Opposing Effects of KLF5 on the Transcription of MYC in Epithelial Proliferation in the Context of Transforming Growth Factor β

• Published in: The Journal of biological chemistry Vol. 284; no. 41; pp. 28243 - 28252
• Main Authors: Guo, Peng, Dong, Xue-Yuan, Zhao, Kewen, Sun, Xiaodong, Li, Qunna, Dong, Jin-Tang
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 09.10.2009; American Society for Biochemistry and Molecular Biology
• Subjects: Cell Line; Cell Proliferation; Epithelial Cells - cytology; Epithelial Cells - physiology; Humans; Kruppel-Like Transcription Factors - genetics; Kruppel-Like Transcription Factors - metabolism; Mechanisms of Signal Transduction; Mutation; Promoter Regions, Genetic; Proto-Oncogene Proteins c-myc - genetics; Proto-Oncogene Proteins c-myc - metabolism; RNA, Small Interfering - genetics; RNA, Small Interfering - metabolism; Transcription, Genetic; Transforming Growth Factor beta - genetics; Transforming Growth Factor beta - metabolism
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M109.036160

The proto-oncogene MYC plays a critical role in cell proliferation and tumorigenesis, and its down-regulation by transforming growth factor β (TGFβ) signaling is necessary for TGFβ to inhibit cell proliferation. KLF5, on the other hand, is a pro-proliferative basic transcription factor that reverses function to become an anti-proliferative TGFβ cofactor upon TGFβ stimulation in epithelial homeostasis. In this study we investigated whether KLF5 directly regulates MYC transcription in epithelial cells in the context of TGFβ. Knockdown of KLF5 significantly reduced MYC expression in the HaCaT epidermal epithelial cells. When TGFβ was applied, however, whereas MYC expression was significantly inhibited, knockdown of KLF5 increased MYC expression. Furthermore, re-expression of KLF5 restored the inhibitory effect of TGFβ on MYC expression in two cancer cell lines. Chromatin immunoprecipitation and oligo pulldown experiments demonstrated that whereas binding of KLF5 to both KLF5 binding element (KBE) and TGFβ inhibitory element (TIE) DNA elements was necessary for MYC transcription, binding to KBE was decreased by TGFβ, and binding to TIE was increased by TGFβ. These results suggest that KLF5 is not only essential for MYC transcription in proliferating epithelial cells but also mediates the inhibitory effect of TGFβ on MYC transcription. Furthermore, different binding sites mediate different effects of KLF5 in the context of TGFβ.