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26 results on '"Lessnick, S. L."'

1. Does Diphtheria Toxin Have Nuclease Activity?

Author

Bodley, James W., Johnson, Virginia Gray, Wilson, Brenda A., Blanke, Steven R., Murphy, John R., Pappenheimer,, A. M., Collier, R. John, Lessnick, S. L., Bruce, C., Baldwin, R. L., Chang, M. P., Nakamura, L. T., and Wisnieski, B. J.

Published
1990

8. Is There a Predisposition Gene for Ewing's Sarcoma?

Author

Randall, R. L., Lessnick, S. L., Jones, K. B., Gouw, L. G., Cummings, J. E., Cannon-Albright, L., and Schiffman, J. D.

Subjects
Article Subject
Abstract

Ewing's sarcoma is a highly malignant tumor of children and young adults. The molecular mechanisms that underlie Ewing's Sarcoma development are beginning to be understood. For example, most cases of this disease harbor somatic chromosomal translocations that fuse the EWSR1 gene on chromosome 22 with members of the ETS family. While some cooperative genetic events have been identified, such as mutations in TP53 or deletions of the CDKN2A locus, these appear to be absent in the vast majority of cases. It is therefore uncertain whether EWS/ETS translocations are the only consistently present alteration in this tumor, or whether there are other recurrent abnormalities yet to be discovered. One method to discover such mutations is to identify familial cases of Ewing's sarcoma and to then map the susceptibility locus using traditional genetic mapping techniques. Although cases of sibling pairs with Ewing's sarcoma exist, familial cases of Ewing's sarcoma have not been reported. While Ewing's sarcoma has been reported as a 2nd malignancy after retinoblastoma, significant associations of Ewing's sarcoma with classic tumor susceptibility syndromes have not been identified. We will review the current evidence, or lack thereof, regarding the potential of a heritable condition predisposing to Ewing's sarcoma.

Published
2010
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9. Protein phosphatase 1 regulatory subunit 1A in ewing sarcoma tumorigenesis and metastasis

Author

Luo, W, Xu, C, Ayello, J, Dela Cruz, F, Rosenblum, J M, Lessnick, S L, and Cairo, M S

Abstract

Protein phosphatase inhibitors are often considered as tumor promoters. Protein phosphatase 1 regulatory subunit 1A (PPP1R1A) is a potent protein phosphatase 1 (PP1) inhibitor; however, its role in tumor development is largely undefined. Here we characterize, for the first time, the functions of PPP1R1A in Ewing sarcoma (ES) pathogenesis. We found that PPP1R1A is one of the top ranked target genes of EWS/FLI, the master regulator of ES, and is upregulated by EWS/FLI via a GGAA microsatellite enhancer element. Depletion of PPP1R1A resulted in a significant decrease in oncogenic transformation and cell migration in vitro as well as xenograft tumor growth and metastasis in an orthotopic mouse model. RNA-sequencing and functional annotation analyses revealed that PPP1R1A regulates genes associated with various cellular functions including cell junction, adhesion and neurogenesis. Interestingly, we found a significant overlap of PPP1R1A-regulated gene set with that of ZEB2 and EWS, which regulates metastasis and neuronal differentiation in ES, respectively. Further studies for characterization of the molecular mechanisms revealed that activation of PPP1R1A by PKA phosphorylation at Thr35, and subsequent PP1 binding and inhibition, was required for PPP1R1A-mediated tumorigenesis and metastasis, likely by increasing the phosphorylation levels of various PP1 substrates. Furthermore, we found that a PKA inhibitor impaired ES cell proliferation, tumor growth and metastasis, which was rescued by the constitutively active PPP1R1A. Together, these results offered new insights into the role and mechanism of PPP1R1A in tumor development and identified an important kinase and phosphatase pathway, PKA/PPP1R1A/PP1, in ES pathogenesis. Our findings strongly suggest a potential therapeutic value of inhibition of the PKA/PPP1R1A/PP1 pathway in the treatment of primary and metastatic ES.

Published
2018
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24. Multiple domains mediate transformation by the Ewing's sarcoma EWS/FLI-1 fusion gene.

Author

Lessnick SL, Braun BS, Denny CT, and May WA

Subjects
3T3 Cells, Animals, Base Sequence, Cloning, Molecular, Gene Rearrangement, Heterogeneous-Nuclear Ribonucleoproteins, Mice, Molecular Sequence Data, Proto-Oncogene Protein c-fli-1, RNA-Binding Protein EWS, Recombinant Fusion Proteins genetics, Sequence Deletion, Cell Transformation, Neoplastic genetics, DNA-Binding Proteins genetics, Neoplasm Proteins genetics, Nuclear Proteins genetics, Proto-Oncogene Proteins, RNA-Binding Proteins genetics, Ribonucleoproteins genetics, Sarcoma, Ewing genetics, Trans-Activators genetics
Abstract

The (11;22) chromosomal translocation found in Ewing's sarcoma and related tumors fuses the amino terminus of the EWS protein to the DNA-binding domain of the FLI-1 transcription factor. In contrast to normal FLI-1, the EWS/FLI-1 fusion transforms NIH3T3 cells and this activity requires both EWS and FLI-1 sequences. Reporter gene assays showed that the portion of EWS fused to FLI-1 encodes a strong transcriptional activation domain. To determine whether this function is necessary for transformation by EWS/FLI-1, deletion analysis of EWS was performed. We found that the EWS domain could be functionally subdivided into two regions: (i) an amino terminal domain (domain A) which transforms efficiently when fused to FLI-1 but has little transactivation activity in a model system and (ii) a distal region (domain B) which transactivates efficiently but transforms less efficiently when fused to FLI-1. Replacement of the EWS domain with known heterologous transcriptional activation domains yielded chimeric FLI-1 fusions that in some instances could transform NIH3T3 cells. Finally we demonstrate that EWS/FLI-1 and related FLI-1 chimeras are able to cooperate with another transcription factor to activate a model reporter gene. These results further demonstrate that EWS/FLI-1 is an aberrant transcription factor and suggest that the EWS domain mediates important protein-protein interactions with other factors resulting in the transcriptional modulation of target genes.

Published
1995

25. A second Ewing's sarcoma translocation, t(21;22), fuses the EWS gene to another ETS-family transcription factor, ERG.

Author

Sorensen PH, Lessnick SL, Lopez-Terrada D, Liu XF, Triche TJ, and Denny CT

Subjects
Amino Acid Sequence, Base Sequence, Child, Child, Preschool, Cloning, Molecular, DNA-Binding Proteins analysis, DNA-Binding Proteins genetics, Early Growth Response Protein 1, Female, Humans, Karyotyping, Molecular Sequence Data, Precipitin Tests, Proto-Oncogene Protein c-fli-1, RNA, Messenger analysis, Recombinant Fusion Proteins analysis, Recombinant Fusion Proteins genetics, Retroviridae Proteins, Oncogenic analysis, Retroviridae Proteins, Oncogenic genetics, Sequence Analysis, DNA, Trans-Activators analysis, Trans-Activators genetics, Transcription, Genetic, Tumor Cells, Cultured, Chromosomes, Human, Pair 21, Chromosomes, Human, Pair 22, Immediate-Early Proteins, Proto-Oncogene Proteins, Sarcoma, Ewing genetics, Transcription Factors genetics, Translocation, Genetic genetics
Abstract

The t(11;22)(q24;q12), present in 85% of Ewing's sarcoma and related tumours, fuses the EWS gene from chromosome 22q12 and the ETS family member, FLI-1. This results in the expression of a chimaeric protein containing the amino-terminal portion of EWS fused to the ETS DNA-binding domain of FLI-1. We have identified a second Ewing's sarcoma translocation, t(21;22)(q22;q12), that fuses EWS to a different ETS family member, the ERG gene located on band 21q22. Identical EWS nucleotide sequences found in the EWS/FLI-1 fusion transcripts are fused to portions of ERG encoding an ETS DNA-binding domain resulting in expression of a hybrid EWS/ERG protein. These findings suggest that fusion of EWS to different members of the ETS family of transcription factor genes may result in the expression of similar disease phenotypes.

Published
1994
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