with human mesenchymal cambial layer precursor cells as an alternative for sinus floor augmentation: an in vitro study.

Bone tissue engineering is a promising approach for treatment of defective and lost bone in the maxillofacial region. Creating functional tissue for load bearing bone reconstruction using biocompatible and biodegradable scaffolds seeded with living cells is of crucial importance. The aim of our study was to compare the effects of poly-lactic-co-glycolic acid (PLGA) and hydroxyapatite (HA) ceramic granulae on growth, differentiation, mineralization and gene expression of mandibular mesenchymal cambial layer precursor cells (MCLPCs) cultured onto tissue engineered three-dimensional (3-D) composites in vitro. These 3-D composites were cultivated in a rotating cultivation system under osteogenic differentiation conditions for a maximum period of 21 days. After 6 and 21 days, histological examination was performed; scanning electron microscopy (SEM), alkaline phosphatase (ALP) activity and levels of DNA were investigated. Expression of bone-specific genes osteocalcin, osteonectin, osteopontin, ALP, core binding factor alpha 1 and collagen type I were investigated by using a reverse transcription-polymerase chain reaction (RT-PCR) method. After 6 and 21 days of incubation an initiation of mineralization and the presence of newly formed bone at the surface of the composites were shown after evaluation of ALP activity, DNA content, SEM and histological staining. Expression of bone-specific genes confirmed the bone-like character of these composites and different effects of PLGA or HA granulae on the osteogenic differentiation of human MCLPCs in vitro. The results of this study support the concept that substrate signals significantly influence MCLPCs growth, differentiation, mineralization and gene expression in vitro, and that the use of these cells in the manufacturing of 3-D cell/HA composites is a promising approach for load bearing bone reconstruction in the maxillofacial region in vivo.

Alkaline Phosphatase↗
PubMed2002

Molecular genetics of acute myeloid leukemia.

Recurring chromosomal abnormalities are detected in most patients with acute myeloid leukemia (AML). They may be associated with a distinct AML FAB subtype or may identify distinct clinicobiological entities within the same FAB subtype. Therefore, cytogenetic investigation has a pivotal role in AML diagnosis. In addition, it is one of the most valuable prognostic determinants of the disease, as recently demonstrated. The development of new molecular techniques, such as reverse transcriptase polymerase chain reaction and fluorescence in situ hybridization, has allowed perfect definition of the chromosome regions containing genes with a crucial role in normal hemopoiesis and leukemia. Understanding the action of such genes provides new insights into AML pathogenesis and has led us to envisage new therapeutic options.

Acute Disease↗
PubMed2001

New model for the yeast RNA polymerase I transcription cycle.

Using an immobilized template assay, we observed two steps in assembly of the yeast RNA polymerase I (Pol I) preinitiation complex: stable binding of upstream activating factor (UAF) followed by recruitment of Pol I-Rrn3p and core factor (CF). Pol I is required for stable association of CF with the promoter and can be recruited in the absence of Rrn3p. Upon transcription initiation, Pol I-Rrn3p and CF dissociate from the promoter while UAF remains behind. These findings support a novel model in which the Pol I basal machinery cycles on and off the promoter with each round of transcription. This model accounts for previous observations that rRNA synthesis may be controlled by regulating both promoter accessibility and polymerase activity.

Blotting, Western↗
PubMed2005

The genetics of psoriasis and autoimmunity.

Psoriasis is an inflammatory/autoimmune disease and, as with many autoimmune diseases, is associated with alleles from the major histocompatibility complex (MHC). With psoriasis and autoimmune disease, the penetrance of the MHC-associated alleles is never 100%, even for monozygotic twins. This may be because development requires additional environmental and/or genetic modifiers or requires specific T-cell receptor arrangements. Families segregating single or multilocus susceptibility alleles other than the MHC have also been reported. Overlapping genetic locations of loci for different autoimmune diseases have been known for several years and are starting to reveal common genes or genetic variants. These include genes normally involved in preventing spontaneous T-cell activation or proliferation, immune synapse formation, or cytokine production via pathways such as those mediated by NFkappaB and those involved in thymic selection. Autoimmunity may also involve dysregulation of genes or pathways regulated by the RUNX family of transcription factors. RUNX is involved in hematopoietic cell development, development of T cells in the thymus, chromatin remodeling, and gene silencing. Hence, its effect on cells of the immune system may be due to variable changes in gene expression and could account for variable body surface involvement and waxing and waning of disease.

Autoantibodies↗
PubMed2004

Pathophysiology of vascular calcification in chronic kidney disease.

Patients with chronic kidney disease (CKD) on dialysis have 2- to 5-fold more coronary artery calcification than age-matched individuals with angiographically proven coronary artery disease. In addition to increased traditional risk factors, CKD patients also have a number of nontraditional cardiovascular risk factors that may play a prominent role in the pathogenesis of arterial calcification, including duration of dialysis and disorders of mineral metabolism. In histological specimens from the inferior epigastric artery of dialysis patients, we have found expression of the osteoblast differentiation factor core binding factor alpha-1 (Cbfa1) and several bone-associated proteins (osteopontin, bone sialoprotein, alkaline phosphatase, type I collagen) in both the intima and medial layers when calcification was present. In cultured vascular smooth muscle cells, the addition of pooled serum from dialysis patients (versus normal healthy controls) accelerated mineralization and increased expression of Cbfa1, osteopontin, and alkaline phosphatase to a similar magnitude as does beta-glycerophosphate alone. However, a lack of inhibitors of calcification may also be important. Dialysis patients with low levels of serum fetuin-A, a circulating inhibitor of mineralization, have increased coronary artery calcification and fetuin-A can inhibit mineralization of vascular smooth muscle cells in vitro. These data support that elevated levels of phosphorus and/or other potential uremic toxins may play an important role by transforming vascular smooth muscle cells into osteoblast-like cells, which can produce a matrix of bone collagen and noncollagenous proteins. This nidus can then mineralize if the balance of pro-mineralizing factors outweighs inhibitory factors.

Animals↗
PubMed2000

Links among growth factors, hormones, and nuclear factors with essential roles in bone formation.

Research performed during the last several years implicates important roles for a variety of growth factors that affect osteoblasts or their precursors during bone development, remodeling, or repair. Of these, three families of growth factors in particular-the transforming growth factor betas (TGF-betas), insulin-like growth factors (IGFs), and bone morphogenetic proteins (BMPs)-are considered to be principal local regulators of osteogenesis, although none is specific for cells of the osteoblast lineage. Therefore, mechanisms to induce skeletal tissue specificity might occur through interactions among these growth factors, with circulating hormones, or through specific intracellular mediators. In the latter case, even more recent studies point to two nuclear transcription factors, termed Core Binding Factor a1 (CBFa1) and CCAAT/Enhancer Binding Protein delta (C/EBPdelta), as significant regulators of the expression or activity of specific bone growth factors or their receptors. Perhaps more importantly, events that link these growth factors to nuclear proteins occur in response to glucocorticoids, sex steroids, parathyroid hormone (PTH), or prostaglandin E2 (PGE2), which themselves have well-known effects on bone biology. In this review, we discuss the situations and processes that initially suggested growth-factor- and hormone-specific interactions on cells within the osteoblast lineage, and present evidence for roles that CBFa1 and C/EBPdelta have on osteoblast function. Finally, we offer examples for how these factors integrate events that are associated with various aspects of bone formation.

Animals↗
PubMed2005

Runx-dependent expression of PKC is critical for cell survival in the sea urchin embryo.

BACKGROUND: Runx transcription factors play critical roles in the developmental control of cell fate and contribute variously as oncoproteins and tumor suppressors to leukemia and other cancers. To discover fundamental Runx functions in the cell biology of animal development, we have employed morpholino antisense-mediated knockdown of the sea urchin Runx protein SpRunt-1. Previously we showed that embryos depleted of SpRunt-1 arrest development at early gastrula stage and underexpress the conventional protein kinase C SpPKC1. RESULTS: We report here that SpRunt-1 deficiency leads to ectopic cell proliferation and extensive apoptosis. Suppression of the apoptosis by pharmacological inhibition of caspase-3 prevents the ectopic proliferation and rescues gastrulation, indicating that many of the overt defects obtained by knockdown of SpRunt-1 are secondary to the apoptosis. Inhibition or knockdown of SpPKC1 also causes apoptosis, while cell survival is rescued in SpRunt-1 morphant embryos coinjected with SpPKC1 mRNA, suggesting that the apoptosis associated with SpRunt-1 deficiency is caused by the deficit in SpPKC1 expression. Chromatin immunoprecipitation indicates that SpRunt-1 interacts physically with SpPKC1 in vivo, and cis-regulatory analysis shows that this interaction activates SpPKC1 transcription. CONCLUSIONS: Our results show that Runx-dependent activation of SpPKC1 is essential for maintaining protein kinase C activity at levels conducive to cell survival during embryogenesis.

Animals↗
PubMed2004

Individual patient data-based meta-analysis of patients aged 16 to 60 years with core binding factor acute myeloid leukemia: a survey of the German Acute Myeloid Leukemia Intergroup.

PURPOSE: To evaluate prognostic factors for relapse-free survival (RFS) and overall survival (OS) and to assess the impact of different postremission therapies in adult patients with core binding factor (CBF) acute myeloid leukemias (AML). PATIENTS AND METHODS: Individual patient data-based meta-analysis was performed on 392 adults (median age, 42 years; range, 16 to 60 years) with CBF AML (t(8;21), n = 191; inv(16), n = 201) treated between 1993 and 2002 in prospective German AML treatment trials. RESULTS: RFS was 60% and 58% and OS was 65% and 74% in the t(8;21) and inv(16) groups after 3 years, respectively. For postremission therapy, intention-to-treat analysis revealed no difference between intensive chemotherapy and autologous transplantation in the t(8;21) group and between chemotherapy, autologous, and allogeneic transplantation in the inv(16) group. In the t(8;21) group, significant prognostic variables for longer RFS and OS were lower WBC and higher platelet counts; loss of the Y chromosome in male patients was prognostic for shorter OS. In the inv(16) group, trisomy 22 was a significant prognostic variable for longer RFS. For patients who experienced relapse, second complete remission rate was significantly lower in patients with t(8;21), resulting in a significantly inferior survival duration after relapse compared with patients with inv(16). CONCLUSION: We provide novel prognostic factors for CBF AML and show that patients with t(8;21) who experience relapse have an inferior survival duration.

Acute Disease↗
PubMed2005

mab-2 encodes RNT-1, a C. elegans Runx homologue essential for controlling cell proliferation in a stem cell-like developmental lineage.

In this report, we demonstrate that C. elegans mab-2 mutants have defects in the development of a male-specific sense organ because of a failure in the proliferation of the stem cell-like lateral hypodermal (seam) cells. We show, by positional cloning, that mab-2 encodes RNT-1, the only C. elegans member of the Runx family of transcriptional regulators, which are postulated to act both as oncogenes and tumour suppressors in mammalian cells. Importantly, we find that rnt-1 is a rate-limiting regulator of seam cell proliferation in C. elegans, as overexpression of rnt-1 at particular developmental stages is capable of driving extra cell divisions, leading to seam cell hyperplasia. Loss of rnt-1 is correlated with upregulation of cki-1, a CDK inhibitor. Deregulated expression of Runx genes in humans is associated with various cancers, particularly leukaemias, suggesting a conserved role for Runx genes in controlling cell proliferation during development, especially in stem cell lineages. C. elegans is therefore an important model system for studying the biology, and oncogenic potential, of Runx genes.

Animals↗