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C/EBPβ mediates tumour‐induced ubiquitin ligase atrogin1/MAFbx upregulation and muscle wasting
Author(s) -
Zhang Guohua,
Jin Bingwen,
Li YiPing
Publication year - 2011
Publication title -
the embo journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.484
H-Index - 392
eISSN - 1460-2075
pISSN - 0261-4189
DOI - 10.1038/emboj.2011.292
Subject(s) - biology , ubiquitin ligase , downregulation and upregulation , wasting , ubiquitin , dna ligase , ubiquitin protein ligases , microbiology and biotechnology , cancer research , endocrinology , biochemistry , enzyme , gene
Upregulation of ubiquitin ligase atrogin1/MAFbx and muscle wasting are hallmarks of cancer cachexia; however, the underlying mechanism is undefined. Here, we describe a novel signalling pathway through which Lewis lung carcinoma (LLC) induces atrogin1/MAFbx upregulation and muscle wasting. C2C12 myotubes treated with LLC‐conditioned medium (LCM) rapidly activates p38 MAPK and AKT while inactivating FoxO1/3, resulting in atrogin1/MAFbx upregulation, myosin heavy chain loss, and myotube atrophy. The p38α/β MAPK inhibitor SB202190 blocks the catabolic effects. Upon activation, p38 associates with C/EBPβ resulting in its phosphorylation and binding to a C/EBPβ‐responsive cis ‐element in the atrogin1/MAFbx gene promoter. The promoter activity is stimulated by LCM via p38β‐mediated activation of the C/EBPβ‐responsive cis ‐element, independent of the adjacent FoxO1/3‐responsive cis ‐elements in the promoter. In addition, p38 activation is observed in the muscle of LLC tumour‐bearing mice, and SB202190 administration blocks atrogin1/MAFbx upregulation and muscle protein loss. Furthermore, C/EBPβ −/− mice are resistant to LLC tumour‐induced atrogin1/MAFbx upregulation and muscle wasting. Therefore, activation of the p38β MAPK–C/EBPβ signalling pathway appears a key component of the pathogenesis of LLC tumour‐induced cachexia.