Genome-wide screening reveals a role for subcellular localization of CRBN in the anti-myeloma activity of pomalidomide
Year: 2020
Type: article
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.
Source: Scientific Reports
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $1,870
Awards: G1120421960, G1335276476, G2382244037, G2620965724, G279616772, G2900416955, G3291055677, Elucidation of the molecular basis of IMiDs' action, Search for novel modulators of cereblon, the target of thalidomide that regulates neural stem cell proliferation and deifferentiation, G4103941422, G4238086841, G4344579159, Elucidation of the selection mechanism of transcription termination and polyadenylation sites by using novel proteomic approach, G501204033, G5056374651, G5499229459, G6450507048, G6504383915, An investigation of the molecular mechanisms of action of lenalidomide in adult T-cell leukemia (ATL), G7673554257, G825254133, G9000084746
OpenAlex ID: W3010312076