E2A-PBX1 is the oncogene produced at the t(1;19) chromosomal breakpoint of pediatric pre-B-cell leukemia. Expression of E2A-Pbx1 induces fibroblast transformation and myeloid and T-cell leukemia in mice and arrests differentiation of granulocyte macrophage colony-stimulating factor-dependent myeloblasts in cultured marrow. Recently, the Drosophila melanogaster protein Exd, which is highly related to Pbx1, was shown to bind DNA cooperatively with the Drosophila homeodomain proteins Ubx and Abd-A. Here, we demonstrate that the normal Pbx1 homeodomain protein, as well as its oncogenic derivative, E2A-Pbx1, binds the DNA sequence ATCAATCAA cooperatively with the murine Hox-A5, Hox-B7, Hox-B8, and Hox-C8 homeodomain proteins, which are themselves known oncoproteins, as well as with the Hox-D4 homeodomain protein.
E2A-PBXI is a chimeric gene formed by the t(1;19)(q23;pl3.3) chromosomal translocation of pediatric pre-B-cell leukemia. The E2A-Pbxl fusion protein contains sequences encoding the transactivation domain of E2A joined to a majority of the Pbxl protein, which contains a novel homeodomain. Earlier, we found that expression of E2A-Pbxl causes malignant transformation of NIH 3T3 fibroblasts and induces myeloid leukemia in mice. Here we demonstrate that the homeodomains encoded by PBX], as well as by the highly related PBX2 and PBX3 genes, bind the DNA sequence ATCAATCAA. E2A-Pbxl strongly activates transcription in vivo through this motif, while Pbxl does not. This finding suggests that E2A-Pbxl transforms cells by constitutively activating transcription of genes regulated by Pbxl or by other members of the Pbx protein family.
The tyrosine protein kinase p56ick transduces signals important for antigen-induced T-cell The lymphocyte-specific tyrosine protein kinase, p561ck, is expressed predominantly in T cells (13,30,53), where it is physically associated with the T-cell transmembrane proteins CD4 and CD8 (43,45,52). During T-cell activation, CD4 and CD8 bind to the major histocompatibility complex glycoprotein (class II or class I, respectively) on an antigen-presenting cell, bringing p56ick in close physical proximity to the T-cell receptor (16). Binding of the antigen-major histocompatibility complex to CD4 and the T-cell receptor subunits triggers the rapid phosphorylation of a set of T-cell proteins on tyrosine (20). pS6ick is thought to mediate some of these phosphorylations, because the addition of antibodies that cross-link cell surface CD4 induces tyrosine phosphorylation of p56ick and activates its phosphotransferase activity in vitro (19, 27).Genetic evidence likewise indicates that enhancement of T-cell activation by CD4 is mediated through pS6Ick. Deletion of the cytoplasmic domain of CD4 that binds p56 ck abrogates the ability of CD4 to enhance antigen-induced interleukin 2 (IL-2) production in CD4-dependent cells (18,33,46), and T cells expressing activated p56Ik are hypersensitive to stimulation through the T-cell receptor (1) while those lacking functional p56iCk are defective in inducing the transient increase in intracellular free calcium that accompanies antigenic stimulation through the T-cell receptor (48). Therefore, p56 Ck performs a pivotal role in T-cell activation.
Full development of the frontal sinus is not achieved until approximately 19 years of age. An evaluation of frontal sinus injuries isolated to the subset of patients less than 20 years old has yet to be reported. In order to determine whether age was a factor in the clinical course of patients with frontal sinus fractures, 209 patients who sustained frontal sinus fractures from January 1985 to April 1990 were identified using the trauma registry from all six major trauma centers, one of which is a pediatric trauma center, in a county of 2.5 million people. Forty patients (19%) were between the ages of 6 and 19 years at the time of their injury. Computed tomography imaging of these pediatric patients identified associated head and neck fractures in 37 (93%) as well as significant central nervous system injury in 22 (55%). Seventeen pediatric patients were treated nonoperatively and 1 died prior to the planned surgery. A detailed analysis of extent of injury and treatment together with a comparison of the 169 adult and the 40 pediatric patients is presented.
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