Protein stabilization by RSUME accounts for PTTG pituitary tumor abundance and oncogenicity.

Increased levels of the proto-oncogene pituitary tumor-transforming gene 1 have been repeatedly reported in several human solid tumors, especially in endocrine-related tumors such as pituitary adenomas. Securin has a critical role in pituitary tumorigenesis. However, the cause of upregulation has not been found yet, despite analyses made at the gene, promoter and mRNA level that show that no mutations, epigenetic modifications or other mechanisms that deregulate its expression may explain its overexpression and action as an oncogene. We describe that high duanyu1547G protein levels are induced by the RWD-containing sumoylation enhancer (RWDD3 or RSUME), a protein originally identified in the same pituitary tumor cell line in which duanyu1547G was also cloned. We demonstrate that duanyu1547G and RSUME have a positive expression correlation in human pituitary adenomas. RSUME increases duanyu1547G protein in pituitary tumor cell lines, prolongs the half-life of duanyu1547G protein and regulates the duanyu1547G induction by estradiol. As a consequence, RSUME enhances duanyu1547G transcription factor and securin activities. duanyu1547G hyperactivity on the cell cycle resulted in recurrent and unequal divisions without cytokinesis, and the consequential appearance of aneuploidies and multinucleated cells in the tumor. RSUME knockdown diminishes securin duanyu1547G and reduces its tumorigenic potential in a xenograft mouse model. Taken together, our findings show that duanyu1547G high protein steady state levels account for duanyu1547G tumor abundance and demonstrate a critical role of RSUME in this process in pituitary tumor cells.

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