Furthermore, post-translational modifications of the TERT protein Posted on by admin
Furthermore, post-translational modifications of the TERT protein through phosphorylation or ubiquitination have been shown to affect the catalytic activity and stability of TERT . Anyhow, our data suggest that mutation of the TERT promoter causes telomerase reactivation in MLS and thereby most probably provides unlimited selleckchem proliferative potential. This assumption is also underpinned by a reporter gene assay of the two most common mutation variants within the promoter region of TERT, namely C228T and C250T, which were shown to lead to an augmented expression of TERT. Further, the high prevalence of TERT promoter mutations not only
in MLS round cell variants but also in MLS with a pure myxoid phenotype, and this irrespective of tumor grading, find more implies that these mutations act rather as driver than passenger mutations. TERT promoter mutations might also have a diagnostic impact in myxoid sarcomas. Mutations were found neither in dedifferentiated GSK3326595 ic50 liposarcomasa (DDLS), nor in pleomorphic liposarcomas (PLS), which presented myxoid areas in many cases, and were also not detectable in our series of myxofibrosarcomas, extraskeletal myxoid chondrosarcomas, dermatofibrosarcomata
protuberans, and low-grade fibromyxoid sarcomas. The absence of TERT promoter hotspot mutations in our series of DDLS and PLS is in line with previous studies, which largely observed deficient telomerase activity in high-grade liposarcomas. Instead, high-grade liposarcomas often use the ALT mechanism [28, 35, 36]. ALT overcomes telomere attrition through homologous recombination of telomeric DNA and characteristically presents with a pattern of telomere lengths that range from very short to abnormally long. This telomere pattern is clearly Oxymatrine different compared to tumors
with telomerase reactivation, where telomere length is found almost equal .It has been shown that ALT-positive liposarcomas have a notably worse outcome, and may imply a more favorable prognosis for TERT promoter mutated liposarcomas [28, 37, 38]. However, differences in patients outcome might be dedicated to the fact that telomere maintenance via ALT is more often applied by tumors with complex karyotypes or with a higher level of genomic instability [39, 40], whereas sarcomas characterized by type specific translocations rather use telomerase reactivation for telomere maintenance [39, 41]. According to our data, this concept holds true for the group of liposarcomas. MLS are characterized by a translocation that fuses the DDIT3 (CHOP) gene on chromosome 12q13 with the FUS (TLS) gene on chromosome 16p11 in approximately 90% of cases, or the DDIT3 (CHOP) with the EWSR1 on chromosome 22q12 in the remaining cases . This entry was posted in Uncategorized by admin . Bookmark the permalink .