BLM Potentiates c-Jun Degradation and Alters Its Function as an Oncogenic Transcription Factor.

Autor:	Priyadarshini R; National Institute of Immunology, Aruna Asaf Ali Marg, New Delhi 110067, India., Hussain M; National Institute of Immunology, Aruna Asaf Ali Marg, New Delhi 110067, India., Attri P; National Institute of Immunology, Aruna Asaf Ali Marg, New Delhi 110067, India., Kaur E; National Institute of Immunology, Aruna Asaf Ali Marg, New Delhi 110067, India., Tripathi V; National Institute of Immunology, Aruna Asaf Ali Marg, New Delhi 110067, India., Priya S; National Institute of Immunology, Aruna Asaf Ali Marg, New Delhi 110067, India., Dhapola P; Institute of Genomics and Integrative Biology, CSIR, Mathura Road, New Delhi 110025, India., Saha D; Institute of Genomics and Integrative Biology, CSIR, Mathura Road, New Delhi 110025, India., Madhavan V; National Institute of Immunology, Aruna Asaf Ali Marg, New Delhi 110067, India., Chowdhury S; Institute of Genomics and Integrative Biology, CSIR, Mathura Road, New Delhi 110025, India., Sengupta S; National Institute of Immunology, Aruna Asaf Ali Marg, New Delhi 110067, India. Electronic address: sagar@nii.ac.in.
Jazyk:	angličtina
Zdroj:	Cell reports [Cell Rep] 2018 Jul 24; Vol. 24 (4), pp. 947-961.e7.
DOI:	10.1016/j.celrep.2018.06.101
Abstrakt:	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, Fbw7α. BLM enhances the K48/K63-linked ubiquitylation on c-Jun, thereby enhancing the rate of its subsequent degradation. Functionally defective Fbw7α mutants prevalent in multiple human cancers are reactivated by BLM. However, BS patient-derived BLM mutants cannot potentiate Fbw7α-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. (Copyright © 2018 The Author(s). Published by Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
Externí odkaz:	Zobrazit plný text záznamu