title: Antagonistic TSC22D1 variants control BRAF(E600)-induced senescence.
abstract: 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.
authors: Division of Molecular Genetics, The Netherlands Cancer Institute, Amsterdam, The Netherlands.
authors: Cornelia
authors: C
authors: Hömig-Hölzel
authors: Remco
authors: R
authors: van Doorn
authors: Celia
authors: C
authors: Vogel
authors: Markus
authors: M
authors: Germann
authors: Marco G
authors: MG
authors: Cecchini
authors: Els
authors: E
authors: Verdegaal
authors: Daniel S
authors: DS
authors: Peeper
mesh_terms: D016922:Cellular Senescence / Q000502:physiology*; D017931:DNA Primers / Q000235:genetics; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic / Q000502:physiology*; D006801:Humans; D047468:Immunoprecipitation; D008544:Melanocytes / Q000378:metabolism*; D046228:Microarray Analysis; D010957:Plasmids / Q000235:genetics; D048493:Proto-Oncogene Proteins B-raf / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000235:genetics; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000502:physiology*; D025521:Tumor Suppressor Proteins / Q000378:metabolism*
chemical_list: D017931:DNA Primers; D034741:RNA, Small Interfering; D012097:Repressor Proteins; C099726:TSC22D1 protein, human; D025521:Tumor Suppressor Proteins; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf