Unknown

Dataset Information

0

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


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.

SUBMITTER: Hong X 

PROVIDER: S-EPMC5062998 | biostudies-literature |

REPOSITORIES: biostudies-literature

Similar Datasets

| S-EPMC11348240 | biostudies-literature
| S-EPMC3371408 | biostudies-literature
| S-EPMC5397900 | biostudies-literature
| S-EPMC7033647 | biostudies-literature
| S-EPMC5155141 | biostudies-literature
| S-EPMC10865846 | biostudies-literature
| S-EPMC4176355 | biostudies-other
| S-EPMC9971319 | biostudies-literature
| S-EPMC4884989 | biostudies-literature
| S-EPMC7065954 | biostudies-literature