The myc family of cellular oncogenes contains three known members. The N-myc and c-myc genes have 5'-noncoding exons, strikingly homologous coding regions, and display similar oncogenic potential in an in vitro transformation assay. The L-myc gene is less well characterized, but shows homology to N-myc and c-myc (ref. 6; also see below). c-myc is expressed in most dividing cells, and deregulated expression of this gene has been implicated in the development of many classes of tumours. In contrast, expression of N-myc has been found only in a restricted set of tumours, most of which show neural characteristics; these include human neuroblastoma, retinoblastoma and small cell lung carcinoma (SCLC). L-myc expression has so far been found only in SCLC. Activated N-myc and L-myc expression has been implicated in oncogenesis; for example, although N-myc expression has been found in all neuroblastomas tested, activated (greatly increased) N-myc expression, resulting from gene amplification, is correlated with progression of the tumour. We now report that high-level expression of N- and L-myc is very restricted with respect to tissue and stage in the developing mouse, while that of c-myc is more generalized. Furthermore, we demonstrate that N-myc is not simply a neuroectoderm-specific gene; both N- and L-myc seem to be involved in the early stages of multiple differentiation pathways. Our findings suggest that differential myc gene expression has a role in mammalian development and that the normal expression patterns of these genes generally predict the types of tumours in which they are expressed or activated.
We have generated transgenic mouse lines that carry one of three different constructs in which the murine N‐myc gene is expressed under the control of the immunoglobulin heavy chain transcriptional enhancer element (E mu‐N‐myc genes). High‐level expression of the E mu‐N‐myc transgenes occurred in lymphoid tissues; correspondingly, many of these E mu‐N‐myc lines reproducibly developed pre‐B‐ and B‐lymphoid malignancies. The E mu‐N‐myc transgene also appeared to participate in the generation of a T cell malignancy that developed in one E mu‐N‐myc mouse. These tumors and cell lines adapted from them expressed exceptionally high levels of the E mu‐N‐myc transgene; the levels were comparable to those observed in human neuroblastomas with highly amplified N‐myc genes. In contrast, all of the E mu‐N‐myc cell lines had exceptionally low or undetectable levels of the c‐myc RNA sequences, consistent with the possibility that high‐level N‐myc expression can participate in the negative ‘cross‐regulation’ of c‐myc gene expression. Our findings demonstrate that deregulated expression of the N‐myc gene has potent oncogenic potential within the B‐lymphoid lineage despite the fact that the N‐myc gene has never been implicated in naturally occurring B‐lymphoid malignancies. Our results also are discussed in the context of differential myc gene activity in normal and transformed cells.
The T4 molecule may serve as a T-cell receptor recognizing molecules on the surface of specific target cells and also serves as the receptor for the human immunodeficiency virus. To define the mechanisms of interaction of T4 with the surface of antigen-presenting cells as well as with human immunodeficiency virus, we have further analyzed the sequence, structure, and expression of the human and mouse T4 genes. T4 consists of an extracellular segment comprised of a leader sequence followed by four tandem variable-joining (VJ)-like domains, a transmembrane domain, and a cytoplasmic segment. The structural domains of the T4 protein deduced from amino acid sequence are precisely reflected in the intron-exon organization of the gene. Analysis of the expression of the T4 gene indicates that T4 RNA is expressed not only in T lymphocytes, but in B cells, macrophages, and granulocytes. T4 is also expressed in a developmentally regulated manner in specific regions of the brain. It is, therefore, possible that T4 plays a more general role in mediating cell recognition events that are not restricted to the cellular immune response.Analysis of the surface glycoproteins of peripheral T lymphocytes demonstrates that mature T cells segregate into one of two classes: those that express the surface glycoprotein T4 (CD4) and those that express the glycoprotein T8 (CD8) (1). The T4 molecule is primarily expressed on helper T lymphocytes, whereas T8 is expressed on cytotoxic and suppressor T cells (2, 3). T8+ T lymphocytes interact with a broad set of target cells that express class I major histocompatibility complex (MHC) gene products whereas T4+ T cells interact with a more restricted subset of targets, largely macrophages and B cells, that express class II MHC molecules (2, 3). This has led to the suggestion that the specificity of interaction of subpopulations of T lymphocytes with various target cells results in part from the association of T4 and T8 with the products of different MHC genes. T4 may not only serve as a receptor recognizing molecules on the surface of target cells, but also serves as the receptor for the human immunodeficiency virus (HIV) (4-7).We have isolated (8) the cDNA and the gene encoding T4 and have determined the nucleotide sequence of the fulllength cDNA clone. To define the mechanisms of interaction of T4 with the surface of both antigen-presenting cells as well as with HIV, we have further analyzed the sequence, structure, and expression of the human and mouse § T4 genes. Human T4, as well the mouse homologue L3T4, exhibit a polyimmunoglobulin-like structure with four tandem variable-joining (VJ)-like domains. This polyimmunoglobulinlike structure of T4 is homologous to an increasingly large number of recognition molecules. Moreover, we observe that T4 expression is not restricted to T cells, suggesting that T4 plays a more general role in cell-cell interactions. MATERIALS AND METHODSAll materials and procedures have been described (7-9). RESULTS T4 Exhibits a Polyimmunoglobulin-like Structur...
Recently botanical evidence has been studied to determine if it is useful in forensic investigations. This study was performed to examine stillborn piglet decomposition in a brackish water environment and to semi-quantitatively document stages of decomposition, degree day accumulation per stage as well as the algal/diatom diversity useful in determining a postmortem submersion interval (PMSI). Piglets and ceramic tiles were submerged in brackish ponds and sampled on a regular basis to document algal diversity and succession between substrates and stages of decomposition. Significantly greater weight was lost from piglet carcasses during the early floating and advanced floating decay stages. Seasonal effects were observed in degree-day accumulations. Diatom diversity was significantly greater on piglet carcasses compared to tile substrates. Algal diversity decreased over time on the piglet carcasses as well as the stage of decomposition. A significant relationship and strong correlation between algal diversity found on the piglet substrate with time was observed. Our results indicate that more research is needed to examine the potential to use diatoms in not only determining manner of death but also the duration of time (PMSI) a victim may have been immersed in an aquatic environment.
Both gain- and loss-of-function analyses indicate that proneural basic/helix-loop-helix (bHLH) proteins direct not only general aspects of neuronal differentiation but also specific aspects of neuronal identity within neural progenitors. In order to better understand the function of this family of transcription factors, we have used hormone-inducible fusion constructs to assay temporal patterns of downstream target regulation in response to proneural bHLH overexpression. In these studies, we have compared two distantly related Xenopus proneural bHLH genes, Xash1 and XNgnr1. Our findings indicate that both Xash1 and XNgnr1 induce expression of the general neuronal differentiation marker, N-tubulin, with a similar time course in animal cap progenitor populations. In contrast, these genes each induce distinct patterns of early downstream target expression. Both genes induce expression of the HLH-containing gene, Xcoe2, at early time points, but only XNgnr1 induces early expression of the bHLH genes, Xath3 and XNeuroD. Structure:function analyses indicate that the distinct pattern of XNgnr1-induced downstream target activation is linked to the XNgnr1 HLH domain, demonstrating a novel role for this domain in mediating the differential function of individual members of the proneural bHLH gene family.
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