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Ras inhibits TGF‐β‐induced KLF5 acetylation and transcriptional complex assembly via regulating SMAD2/3 phosphorylation in epithelial cells
Author(s) -
Guo Peng,
Xing Changsheng,
Fu Xiaoying,
He Dalin,
Dong JinTang
Publication year - 2020
Publication title -
journal of cellular biochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.028
H-Index - 165
eISSN - 1097-4644
pISSN - 0730-2312
DOI - 10.1002/jcb.29443
Subject(s) - acetylation , transforming growth factor , crosstalk , transcription factor , phosphorylation , microbiology and biotechnology , psychological repression , promoter , signal transduction , biology , cancer research , chemistry , gene , gene expression , biochemistry , physics , optics
Acetylated Kruppel‐like factor 5 (KLF5) is essential for transforming growth factor‐β (TGF‐β) to properly regulate gene transcription in the inhibition of cell proliferation and tumor growth. Ras oncogenic signaling can convert TGF‐β from a tumor suppressor to a tumor promoter; however, its ability to utilize the KLF5 transcription factor to modulate TGF‐β functions is still unknown. Therefore, in this study, we sought to determine whether Ras signaling altered TGF‐β‐induced KLF5 acetylation and the assembly of the p300‐KLF5‐SMADs transcriptional complex in gene regulation. Not only did we determine that Ras signaling inhibited TGF‐β‐induced KLF5 acetylation and interfered with TGF‐β function in p15 induction and Myc repression, but also TGF‐β‐induced SMAD3 C‐terminal region phosphorylation was necessary for TGF‐β to induce KLF5 acetylation. Moreover, Ras activation further interrupted the interactions amongst p300, KLF5, and SMAD4, as well as the binding of p300‐KLF5‐SMADs complex onto the TGF‐β‐responsive promoter elements for both p15 and Myc . These findings suggested that KLF5 mediated the crosstalk between TGF‐β and Ras signaling, and that suppression of TGF‐β‐induced KLF5 acetylation by Ras activation; this altered TGF‐β‐induced assembly of p300‐KLF5‐SMADs complex onto gene promoters to convert the function of TGF‐β in gene regulation.