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TRIM25 promotesCapicua degradationindependently of ERKin the absence ofATXN1L Derek WongLisa SogererSamantha S. Lee2020 год

TRIM25 promotes Capicua degradation independently of ERK in the absence of ATXN1L
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Аннотация: Abstract Background Aberrations in Capicua ( CIC ) have recently been implicated as a negative prognostic factor in a multitude of cancer types through the derepression of targets downstream of the mitogen-activated protein kinase (MAPK) signaling cascade, such as oncogenic E26 transformation-specific (ETS) transcription factors. The Ataxin-family protein ATXN1L has previously been reported to interact with CIC in both developmental and disease contexts to facilitate the repression of CIC target genes and promote the post-translational stability of CIC. However, little is known about the mechanisms at the base of ATXN1L-mediated CIC post-translational stability. Results Functional in vitro studies utilizing ATXN1L KO human cell lines revealed that loss of ATXN1L leads to the accumulation of polyubiquitinated CIC protein, promoting its degradation through the proteasome. Although transcriptomic signatures of ATXN1L KO cell lines indicated upregulation of the mitogen-activated protein kinase pathway, ERK activity was found to contribute to CIC function but not stability. Degradation of CIC protein following loss of ATXN1L was instead observed to be mediated by the E3 ubiquitin ligase TRIM25 which was further validated using glioma-derived cell lines and the TCGA breast carcinoma and liver hepatocellular carcinoma cohorts. Conclusions The post-translational regulation of CIC through ATXN1L and TRIM25 independent of ERK activity suggests that the regulation of CIC stability and function is more intricate than previously appreciated and involves several independent pathways. As CIC status has become a prognostic factor in several cancer types, further knowledge into the mechanisms which govern CIC stability and function may prove useful for future therapeutic approaches.
Год издания: 2020
Авторы: Derek Wong, Lisa Sogerer, Samantha S. Lee, Victor Wong, Amy Lum, Adrian Levine, Marco A. Marra, Stephen Yip
Издательство: BioMed Central
Источник: BMC Biology
Ключевые слова: Retinal Development and Disorders, Ubiquitin and proteasome pathways, Microtubule and mitosis dynamics
Другие ссылки: BMC Biology (PDF)
BMC Biology (HTML)
PubMed Central (HTML)
PubMed (HTML)