Non-canonical STAT3 function reduces REDD1 transcription.

Publisher: Published by Blackwell Pub. on behalf of the Federation of European Biochemical Societies Country of Publication: England NLM ID: 101229646 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1742-4658 (Electronic) Linking ISSN: 1742464X NLM ISO Abbreviation: FEBS J Subsets: MEDLINE

Original Publication: Oxford, UK : Published by Blackwell Pub. on behalf of the Federation of European Biochemical Societies, c2005-

Signal Transduction* ; STAT3 Transcription Factor*/genetics ; STAT3 Transcription Factor*/metabolism; Gene Expression Regulation ; Transcription, Genetic ; STAT1 Transcription Factor/genetics ; RNA, Messenger/genetics ; Transcriptional Activation

The transcription factor STAT3 is a potent activator of transcription, but evidence exists that STAT3 can also repress gene expression. However, little is known about the molecular mechanisms involved in STAT3-dependent gene repression. Notably, STAT3 reduces the expression of the stress-induced mTOR inhibitor REDD1 by reducing REDD1 mRNA transcription. Here, we determined the functional domains of STAT3 responsible for the reduction of REDD1 mRNA and protein expression. Within STAT3, the N-terminal domain and tyrosine 705 are crucial for STAT3-dependent reduction of REDD1 expression. Interestingly, binding of STAT3 to canonical STAT-binding sides within the REDD1 promoter is not necessary for STAT3-mediated reduction of REDD1 expression. Still, STAT3 is recruited to the REDD1 promoter upon stimulation with IL-6, and reduces REDD1 promoter activity. The reduction of REDD1 expression is specific for STAT3, as neither expression nor activation of STAT1 reduces REDD1 mRNA and protein expression. In summary, we present a novel, non-canonical STAT3-dependent mechanism for reducing gene expression. This transcriptional repression increases the functions of STAT3 proteins beyond classical transcriptional activation of cytokine-regulated target genes to a more complex function in modulating gene expression in immunity and cellular stress.
(© 2022 The Authors. The FEBS Journal published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies.)

Comment in: FEBS J. 2023 Apr;290(7):1735-1739. doi: 10.1111/febs.16727. (PMID: 36715132)

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Keywords: IL-6; REDD1; STAT1; STAT3; transcription

RefSeq NC_000010.11; NC_000076.7

0 (STAT3 Transcription Factor)
0 (STAT1 Transcription Factor)
0 (RNA, Messenger)

Date Created: 20221116 Date Completed: 20230406 Latest Revision: 20230407

20250114

10.1111/febs.16679

36380685