Increased eating frequency linked to decreased obesity and improved metabolic outcomes.

BACKGROUND: We previously reported that more frequent eating in overweight minority youth was linked to lower visceral adiposity and circulating triglycerides. The aim of this study was to examine this issue in more detail by assessing the relationship between eating frequency and adiposity and metabolic disease risk in a cohort of exclusively overweight Hispanic youth. METHODS: This analysis included 191 overweight (⩾ 85th percentile body mass index (BMI)) Hispanic youth (8-18 years) with the following cross-sectional measures: height, weight, BMI, dietary intake via multiple 24 h recalls, body composition via dual-energy X-ray absorptiometry, lipids and insulin action (insulin sensitivity, acute insulin response (AIR) and disposition index, a measure of ß-cell function) via a frequently sampled intravenous glucose tolerance test. Each eating occasion (EO) was defined as ⩾ 50 calories and ⩾ 15 min from any prior EO. Infrequent eaters (IEs) were classified as any subject who ate <3 EOs on any dietary recall (n = 32), whereas frequent eaters (FEs) always consumed ⩾ 3 EOs (n = 159). RESULTS: Using analyses of covariance, FEs compared with IEs consumed 23% more calories per day (P ⩽ 0.01), ate 40% more often and consumed 19% less calories per EO (P ⩽ 0.01). FEs also exhibited 9% lower BMI Z-scores (P ⩽ 0.01), 9% lower waist circumferences (P ⩽ 0.01), 29% lower fasting insulin (P = 0.02), 31% lower HOMA-IR (Homeostatic Model Assessment: Insulin Resistance) values (P = 0.02) and 19% lower triglycerides (P ⩽ 0.01), as well as an 11% higher AIR (P = 0.02) and 31% higher disposition index (P=0.01). The following a priori covariates were included: Tanner, sex, body fat and reported energy intake. CONCLUSION: These findings suggest that increased eating frequency is related to decreased obesity and metabolic disease risk in overweight Hispanic youth, despite increases in energy intake.

Lassa-VSV chimeric virus targets and destroys human and mouse ovarian cancer by direct oncolytic action and by initiating an anti-tumor response.

Ovarian cancer is the third most common female cancer, with poor survival in later stages of metastatic spread. We test a chimeric virus consisting of genes from Lassa and vesicular stomatitis viruses, LASV-VSV; the native VSV glycoprotein is replaced by the Lassa glycoprotein, greatly reducing neurotropism. Human ovarian cancer cells in immunocompromised nude mice were lethal in controls. Chemotherapeutic paclitaxel and cisplatin showed modest cancer inhibition and survival extension. In contrast, a single intraperitoneal injection of LASV-VSV selectively infected and killed ovarian cancer cells, generating long-term survival. Mice with human ovarian cancer cells in brain showed rapid deterioration; LASV-VSV microinjection into brain blocked cancer growth, and generated long-term survival. Treatment of immunocompetent mice with infected mouse ovarian cancer cells blocked growth of non-infected ovarian cancer cells peritoneally and in brain. These results suggest LASV-VSV is a viable candidate for further study and may be of use in the treatment of ovarian cancer.

Brain tryptophan hydroxylation: dependence on arterial oxygen tension.

The accumulation of cerebral 5-hydroxytryptophan after decarboxylase inhibition was decreased in rats maintained at arterial O(2) tensions below 60 mm-Hg. In contrast, brain lactate was stable above 40 mm-Hg and brain adenosine triphosphate, adenosine diphosphate, and adenosine monophosphate were unchanged above 30 mm-Hg. There was a linear correlation of brain 5-hydroxytryptophan accumulation to cerebral venous O(2) tension. Cerebral tryptophan hydroxylase appears to have a poor affinity for oxygen and to be affected by slight hypoxia. The resultant decreases in monoamine neurotransmitter metabolism may explain the behavioral changes of mild oxygen deprivation.

Validity and Reliability of an Expanded Vegetable Questionnaire Among Elementary School Children.

BACKGROUND: The purpose of this study was to expand the School Physical Activity and Nutrition questionnaire to include a greater variety of vegetables and to evaluate the relative validity and reliability of these revised items. OBJECTIVES: This study utilized 2 convenience samples of third to fifth graders for an analysis: validity (n = 70) and reliability (n = 76). Validity was assessed by comparing questionnaire items with vegetable intake reported from a 24-hour dietary recall covering the same reference period. Reliability estimates were assessed via same-day test-retest. RESULTS: Agreement correlations ranged from 0.35 to 0.71. Kappa statistics varied from 0.16 to 0.66. Percentage agreements ranged from 57% to 87%. Test-retest Spearman coefficients were greater than 0.50 for 6 items, weighted Kappa values were greater than 0.40 for all 7 items, and percentage agreement exceeded 75% for 5 items. CONCLUSIONS: Results suggest that the questionnaire is a valid and reliable measure of the previous day's vegetable intake in third- to fifth-grade students. This trial was registered at ClinicalTrials.gov as NCT02668744.

Impact of food security on glycemic control among low-income primarily Hispanic/Latino children in Los Angeles, California: A cross-sectional study.

Studies examining the impact of food insecurity on metabolic markers are limited, specifically in Hispanic youth. This study was a cross-sectional analysis of 218 3rd-5th grade students (83% Hispanic and 49% male). Anthropometrics, blood glucose, insulin, and lipids via fasting blood draw, dietary intake via Block screener, and a 5-item food security scale were collected. HOMA-Insulin Resistance was calculated. Multivariate analyses of covariance were used to examine differences in glucose and insulin indices, adiposity, metabolic and dietary intake variables between categories of food security. Food secure children had greater glycemic control and decreased insulin resistance compared to food insecure children.

Combined association of maternal and paternal family history of diabetes with plasma leptin and adiponectin in overweight Hispanic children.

AIMS: To investigate the importance of a maternal and paternal family history of Type 2 diabetes and their combined association with plasma leptin and adiponectin levels in overweight Latino children with a family history of Type 2 diabetes (T2DM). METHODS: This cross-sectional study investigated the combined association of a maternal and paternal family history of T2DM with leptin and adiponectin in 175 overweight Latino children (age 11.1 +/- 1.7 years). All subjects had a family history of T2DM. Plasma adiponectin and leptin levels, body fat measured by dual-energy X-ray absorptiometry, Tanner stage, age and insulin sensitivity were assessed. RESULTS: After adjustment for age, gestational diabetes, insulin sensitivity and body fat, a combined maternal and paternal family history of T2DM was associated with higher leptin concentrations (P = 0.004) compared with a maternal or paternal family history alone. This association was most pronounced at Tanner stage 1 (P for interaction family history x tanner stage = 0.022). The presence of a combined maternal and paternal family history of T2DM accounted for 4% (P = 0.003) of the variation in leptin concentrations. No such combined association was observed for adiponectin levels. CONCLUSIONS: Maternal and paternal family history of T2DM may have an additive impact on leptin, but not on adiponectin levels independent of adiposity and insulin sensitivity in overweight Latino children. This may contribute to a further clinically relevant deterioration of metabolic health in this population.

Consumption of artificial sweetened beverages associated with adiposity and increasing HbA1c in Hispanic youth.

Research examining the impact of artificial sweetened beverages (ASBs) on obesity and metabolic diseases in adolescents is limited. The overall goal is to examine the longitudinal effects of ASBs on changes in adiposity and metabolic parameters in Hispanic adolescents. Longitudinal cohort with 98 Hispanics (12-18 years) who were overweight or had obesity with the following data at baseline and 1-year later: anthropometrics, diet (24-h recalls), body composition (DXA), glucose and insulin dynamics (oral glucose tolerance and frequently sampled intravenous glucose tolerance test) and fasting lipids. Repeated measures analyses of covariance assessed changes over time between control (no ASBs at either visit), ASB initiators (no ASBs at baseline/ASBs at 1-year) and chronic ASB consumers (ASBs at both visits). ASB initiators (n = 14) and chronic ASB consumers (n = 9) compared to control (n = 75) had higher total body fat at baseline and 1-year (P = 0.05 for group effect). Chronic ASB consumers had a 6% increase in haemoglobin A1c, 34% increase in energy intake (kcal d-1 ) and 39% increase in carbohydrate intake (g d-1 ) over time, while control and ASB initiators maintained (P < 0.05 for group-by-time interactions). These results do not support promoting ASBs as a strategy for adiposity loss or to improve metabolic health.

A potential role for Elf-1 in terminal transferase gene regulation.

The terminal deoxynucleotidyltransferase (TdT) gene represents an attractive model for the analysis of gene regulation during an early phase of lymphocyte development. In previous studies, we identified a DNA element, termed D', which is essential for TdT promoter activity in immature lymphocytes, and two classes of D'-binding factors, Ikaros proteins and Ets proteins. Here, we report a detailed mutant analysis of the D' element which suggests that an Ets protein, rather than an Ikaros protein, activates TdT transcription. Since multiple Ets proteins are expressed in developing lymphocytes and are capable of binding to the D' element, DNA affinity chromatography was used to determine if one of the Ets proteins might bind to the D' element with a uniquely high affinity, thereby implicating that protein as a potential TdT activator. Indeed, one binding activity was greatly enriched in the high-salt eluates from a D' affinity column. Peptide microsequencing revealed that the enriched protein was Elf-1. Immunoblot analyses confirmed that in nuclear extracts, Elf-1 has a significantly higher affinity for the D' sequence than does another Ets protein, Ets-1. Transactivation and expression studies support the hypothesis that Elf-1 activates TdT transcription in immature T and B cells. Finally, a D' mutation which selectively reduces Elf-1 binding, but not the binding of other Ets proteins, was found to greatly reduce TdT promoter activity. Although Elf-1 previously had been implicated in the inducible activation of genes in mature T and B cells, our results suggest that it also plays an important role in regulating genes during an early phase of lymphocyte development.

Complementation of growth factor receptor-dependent mitogenic signaling by a truncated type I phosphatidylinositol 4-phosphate 5-kinase.

Substitution of phenylalanine for tyrosine at codon 809 (Y809F) of the human colony-stimulating factor 1 (CSF-1) receptor (CSF-1R) impairs ligand-stimulated tyrosine kinase activity, prevents induction of c-MYC and cyclin D1 genes, and blocks CSF-1-dependent progression through the G1 phase of the cell cycle. We devised an unbiased genetic screen to isolate genes that restore the ability of CSF-1 to stimulate growth in cells that express mutant CSF-1R (Y809F). This screen led us to identify a truncated form of the murine type Ibeta phosphatidylinositol 4-phosphate 5-kinase (mPIP5K-Ibeta). This truncated protein lacks residues 1 to 238 of mPIP5K-Ibeta and is catalytically inactive. When we transfected cells expressing CSF-1R (Y809F) with mPIP5K-Ibeta (delta1-238), CSF-1-dependent induction of c-MYC and cyclin D1 was restored and ligand-dependent cell proliferation was sustained. CSF-1 normally triggers the rapid disappearance of CSF-1R (Y809F) from the cell surface; however, transfection of cells with mPIP5K-Ibeta (delta1-238) stabilized CSF-1R (Y809F) expression on the cell surface, resulting in elevated levels of ligand-activated CSF-1R (Y809F). These results suggest a role for PIP5K-Ibeta in receptor endocytosis and that the truncated enzyme compensated for a mitogenically defective CSF-1R by interfering with this process.

The t(12;21) translocation converts AML-1B from an activator to a repressor of transcription.

The t(12;21) translocation is present in up to 30% of childhood B-cell acute lymphoblastic and fuses a potential dimerization motif from the ets-related factor TEL to the N terminus of AML1. The t(12;21) translocation encodes a 93-kDa fusion protein that localizes to a high-salt- and detergent-resistant nuclear compartment. This protein binds the enhancer core motif, TGTGGT, and interacts with the AML-1-binding protein, core-binding factor beta. Although TEL/AML-1B retains the C-terminal domain of AML-1B that is required for transactivation of the T-cell receptor beta enhancer, it fails to activate transcription but rather inhibits the basal activity of this enhancer. TEL/AML-1B efficiently interferes with AML-1B dependent transactivation of the T-cell receptor beta enhancer, and coexpression of wild-type TEL does not reverse this inhibition. The N-terminal TEL helix-loop-helix domain is essential for TEL/AML-1B-mediated repression. Thus, the t(12;21) fusion protein dominantly interferes with AML-1B-dependent transcription, suggesting that the inhibition of expression of AML-1 genes is critical for B-cell leukemogenesis.

The MN1-TEL fusion protein, encoded by the translocation (12;22)(p13;q11) in myeloid leukemia, is a transcription factor with transforming activity.

The Tel gene (or ETV6) is the target of the translocation (12;22)(p13;q11) in myeloid leukemia. TEL is a member of the ETS family of transcription factors and contains the pointed protein interaction (PNT) domain and an ETS DNA binding domain (DBD). By contrast to other chimeric proteins that contain TEL's PNT domain, such as TEL-platelet-derived growth factor beta receptor in t(5;12)(q33;p13), MN1-TEL contains the DBD of TEL. The N-terminal MN1 moiety is rich in proline residues and contains two polyglutamine stretches, suggesting that MN1-TEL may act as a deregulated transcription factor. We now show that MN1-TEL type I, unlike TEL and MN1, transforms NIH 3T3 cells. The transforming potential depends on both N-terminal MN1 sequences and a functional TEL DBD. Furthermore, we demonstrate that MN1 has transcription activity and that MN1-TEL acts as a chimeric transcription factor on the Moloney sarcoma virus long terminal repeat and a synthetic promoter containing TEL binding sites. The transactivating capacity of MN1-TEL depended on both the DBD of TEL and sequences in MN1. MN1-TEL contributes to leukemogenesis by a mechanism distinct from that of other chimeric proteins containing TEL.

Leptin-to-adiponectin ratio as independent predictor of insulin sensitivity during growth in overweight Hispanic youth.

Because leptin and adiponectin are counter-regulated in vivo and exert opposing effects on glucose metabolism, fat oxidation and insulin sensitivity, the ratio of leptin-to-adiponectin has been investigated as a potential atherogenic index, suggesting that the index is a better biomarker for atherosclerotic risk in obese Type 2 diabetic patients than either leptin or adiponectin alone. However, no information is available regarding the leptin-to-adiponectin ratio during adolescence in Hispanic adolescents. Therefore, the present study was designed to investigate the leptin-to-adiponectin ratio during growth and to establish whether the leptin-to-adiponectin ratio is a better predictor for insulin sensitivity compared to leptin and adiponectin alone in a regression model. From the age of 8 to 14, the leptin-to-adiponectin ratio increased from 2.0+/-0.8 to 5.8+/-2.2 in girls, with no significant change noted in boys (gender x age interaction p=0.007). In a multiple regression analysis, including both adiponectin and leptin as independent variables, leptin and adiponectin explained 5% of the variation in insulin sensitivity independent of gender, age, Tanner stage, total fat mass and lean body mass (p for R2-change <0.001). The leptin-to-adiponectin ratio also explained 5% of the variation in insulin sensitivity, after controlling for the same covariates (p for R2-change <0.001). These data indicate that the leptin-to-adiponectin ratio is not a better predictor of insulin sensitivity during growth than the additive effects of leptin and adiponectin levels.

LA sprouts randomized controlled nutrition, cooking and gardening programme reduces obesity and metabolic risk in Hispanic/Latino youth.

BACKGROUND: Many programmes for children that involve gardening and nutrition components exist; however, none include experimental designs allowing more rigorous evaluation of their impact on obesity. OBJECTIVES: The objective of this study is to explore the effects of a novel 12-week gardening, nutrition and cooking intervention {'LA Sprouts'} on dietary intake, obesity parameters and metabolic disease risk among low-income, primarily Hispanic/Latino youth in Los Angeles.. METHODS: This study used a randomized control trial involving four elementary schools [two randomized to intervention {172, 3rd-5th grade students}; two randomized to control {147, 3rd-5th grade students}]. Classes were taught in 90-min sessions once per week for 12 weeks. Data collected at pre-intervention and post-intervention included dietary intake via food frequency questionnaire, anthropometric measures {body mass index, waist circumference}, body fat, and fasting blood samples. RESULTS: LA Sprouts participants compared with controls had significantly greater reductions in body mass index z-scores {-0.1 vs. -0.04, respectively; p = 0.01} and waist circumference {-1.2 vs. 0.1 cm; p < 0.001}. Fewer LA Sprouts participants had the metabolic syndrome after the intervention than before, while controls with metabolic syndrome increased. LA Sprouts participants compared with controls increased dietary fiber intake {+3.4% vs. -16.5%; p = 0.04}. All participants decreased vegetable intake, but decreases were less in LA Sprouts than controls {-3.7% vs. -26.1%; p = 0.04}. Change in fruit intake did not differ between LA Sprouts and controls. CONCLUSIONS: LA Sprouts was effective in reducing obesity and metabolic risk; however, additional larger and longer-term studies are warranted.

A Phase I trial of the farnesyl transferase inhibitor SCH66336: evidence for biological and clinical activity.

Farnesyl protein transferase (FT), an enzyme that catalyzes the first step in the posttranslational modification of ras and a number of other polypeptides, has emerged as an important target for the development of anticancer agents. SCH66336 is one of the first FT inhibitors to undergo clinical testing. We report a Phase I trial to assess the maximum tolerated dose, toxicities, and biological effectiveness of SCH66336 in inhibiting FT in vivo. Twenty patients with solid tumors received 92 courses of escalating SCH66336 doses given orally twice a day (b.i.d.) for 7 days out of every 3 weeks. Gastrointestinal toxicity (nausea, vomiting, and diarrhea) and fatigue were dose-limiting at 400 mg of SCH66336 b.i.d. Moderate reversible renal insufficiency, secondary to dehydration from gastrointestinal toxicity, was also seen. Inhibition of prelamin A farnesylation in buccal mucosa cells of patients treated with SCH66336 was demonstrated, confirming that SCH66336 inhibits protein farnesylation in vivo. One partial response was observed in a patient with previously treated metastatic non-small cell lung cancer, who remained on study for 14 months. This study not only establishes the dose for future testing on this schedule (350 mg b.i.d.) but also provides the first evidence of successful inhibition of FT in the clinical setting and the first hint of clinical activity for this class of agents.

Dietary fibre linked to decreased inflammation in overweight minority youth.

OBJECTIVE: The objective of this study was to examine the relationship between diet and inflammation, and adiposity in minority youth. DESIGN AND METHODS: The study was designed as a cross-sectional analysis of 142 overweight (≥85th body mass index percentile) Hispanic and African-American adolescents (14-18 years) with the following measures: anthropometrics, adiposity via magnetic resonance imaging, dietary intake via 24-h dietary recalls, and inflammation markers from fasting blood draws utilizing a multiplex panel. Partial correlations were estimated and analysis of covariance (ancova) models fit to examine the relationship among dietary variables, inflammation markers and adiposity measures with the following a priori covariates: Tanner stage, ethnicity, sex, total energy intake, total body fat and total lean mass. RESULTS: Inference based on ancova models showed that the highest tertile of fibre intake (mean intake of 21.3 ± 6.1 g d(-1) ) vs. the lowest tertile of fibre intake (mean intake of 7.4 ± 1.8 g d(-1) ) was associated with 36% lower plasminogen activator inhibitor-1 (P = 0.02) and 43% lower resistin (P = 0.02), independent of covariates. Similar results were seen for insoluble fibre. No other dietary variables included in this study were associated with inflammation markers. CONCLUSIONS: These results suggest that increases in dietary fibre could play an important role in lowering inflammation and therefore metabolic disease risk in high-risk minority youth.

Associations among sugar sweetened beverage intake, visceral fat, and cortisol awakening response in minority youth.

CONTEXT: Abdominal adiposity has long been associated with excess caloric intake possibly resulting from increased psychosocial stress and associated cortisol dysfunction. However, the relationship of sugar-sweetened beverage (SSB) intake specifically with cortisol variability and visceral adipose tissue (VAT) is unknown. OBJECTIVE: To examine the relationships between SSB intake, VAT, and cortisol response in minority youth. DESIGN: A cross-sectional analysis. SETTING: The University of Southern California. PARTICIPANTS: 60 overweight/obese Non-Hispanic Black and Hispanic adolescents ages 14-18years. MAIN OUTCOME MEASURES: VAT via Magnet Resonance Imaging (MRI), cortisol awakening response (CAR) via multiple salivary samples, and SSB intake via multiple 24-hour diet recalls. SSB intake was divided into the following: low SSB consumers (<1 servings per day), medium SSB consumers (≥1-<2 servings per day), high SSB consumers (≥2 servings per day). Analysis of covariance were run with VAT and CAR as dependent variables and SSB intake categories (independent variable) with the following a priori covariates: sex, Tanner stage, ethnicity, caloric intake, and body mass index. RESULTS: The high SSB intake group exhibited a 7% higher VAT compared to the low SSB intake group (ß=0.25, CI:(0.03, 0.33), p=0.02). CAR was associated with VAT (ß=0.31, CI:(0.01,0.23), p=0.02). The high SSB intake group exhibited 22% higher CAR compared to the low SSB intake group (ß=0.30, CI:(0.02,0.48), p=0.04). CONCLUSION: This is the first study exploring the relationship between SSB, VAT, and CAR. SSB consumption appears to be independently associated greater abdominal adiposity and higher morning cortisol variability in overweight and obese minority youth. This study highlights potential targets for interventions specifically to reduce SSB intake in a minority youth population.

Identification of protein complexes containing the c-rel proto-oncogene product in avian hematopoietic cells.

The c-rel proto-oncogene product has been identified as a 75 kDa protein expressed in lymphoid cells transformed by REV-T and Marek's disease virus. A 4.0 kb c-rel transcript is expressed in the bursa, spleen and thymus of chickens with highest levels of expression at 10 days post hatch. Using antiserum specific for the v-rel oncogene product, P75c-rel has been precipitated from [35S]methionine-labeled extracts of bursal, splenic and thymic lymphocytes. Additionally, proteins with the molecular mass of 40 kDa, 115 kDa, and 124 kDa co-immunoprecipitate. These proteins co-migrate with the proteins found associated with pp59v-rel in REV-T transformed lymphoid cells. Antiserum specific for pp40, the most abundant cellular protein associated with pp59v-rel, co-precipitates p75c-rel verifying the existence of p75c-rel/pp40 complexes in normal avian lymphocytes. Antiserum directed against the amino-terminal region of pp59v-rel fails to precipitate native p75c-rel complexes from normal lymphoid cells. In the presence of ionic detergents, antisera directed against the amino, middle and carboxy-regions precipitate equivalent amounts of p75v-rel. These results suggest that the amino-terminal region of p75c-rel is active in binding other proteins or is inaccessible to the antiserum due to the conformation of p75c-rel in the complex. Two p75c-rel complexes exist in the cytosol of normal lymphocytes. The most abundant complex contains 60% of the p75c-rel associated with p115 and p124. The remaining p75c-rel is associated with pp40.

Dual control of myc expression through a single DNA binding site targeted by ets family proteins and E2F-1.

NIH3T3 cells expressing a mutant colony-stimulating factor-1 receptor (CSF-1R) containing a phenylalanine for tyrosine substitution in the tyrosine kinase domain at codon 809 exhibit defective myc regulation and do not enter S phase when stimulated by CSF-1. Enforced expression of either ets-1 or ets-2 in these cells restores their mitogenic response, albeit less efficiently than myc itself, suggesting that ets proteins may regulate c-myc expression. Ets-1 transactivates reporter genes driven by the human and mouse c-myc promoters through the binding site for the transcription factor E2F, the latter being required for E1A- and serum-induced c-myc expression. Analysis of E2F-1 sequences identified a minimal DNA binding domain that is related to those of ets proteins. Although E2F and ets proteins interact with similar consensus DNA binding sites, in vitro binding assays revealed that E2F can bind DNA as a homodimer, whereas ets proteins bind these sites as monomers. E2F and ets proteins do not form heterodimers in vitro and do not transactivate c-myc synergistically. Thus, E2F-1 and ets family members may independently regulate c-myc transcription through the same binding site at different times following growth factor stimulation.

ETO-2, a new member of the ETO-family of nuclear proteins.

The t(8;21) is associated with 12-15% of acute myelogenous leukemias of the M2 subtype. The translocation results in the fusion of two genes, AML1 (CBFA2) on chromosome 21 and ETO (MTG8) on chromosome 8. AML1 encodes a DNA binding factor; the ETO protein product is less well characterized, but is thought to be a transcription factor. Here we describe the isolation and characterization of ETO-2, a murine cDNA that encodes a new member of the ETO family of proteins. ETO-2 is 75% identical to murine ETO and shares very high sequence identities over four regions of the protein with ETO (domain I-III and zinc-finger). Northern analysis identifies ETO-2 transcripts in many of the murine tissues analysed and in the developing mouse embryo. ETO-2 is also expressed in myeloid and erythroid cell lines. We confirmed the nuclear localization of ETO-2 and demonstrated that domain III and the zinc-finger region are not required for nuclear localization. We further showed that a region within ETO, containing domain II, mediates dimerization among family members. This region is conserved in the oncoprotein AML-1/ETO. The recent identification of another ETO-like protein, myeloid translocation gene-related protein 1, together with the data presented here, demonstrates that at least three ETO proteins exist with the potential to form dimers in the cell nucleus.

A variant Ewing's sarcoma translocation (7;22) fuses the EWS gene to the ETS gene ETV1.

Most Ewing's sarcomas or related primitive neuroectodermal tumors have the (11;22)(q24;q12) or less frequently the (21;22)(q22;q12) translocation. These rearrangements fuse the EWS gene on chromosome 22q12 to either the FLI1 or ERG genes, both members of the ETS family of transcription factors. Simple variant chromosomal translocations have been occasionally described in these tumors. We have identified a third Ewing's sarcoma translocation, the t(7;22)(p22;q12), that fuses EWS to the human homologue of the murine ETS gene ER81. This gene, designated ETV1 (for ETS Translocation Variant), is located on chromosome band 7p22. Identical EWS nucleotide sequences found in the majority of EWS-FLI1 and EWS-ERG chimeric transcripts are fused to a portion of ETV1 encoding an ETS domain with sequence specific DNA-binding activity. These findings confirm that the fusion of EWS to different ETS family members can result in a similar tumor phenotype.