Oncogenic fusion protein BCR-FGFR1 requires BCR-mediated oligomerization and chaperonin Hsp90 for activation.

Oncogenic fusion protein BCR-FGFR1 requires BCR-mediated oligomerization and chaperonin Hsp90 for activation. Haematologica. 2019 Aug 22;: Authors: Peiris MN, Meyer AN, Nelson KN, Bisom-Rapp EW, Donoghue DJ Abstract Mutation and translocation of fibroblast growth factor receptors often lead to aberrant signaling and cancer. This work focuses on the t(8;22)(p11;q11) chromosomal translocation which creates the BCR-FGFR1 fusion protein. This fusion occurs in stem cell leukemia/lymphoma, which can progress to atypical chronic myeloid leukemia, acute myeloid leukemia, or B-Cell lymphoma. This work focuses on biochemical characterization of BCR-FGFR1 and identification of novel therapeutic targets. The tyrosine kinase activity of FGFR1 is required for biological activity as shown using transformation assays, IL-3 independent cell proliferation, and liquid chromatography/mass spectroscopy analyses. Furthermore, BCR contributes a coiled-coil oligomerization domain, also essential for oncogenic transformation by BCR-FGFR1. The importance of salt bridge formation within the coiled-coil domain is demonstrated, as disruption of three salt bridges abrogates cellular transforming ability. Lastly, BCR-FGFR1 acts as a client of the chaperone protein Hsp90, suggesting that BCR-FGFR1 relies on the Hsp90 complex to evade proteasomal degradation. Transformed cells expressing BCR-FGFR1 are sensitive to the Hsp90 inhibitor Ganetespib, and also respond to combined treatment wi...
Source: Haematologica - Category: Hematology Authors: Tags: Haematologica Source Type: research

Related Links:

Publication date: Available online 14 October 2019Source: Pulmonary Pharmacology &TherapeuticsAuthor(s): Huda Badri, Jaclyn A. SmithAbstractCough is mediated by vagal afferent fibres innervating the larynx and proximal airways. Pre-clinical studies suggest that vagal C fibres produce Substance P, one of the tachykinin family of neuropeptides, which has been shown to enhance cough via the neurokinin-1 (NK-1) receptor and studies in animal models have also shown that NK-1 antagonists are effective at blocking induced cough. In the past, tachykinin receptor antagonists have yielded disappointing results in treating asthma...
Source: Pulmonary Pharmacology and Therapeutics - Category: Respiratory Medicine Source Type: research
Objectives The goals of this study were to compare the efficacy of the new manganese-based magnetic resonance imaging (MRI) contrast agent Mn-PyC3A to the commercial gadolinium-based agents Gd-DOTA and to Gd-EOB-DTPA to detect tumors in murine models of breast cancer and metastatic liver disease, respectively, and to quantify the fractional excretion and elimination of Mn-PyC3A in rats. Methods T1-weighted contrast-enhanced MRI with 0.1 mmol/kg Mn-PyC3A was compared with 0.1 mmol/kg Gd-DOTA in a breast cancer mouse model (n = 8) and to 0.025 mmol/kg Gd-EOB-DTPA in a liver metastasis mouse model (n = 6). The fractional...
Source: Investigative Radiology - Category: Radiology Tags: Original Articles Source Type: research
This study aims at prospectively evaluating an adapted DWI sequence ex vivo and in vivo in oncologic patients undergoing abdominal MRI. Methods This institutional review board–approved, prospective study included phantom measurements, volunteer examinations, and oncologic patient examinations of the abdomen. Fifty-seven MRI examinations in 54 patients (mean age, 58 years; range, 21–90 years) were included into the analysis. The MRI examination were performed at a 1.5 T MRI scanner (MAGNETOM Aera; Siemens Healthcare, Erlangen, Germany) and included both a standard EPI-DWI (s-DWI; b = 50, 900 s/mm2) and an ada...
Source: Investigative Radiology - Category: Radiology Tags: Original Articles Source Type: research
ConclusionOur clinical outcomes are comparable overall to the three main published articles on this topic. The risk of infection and benefits of preventative fixation were apparent in our cohort.Level of evidenceIV, retrospective study.
Source: Orthopaedics and Traumatology: Surgery and Research - Category: Orthopaedics Source Type: research
ConclusionSub-cutaneous and/ or intra-peritoneal anesthesia were not effective in reducing post-operative pain.
Source: Journal of Minimally Invasive Gynecology - Category: OBGYN Source Type: research
ConclusionNeoadjuvant chemotherapy followed by laparoscopic and open radical hysterectomy seems to be a safe treatment option for locally advanced cervical cancer, in terms of similar survival outcomes and morbidity of treatment with CCRT. However, the present study is too limited to permit conclusions due to its small sample size and retrospective design despite statistical methods for adjusting confounding factors.
Source: Journal of Minimally Invasive Gynecology - Category: OBGYN Source Type: research
ConclusionOverall hyperplasia incidence is increasing. While BMI is elevated, there was no upward trend observed. Does the insidious decline in age demographic suggest that hyperplasia is occurring in younger women? Our review did not demonstrate a continuous increase in atypia, however there was a higher incidence in the 2013 group, who were also the most obese. Adherence to best practice surveillance in our hospitals was falling short.
Source: Journal of Minimally Invasive Gynecology - Category: OBGYN Source Type: research
ConclusionSingle-site laparoscopy is an alternative surgical choice for endometrial cancer.
Source: Journal of Minimally Invasive Gynecology - Category: OBGYN Source Type: research
Markus Hartl* and Rainer Schneider Center of Molecular Biosciences (CMBI), Institute of Biochemistry, University of Innsbruck, Innsbruck, Austria The neuronal proteins GAP43 (neuromodulin), MARCKS, and BASP1 are highly expressed in the growth cones of nerve cells where they are involved in signal transmission and cytoskeleton organization. Although their primary structures are unrelated, these signaling proteins share several structural properties like fatty acid modification, and the presence of cationic effector domains. GAP43, MARCKS, and BASP1 bind to cell membrane phospholipids, a process reversibly regulate...
Source: Frontiers in Oncology - Category: Cancer & Oncology Source Type: research
In conclusion, the high structural diversity of these compounds pinpoints the significant range of inhibition strategies that can be conceived to target the class I methyltransferases. Although the structural details of the various members of this family are unique, the success stories of drug design for several enzymes belonging to this family portends the likely achievement of discovering potent and selective inhibitors of METTL3/METTL14. Author Contributions AF and AP wrote the manuscript. ZI revised and edited manuscript and prepared figures. Funding This work was supported by Associazione Italiana Ricerca sul Canc...
Source: Frontiers in Oncology - Category: Cancer & Oncology Source Type: research
More News: Acute Leukemia | Acute Myeloid Leukemia | Cancer | Cancer & Oncology | Chronic Leukemia | Chronic Myeloid Leukaemia | Hematology | Leukemia | Lymphoma | Sodium Chloride | Stem Cell Therapy | Stem Cells | Translocation