TRIM25 promotes Capicua degradation independently of ERK in the absence of ATXN1L
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RESEARCH ARTICLE
Open Access
TRIM25 promotes Capicua degradation independently of ERK in the absence of ATXN1L Derek Wong1,2, Lisa Sogerer3, Samantha S. Lee4, Victor Wong5, Amy Lum2, Adrian B. Levine1, Marco A. Marra6 and Stephen Yip1,2,7*
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 Ataxinfamily 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 ATXN1LKO 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 ATXN1LKO 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. Keywords: Capicua, CIC, ATXN1L, MAPK, Ubiquitin, Proteasomal degradation, TRIM25, Glioblastoma, Breast carcinoma
Background Capicua (CIC), a member of the high-mobility group (HMG) box protein superfamily, is a highly conserved nuclear sensor of receptor tyrosine kinase (RTK) activation. CIC was first identified in Drosophila melanogaster as a regulator of growth and proliferation of specific tissues during development and exists as two isoforms * Correspondence: [email protected] 1 Pathology and Laboratory Medicine, University of British Columbia, Vancouver, Canada 2 Molecular Oncology, BC Cancer Agency, Vancouver, Canada Full list of author information is available at the end of the article
(CIC-S and CIC-L) [1–6]. In general, CIC acts as a repressor of receptor tyrosine kinase (RTK)-responsive genes and is inactivated through phosphorylation by ERK, a member of the mitogen-activated protein kinase (MAPK) cascade [2, 5–8]. The most well-characterized mammalian targets of CIC are the oncogenic E26 transformation-
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