期刊
CELL REPORTS
卷 24, 期 4, 页码 947-+出版社
CELL PRESS
DOI: 10.1016/j.celrep.2018.06.101
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资金
- National Institute of Immunology core funds
- Department of Biotechnology (DBT) of India [BT/MED/30/SP11263/2015]
- Council of Scientific and Industrial Research (CSIR) of India [37[1699]/17/EMR-11]
- Wellcome Trust/DBT India Alliance [500127/Z/09/Z]
Mutations in BLM helicase predispose Bloom syndrome (BS) patients to a wide spectrum of cancers. We demonstrate that MIB1-ubiquitylated BLM in G1 phase functions as an adaptor protein by enhancing the binding of transcription factor c-Jun and its E3 ligase, Fbw7 alpha. BLM enhances the K48/K63-linked ubiquitylation on c-Jun, thereby enhancing the rate of its subsequent degradation. Functionally defective Fbw7 alpha mutants prevalent in multiple human cancers are reactivated by BLM. However, BS patient-derived BLM mutants cannot potentiate Fbw7 alpha-dependent c-Jun degradation. The decrease in the levels of c-Jun in cells expressing BLM prevents effective c-Jun binding to 2,584 gene promoters. This causes decreases in the transcript and protein levels of c-Jun targets in BLM-expressing cells, resulting in attenuated c-Jun-dependent effects during neoplastic transformation. Thus, BLM carries out its function as a tumor suppressor by enhancing c-Jun turnover and thereby preventing its activity as a proto-oncogene.
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