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Antagonistic TSC22D1 variants control BRAF E600 ‐induced senescence
Author(s) -
HömigHölzel Cornelia,
van Doorn Remco,
Vogel Celia,
Germann Markus,
Cecchini Marco G,
Verdegaal Els,
Peeper Daniel S
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.2011.95
Subject(s) - cancer genetics , library science , biology , genetics , cancer , computer science
Oncogene‐induced cellular senescence (OIS) is an increasingly recognized tumour suppressor mechanism that confines the outgrowth of neoplastic cells in vivo . It relies on a complex signalling network, but only few components have been identified so far. Gene‐expression profiling revealed a >100‐fold increase in the levels of the transcription factor and putative tumour suppressor gene TGFβ‐stimulated clone 22 ( TSC22D1 ) in BRAF E600 ‐induced senescence, in both human fibroblasts and melanocytes. Only the short TSC22D1 transcript was upregulated, whereas the abundance of the large protein variant was suppressed by proteasomal degradation. The TSC22D1 protein variants, in complex with their dimerization partner TSC22 homologue gene 1 (THG1), exerted opposing functions, as selective depletion of the short form, or conversely, overexpression of the large variant, resulted in abrogation of OIS. This was accompanied by the suppression of several inflammatory factors and p15 INK4B , with TSC22D1 acting as a critical effector of C/EBPβ. Our results demonstrate that the differential regulation of antagonistic TSC22D1 variants is required for the establishment of OIS and suggest distinct contributions of TSC22 family members to the progression of BRAF E600 ‐driven neoplasia.