Activation of c-Abl Kinase Potentiates the Anti-myeloma Drug Lenalidomide by Promoting DDA1 Protein Recruitment to the CRL4 Ubiquitin Ligase

作者：Gao, Shaobing; Geng, Chenlu; Song, Tianyu; Lin, Xuanru; Liu, Jiye; Cai, Zhen; Cang, Yong^*

来源：JOURNAL OF BIOLOGICAL CHEMISTRY, 2017, 292(9): 3683-3691.

DOI：10.1074/jbc.M116.761551

• cancer biology
• cancer therapy
• molecular cell biology
• ubiquitin ligase
• ubiquitylation (ubiquitination)
• CRL4
• DDA1
• c-Abl
• lenalidomide

Cullin-RING ligase 4 (CRL4), a complex of Cul4 and DDB1, regulates the cell cycle, DNA damage repair, and chromatin replication by targeting a variety of substrates for ubiquitination. CRL4 is also hijacked by viral proteins or thalidomide-derived compounds to degrade host restriction factors. Here we report that the c-Abl non-receptor kinase phosphorylates DDB1 at residue Tyr-316 to recruit a small regulatory protein, DDA1, leading to increased substrate ubiquitination. Pharmacological inhibition or genetic ablation of the Abl-DDB1-DDA1 axis decreases the ubiquitination of CRL4 substrates, including IKZF1 and IKZF3, in lenalidomide-treated multiple myeloma cells. Importantly, panobinostat, a recently approved anti-myeloma drug, and dexamethasone enhance lenalidomide-induced substrate degradation and cytotoxicity by activating c-Abl, therefore providing a mechanism underlying their combination with lenalidomide to treat multiple myeloma.

• 出版日期2017-3-3
• 单位浙江大学