FBXW7 tumor suppressor regulation by dualspecificity tyrosine-regulated kinase 2.
Cell Death Dis
; 14(3): 202, 2023 03 18.
Article
em En
| MEDLINE
| ID: mdl-36934104
ABSTRACT
FBXW7 is a member of the F-box protein family, which functions as the substrate recognition component of the SCF E3 ubiquitin ligase. FBXW7 is a main tumor suppressor due to its ability to control proteasome-mediated degradation of several oncoproteins such as c-Jun, c-Myc, Cyclin E1, mTOR, and Notch1-IC. FBXW7 inactivation in human cancers results from a somatic mutation or downregulation of its protein levels. This work describes a novel regulatory mechanism for FBXW7 dependent on the serine/threonine protein kinase DYRK2. We show that DYRK2 interacts with and phosphorylates FBXW7 resulting in its proteasome-mediated degradation. DYRK2-dependent FBXW7 destabilization is independent of its ubiquitin ligase activity. The functional analysis demonstrates the existence of DYRK2-dependent regulatory mechanisms for key FBXW7 substrates. Finally, we provide evidence indicating that DYRK2-dependent regulation of FBXW7 protein accumulation contributes to cytotoxic effects in response to chemotherapy agents such as Doxorubicin or Paclitaxel in colorectal cancer cell lines and to BET inhibitors in T-cell acute lymphoblastic leukemia cell lines. Altogether, this work reveals a new regulatory axis, DYRK2/FBXW7, which provides an understanding of the role of these two proteins in tumor progression and DNA damage responses.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Proteínas Tirosina Quinases
/
Proteínas Serina-Treonina Quinases
/
Leucemia-Linfoma Linfoblástico de Células T Precursoras
/
Proteína 7 com Repetições F-Box-WD
Limite:
Humans
Idioma:
En
Revista:
Cell Death Dis
Ano de publicação:
2023
Tipo de documento:
Article
País de afiliação:
Espanha