This results in clonal T-cell leukemia arising in the transgenic mice with a long latency, indicating that the transgenes are necessary but not sufficient to cause tumors in these models, as is the case for many transgenic oncogene models Adams and Cory and that mutations in other oncogenes or tumor suppressor genes occur before development of overt disease.
The long latency period before tumors arise in Lmo2 transgenics facilitated detailed studies of possible effects in the asymptomatic thymuses of transgenic mice Larson et al. An outline of normal T-cell differentiation is shown in Figure 3 , which illustrates the individual points in T-cell development. Thus, the role of the transgene products is to cause an inhibition in T-cell differentiation, which appears reversible, presumably by antigenic stimulation occurring after birth, as different transgenic mice exhibit different levels of DN cell accumulation. Inhibition of T-cell differentiation model for Lmo2 function.
The Lmo2 transgenic mice and double Lmo2—Tal1 transgenics Larson et al. Because the LMO1 and LMO2-associated chromosomal translocations seem to result from RAG-mediated recombinase errors, it is proposed that this same target population of DN T cells is affected in humans with the chromosomal translocation.
Oncogenic conversion of transcription factors by chromosomal translocations.
This would be the population from which the overt tumors arise. Chromosomal translocation breakpoint sequencing mentioned earlier suggested that TCR rearrangement, mediated by recombinase, causes the formation of aberrant chromosomes in humans and, in turn, suggests that T-ALL precursors in humans acquire the LMO2 chromosomal translocations within the DN T-cell population. If so, this would produce a cell with inhibited differentiation, analogous to those of transgenic mice Fig. The concept of inhibited differentiation mediated through creation of aberrant transcription complexes can be drawn from two observations.
First, aberrant Lmo2 transgene expression upsets thymocyte differentiation. Second, the Lmo2 protein can be part of a DNA-binding complex in erythroid cells in which Lmo2 is a bridging molecule between the two DNA-binding arms of the complex, suggesting that enforced expression of LMO2 , either by chromosomal translocation or by transgenesis, could mediate the formation of aberrant protein complexes. In a search for evidence of such Lmo2-containing complexes, T-cell lines derived from CD2—Lmo2 transgenic mice were used as a source of Lmo2 protein complexes Grutz et al.
This work resulted in the detection of a Lmo2 complex which, like its analog in erythroid cells, binds to a bipartite recognition site; but in the T-cell line, the complex recognizes a dual E-box motif, in which the two E-box sequences are separated by about one DNA helical turn Grutz et al. By analogy with arguments proposed for the normal erythroid E box—GATA-binding complex, a possible role for the E-box—E-box-binding T-cell complex may be to regulate expression of specific sets of target genes which, based on the difference in DNA-binding site, would differ from those putative genes controlled by the Lmo2—multimeric complex in erythroid cells.
Thus, enforced Lmo2 expression in T cells appears to facilitate the formation of an aberrant multimeric complex, which forms because Lmo2 has a binding affinity for these proteins. In an analogous way that multimeric complexes may vary and determine normal hematopoietic lineages, this aberrant complex may influence the T-cell lineage developmental program. An alternative explanation is worthy of consideration. Although a complex of proteins may form because of affinities for the Lmo2 protein, it remains possible that the crucial interaction is with only one of the partners, thereby sequestering it from its normal function.
Thus, a multicomponent complex may hide the true culprit responsible for a process of transcription dysregulation in tumorigenesis. This sequestration model is illustrated in Figure 4. Here, simple mass action effects, based on the relative concentrations of the interacting component, would influence the availability of individual proteins.
The result of enforced LMO2 expression would be movement of the putative equilibrium to the left. In support of such a model is the evidence that the proportion of transgenic mice expressing Lmo1 or Lmo2 that develop tumors is related to the transgene copy number Fisch et al. It is also worth considering data about components of the Lmo2 T-cell complex. For instance, E2A null mice loss of function develop T-cell tumors Bain et al. No data exist about any possible involvement of Ldb1 in tumors and the chromosomal location of the gene in humans does not show any correlation with known chromosomal abnormalities T.
Rabbitts, A. Agulnick, Y. Ramsey, and N. Carter, unpubl. However, the Drosophila Lmo gene homolog Boehm et al. The recognition of a novel bipartite DNA motif by an LMO2-containing complex in T cells suggests that control of expression of target genes, carrying these binding sites, may be the function of the complex. An alternative sequestration model might be considered.
In this model, the hypothetical proteins X and Y interact with each other and perform a necessary function in T cells. This may be by forming an equilibrium of other interactions, such as with Y—Z interactions or binding to target genes in the DNA. Enforced expression of LMO2 using a transgene or after chromosomal translocation allows interaction of LMO2 with protein X, thereby sequestering this protein from its function in relation it interations with Y.
The aberrant complex involving LMO2 and protein X may in reality also involve other proteins that would be found as part of the T-cell oligomeric complex. Notwithstanding their presence in such an oligomeric complex, the LMO2-X interaction is crucial to the molecular function and thus crucial to the effect of the chromosomal translocation in this model. Analogous models might apply to the role of LMO1. The studies summarized in this paper on the LMO family of genes typify the characteristics that commonly occur in genes activated by chromosomal translocations, especially in acute forms of hematopoietic cancers and in mesenchymal origin tumors such as sarcomas epithelial tumors have yet to characterized well enough in this respect; Rabbitts It is clear that chromosomal translocations are important in tumor etiology.
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These aberrant chromosomes are somatically formed and persist in the overt tumor. Despite their recurring nature, it is also apparent that they are part of the manifold events needed for the appearance of overt disease and generally not sufficient to cause overt cancer. There are two key steps by which the chromosomal translocations become fixed in the tumor cell. The first is to do with mechanism, and the second, with selection.
- Chromosomal Translocations and Oncogenic Transcription Factors.
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Those chromosomal translocations that appear in lymphoid tumors are frequently associated with the rearranging antigen receptor genes and are interchromosomal mistakes of the V D J recombination process either DNA sequence specific or not. The mechanism of those chromosomal translocations that result in gene fusion is not understood. The second step is paramount, as it is the selection of the cell which has acquired the aberrant chromosome because this confers some clonal advantage on the cell with it.
The molecular basis of this clonal advantage is manifested through the function of the proteins made from the translocation-activated genes, namely their apparent ability to affect the transcriptional activity of the cell. Furthermore, the observations that developmental regulators are frequent targets of chromosomal translocations may also give us clues as to the clonal advantage.
Thus, the ability of a protein product to influence cellular development abnormally may reflect a proliferative advantage over its neighboring cells, because of the inappropriate differentiation circumstances of the pretumor cell. These considerations certainly indicate that chromosomal translocations are early events in the outgrowth of tumors. Finally, the studies on proteins like LMO2, which are activated by chromosomal translocations, emphasize the importance of protein—protein interactions in the LMO proteins mediated through LIM domains in hematopoietic lineage determination and in tumorigenesis, and the potential that relatively small perturbations of protein binding equilibria can have for cell homeostasis.
The notion is of negative regulation resulting from chromosomal translocations. Given that transcription regulators are key targets for chromosomal translocations in human cancer, a major objective now is to clone the genes that are affected by the altered transcription in cells with chromosomal translocations and determine their contribution to the malignant phenotype. View all LMO T-cell translocation oncogenes typify genes activated by chromosomal translocations that alter transcription and developmental processes Terence H.
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View this table: In this window In a new window. Table 1. The LMO family of genes and T-cell oncogenes. Previous Section Next Section. Figure 1. Figure 2. Figure 3. Figure 4. Previous Section. Adams J. Science : — Agulnick A. Nature : — Aplan P. EMBO J. Bach I. Bain G. Begley C. Bernard O. Genes Chromosomes Cancer 1 : — Google Scholar.
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Oncogene 9 : — Oncogene 11 : — Look A. Malcolm S. Manolov G. Nature : 33 — Recommend to your librarian. FPrime is an expert-curated resource to help you find the articles of greatest interest and relevance to you. Chromosomal translocations involving transcription factor genes have been identified in an increasingly wide range of cancers.
Some translocations can create a protein "chimera" that is composed of parts from different proteins. How such chimeras cause cancer, and why they cause cancer in some cell types but not others, is not understood. One such chimera is EWS-FLI, the most frequently occurring translocation in Ewing Sarcoma, a malignant bone and soft tissue tumor of children and young adults. Using EWS-FLI and its parental transcription factor, FLI1, we created a unique experimental system to address questions regarding the genomic mechanisms by which chimeric transcription factors cause cancer.
To understand this mistargeting, we examined chromatin organization. In tumor cells, however, bound regions are nucleosome depleted and harbor the chromatin signature of enhancers. Thus, the EWS-FLI chimera acquired chromatin-altering activity, leading to mistargeting, chromatin disruption, and ultimately, transcriptional dysregulation. PMID: This entry form currently does not support special characters. Disclosures Policy Provide sufficient details of any financial or non-financial competing interests to enable users to assess whether your comments might lead a reasonable person to question your impartiality.
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Mechanisms of Oncogene Activation
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