Skip to Content
Merck
  • SOX9 is targeted for proteasomal degradation by the E3 ligase FBW7 in response to DNA damage.

SOX9 is targeted for proteasomal degradation by the E3 ligase FBW7 in response to DNA damage.

Nucleic acids research (2016-08-28)
Xuehui Hong, Wenyu Liu, Ruipeng Song, Jamie J Shah, Xing Feng, Chi Kwan Tsang, Katherine M Morgan, Samuel F Bunting, Hiroyuki Inuzuka, X F Steven Zheng, Zhiyuan Shen, Hatem E Sabaawy, LianXin Liu, Sharon R Pine
ABSTRACT

SOX9 encodes a transcription factor that governs cell fate specification throughout development and tissue homeostasis. Elevated SOX9 is implicated in the genesis and progression of human tumors by increasing cell proliferation and epithelial-mesenchymal transition. We found that in response to UV irradiation or genotoxic chemotherapeutics, SOX9 is actively degraded in various cancer types and in normal epithelial cells, through a pathway independent of p53, ATM, ATR and DNA-PK. SOX9 is phosphorylated by GSK3β, facilitating the binding of SOX9 to the F-box protein FBW7α, an E3 ligase that functions in the DNA damage response pathway. The binding of FBW7α to the SOX9 K2 domain at T236-T240 targets SOX9 for subsequent ubiquitination and proteasomal destruction. Exogenous overexpression of SOX9 after genotoxic stress increases cell survival. Our findings reveal a novel regulatory mechanism for SOX9 stability and uncover a unique function of SOX9 in the cellular response to DNA damage. This new mechanism underlying a FBW7-SOX9 axis in cancer could have implications in therapy resistance.

MATERIALS
Product Number
Brand
Product Description

Sigma-Aldrich
Anti-Urokinase Antibody, NT fragment, clone 2G6.2, clone 2G6.2, Chemicon®, from mouse
Sigma-Aldrich
Anti-Sox9 Antibody, Chemicon®, from rabbit
Sigma-Aldrich
Anti-Glyceraldehyde-3-Phosphate Dehydrogenase Antibody, clone 6C5, clone 6C5, Chemicon®, from mouse