z-logo
Premium
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.

This content is not available in your region!

Continue researching here.

Having issues? You can contact us here
Accelerating Research

Address

John Eccles House
Robert Robinson Avenue,
Oxford Science Park, Oxford
OX4 4GP, United Kingdom