Unknown

Dataset Information

0

Genome-wide screening reveals a role for subcellular localization of CRBN in the anti-myeloma activity of pomalidomide.


ABSTRACT: Pomalidomide, a derivative of thalidomide, is an effective treatment for multiple myeloma. The drug exerts its effects through CRBN, a component of the E3 ubiquitin ligase complex CRL4CRBN. To search for novel factors involved in the anti-cancer activity of pomalidomide, we performed a genome-wide shRNA library screen and identified 445 genes as those affecting pomalidomide sensitivity. Genes encoding components of the ubiquitin-proteasome pathway, such as subunits of the CRL4CRBN complex, the COP9 signalosome, and the 26S proteasome, were among the pomalidomide-affecting genes. Karyopherin beta 1 (KPNB1) was identified as a novel pomalidomide-affecting gene. KPNB1 was required for the nuclear import of CRBN and for the CRBN-directed, pomalidomide-dependent degradation of a clinically relevant substrate, the transcription factor Aiolos. By contrast, the cytoplasmic translation factor GSPT1 was degraded following treatment with the thalidomide derivative CC-885 only when CRBN was present in the cytoplasm, indicating that subcellular distribution of CRBN is critical for the efficacy of thalidomide-based medications.

SUBMITTER: Tateno S 

PROVIDER: S-EPMC7055313 | BioStudies | 2020-01-01

REPOSITORIES: biostudies

Similar Datasets

2017-01-01 | S-EPMC5389304 | BioStudies
1000-01-01 | S-EPMC6172563 | BioStudies
2018-01-01 | S-EPMC6326779 | BioStudies
2020-01-01 | S-EPMC7046148 | BioStudies
2014-01-01 | S-EPMC4423819 | BioStudies
1000-01-01 | S-EPMC3496085 | BioStudies
2017-01-01 | S-EPMC5458144 | BioStudies
2019-01-01 | S-EPMC6475089 | BioStudies
2014-05-13 | E-GEOD-57554 | BioStudies
2021-03-03 | S-SCDT-EMBOJ-2020-105375 | BioStudies