PTPL1 is a direct transcriptional target of EWS-FLI1 and modulates Ewing's Sarcoma tumorigenesis

Abaan, Ogan D.; Levenson, Amy; Khan, Osman; Furth, Priscilla A.; Üren, Aykut; Toretsky, Jeffrey A.

doi:10.1038/sj.onc.1208247

Cited by 64 publications

(65 citation statements)

References 43 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…PTPL1 is highly expressed in ESFT cells both in comparison to other childhood tumors and in EWS-FLI1 expression models [41][42][43]. Our findings in ESFT suggest that PTPL1 is a direct transcriptional target of EWS-FLI1 and both promotes cell growth and oncogenesis [19]. Reduction of PTPL1 protein levels, using an antisense strategy, leads to highly significant reductions in both anchorage-dependent and anchorageindependent cell growth [19].…”

Section: Ptpl1 As a Tumor Promotermentioning

confidence: 95%

“…Our findings in ESFT suggest that PTPL1 is a direct transcriptional target of EWS-FLI1 and both promotes cell growth and oncogenesis [19]. Reduction of PTPL1 protein levels, using an antisense strategy, leads to highly significant reductions in both anchorage-dependent and anchorageindependent cell growth [19]. PTPL1-depleted ESFT cells also displayed an increased sensitivity to etoposide induced apoptosis when compared to control cells, although there was no significant difference in basal levels of apoptosis [19].…”

Section: Ptpl1 As a Tumor Promotermentioning

confidence: 95%

“…PTPL1-depleted ESFT cells also displayed an increased sensitivity to etoposide induced apoptosis when compared to control cells, although there was no significant difference in basal levels of apoptosis [19]. Our results correlated well with a pilot study using an ESFT tissue microarray, which observed a trend towards increased PTPL1 staining in metastatic ESFT samples compared to localized disease [19]. Ongoing studies by our group are focused on the identification of bona fide PTPL1 substrates and PTPL1-modulated pathways of motility and oncogenesis.…”

Section: Ptpl1 As a Tumor Promotermentioning

confidence: 96%

“…An additional promoter sequence may also lie upstream within the MAPK10/JNK3 gene itself [18]. We have also shown that the PTPL1 promoter contains binding sites (GGAA) for the ets-family of transcription factors that are activated by the EWS-FLI1 fusion protein in the Ewing's Sarcoma Family of Tumors [19].…”

Section: Transcriptional and Post-translational Regulationmentioning

confidence: 99%

“…Reduction of PTPL1 protein levels, using an antisense strategy, leads to highly significant reductions in both anchorage-dependent and anchorageindependent cell growth [19]. PTPL1-depleted ESFT cells also displayed an increased sensitivity to etoposide induced apoptosis when compared to control cells, although there was no significant difference in basal levels of apoptosis [19]. Our results correlated well with a pilot study using an ESFT tissue microarray, which observed a trend towards increased PTPL1 staining in metastatic ESFT samples compared to localized disease [19].…”

Section: Ptpl1 As a Tumor Promotermentioning

confidence: 99%

See 4 more Smart Citations

PTPL1: a large phosphatase with a split personality

Abaan

Toretsky

2008

Cancer Metastasis Rev

View full text Add to dashboard Cite

Protein tyrosine phosphatase, PTPL1, (also known as PTPN13, FAP-1, PTP-BAS, PTP1E) is a non-receptor type PTP and, at 270 kDa, is the largest phosphatase within this group. In addition to the well-conserved PTP domain, PTPL1 contains at least 7 putative macromolecular interaction domains. This structural complexity indicates that PTPL1 may modulate diverse cellular functions, perhaps exerting both positive and negative effects. In accordance with this idea, while certain studies suggest that PTPL1 can act as a tumor-promoting gene other experimental studies have suggested that PTPL1 may function as a tumor suppressor. The role of PTPL1 in the cancer cell is therefore likely to be both complex and context dependent with possible roles including the modulation of growth, stress-response, and cytoskeletal remodeling pathways. Understanding the nature of molecular complexes containing PTPL1, its interaction partners, substrates, regulation and subcellular localization are key to unraveling the complex personality of this protein phosphatase.

show abstract

Section: Ptpl1 As a Tumor Promotermentioning

confidence: 95%

Section: Ptpl1 As a Tumor Promotermentioning

confidence: 95%

Section: Ptpl1 As a Tumor Promotermentioning

confidence: 96%

Section: Transcriptional and Post-translational Regulationmentioning

confidence: 99%

Section: Ptpl1 As a Tumor Promotermentioning

confidence: 99%

See 3 more Smart Citations

PTPL1: a large phosphatase with a split personality

Abaan

Toretsky

2008

Cancer Metastasis Rev

View full text Add to dashboard Cite

show abstract

Molecular Genetics of Ewing Sarcoma

Ordóñez

Amaral

Álava

2015

Encyclopedia of Life Sciences

View full text Add to dashboard Cite

Ewing sarcoma (ES) is an aggressive tumour affecting mainly children and young adults. When metastases are detected, the survival rate is compromised as a result of a lack of appropriated treatments. Balanced chromosomal translocations, present in all primary ES, originate gene fusions, such as EWSR1‐FLI1, which act as aberrant transcription factors. Targeting EWSR1 ‐ FLI1 by using RNA interference approaches reduced tumour growth and tumourigenicity of ES cells in vitro and in vivo and is a good tool in order to get knowledge in the ES biology. However, possibility of taking RNA interference into clinic is limited. At present, some drugs affecting gene fusion activity have been reported to reduce tumour growth. In addition, several approaches targeting ES genetic alterations not related to gene fusions or their genetic targets have been recently reported. The use of more appropriated animal models and the study of ES tumour microenvironment and epigenetics will unveil new therapeutic targets. Key Concepts ES is an aggressive developmental tumour. Balanced chromosomal translocation and associated gene fusions are the primary molecular event in ES. Secondary molecular events in ES can define new therapeutic targets and new prognostic markers. The role played by epigenetics in ES and the regulation of chromatin remodelling is beginning to be known. Detection of ES circulating cells or identification of gene expression profiles in peripheral blood cells could become good prognostic markers. Identification of new markers of cancer stem cells could help improve ES therapy. Endoglin could be a relevant therapeutic target in ES. Osteolysis and bone remodelling are important mechanisms of ES tumour growth. ES cells secrete extracellular vesicles, containing aberrant EWSR1‐FLI1 mRNA and other growth factors, which interact with surrounding tumour cells and extracellular matrix components. Combination therapy of a dual inhibitor of IGF1R and IR pathways and a DNA damage agent can avoid resistance to IGF1R inhibitors. At present, there is a lack of appropriate genetically engineered mice (GEM) of ES.

show abstract

Investigation of the insulin‐like growth factor‐1 signaling pathway in localized Ewing sarcoma

Borinstein

Barkauskas

Krailo

et al. 2011

Cancer

View full text Add to dashboard Cite

BACKGROUND The insulin-like growth factor-1 (IGF-1) signaling pathway plays an important role in the pathology of Ewing sarcoma (ES). Retrospective studies have suggested that levels of IGF-1 and IGF binding protein 3 (IGFBP-3) are correlated with the outcome of patients with ES. METHODS The IGF-1 signaling pathway was investigated prospectively in 269 patients who had localized, previously untreated ES. Serum samples were obtained at diagnosis, and concentrations of IGF-1 and IGFBP-3 were determined by enzyme-linked immunosorbent assays. In addition, immunohistochemistry (IHC) was performed to assay for phosphorylated p70S6 kinase, protein kinase B (Akt), and forkhead box protein O1 (FOXO1) and to determine the presence of protein tyrosine phosphatase-L1 (PTPL1). IHC findings along with IGF-1 and IGFBP-3 concentrations were correlated with age, tumor location, sex, event-free survival, and overall survival. RESULTS Patients aged >18 years tended to have higher levels of IGF-1 (P =.10), lower levels of IGFBP-3 (P =.16), and decreased IGFBP-3:IGF-1 ratios (P =.01). No correlations were observed between sex, tumor location, or outcomes and concentrations of IGF-1 or IGFBP-3. Phosphorylation of p70S6 kinase, Akt, and FOXO1 was detected in the majority of patient tissues but was not associated with age, sex, or tumor location. PTPL1 was present in >80% of tumors and also was not correlated with age, sex, or tumor location. There was no difference in survival with respect to the presence of phosphorylated p70S6 kinase, phosphorylated FOXO1, phosphorylated Akt, or PTPL1. CONCLUSIONS The baseline IGFBP-3:IGF-1 ratio was correlated with age but did not affect the outcomes of patients with ES. The authors concluded that additional investigation of the IGF-1 pathway is warranted in patients with ES, and especially in those who have received treatment with IGF-1 receptor antibody inhibitors.

show abstract

PTPL1 is a direct transcriptional target of EWS-FLI1 and modulates Ewing's Sarcoma tumorigenesis

Cited by 64 publications

References 43 publications

PTPL1: a large phosphatase with a split personality

PTPL1: a large phosphatase with a split personality

Molecular Genetics of Ewing Sarcoma

Investigation of the insulin‐like growth factor‐1 signaling pathway in localized Ewing sarcoma

Contact Info

Product

Resources

About