2019年4月11日 · The transcription factor Myeloid Ecotropic Insertion Site 2 (MEIS2) has been identified as a cellular substrate of the E3-ubiquitin ligase complex CRL4-cereblon (CRL4CRBN) in crystal structure...

2014年8月7日 · The structure establishes that CRBN is a substrate receptor within CRL4 (CRBN) and enantioselectively binds IMiDs. Using an unbiased screen, we identified the homeobox transcription factor MEIS2 as an endogenous substrate of CRL4 (CRBN).

2014年7月16日 · Our studies suggest that IMiDs block endogenous substrates (MEIS2) from binding to CRL4CRBN while the ligase complex is recruiting IKZF1 or IKZF3 for degradation.

2024年11月5日 · Cereblon (CRBN), a component of the CRL4 CRBN E3 ligase, is required for IMiD's anti-myeloma activity. Binding of IMiD to CRBN promotes the recruitment of transcription factors IKZF1 and IKZF3 to CRL4 CRBN for ubiquitination and degradation, leading to loss of IRF4, an IKZF1/3 target essential for survival of myeloma cells.

Emerging evidence suggests that IMiDs can block MEIS2 from binding to CRBN facilitating the subsequent activation of a CRL4CRBNIMiD-E3-ubiquitin ligase activity and proteasome-mediated...

2019年4月11日 · It has been proposed that IMiDs can block CRBN binding to MEIS2 preventing its ubiquitination/degradation, suggesting a role for this protein in modulating IMiD’s anti-MM activity via direct molecular competition.

2024年11月5日 · Further biochemical analyses revealed that CDK4/6 inhibition rapidly accelerated the displacement of MEIS2 from CRBN within one hour of Len treatment, concurrent with enhanced ubiquitination and degradation of IKZF1 and IKZF3 in both MM cell lines and primary BMMCs.

2019年4月11日 · The transcription factor Myeloid Ecotropic Insertion Site 2 (MEIS2) has been identified as a cellular substrate of the E3-ubiquitin ligase complex CRL4-cereblon (^CRL4CRBN) in crystal structure and by biochemical screen. Emerging evidence suggests that IMiDs can block MEIS2 from binding to …

2013年12月5日 · The structure establishes that CRBN is a substrate receptor within CRL4 (CRBN) and enantioselectively binds IMiDs. Using an unbiased screen, we identified the homeobox transcription factor MEIS2 as an endogenous substrate of CRL4 (CRBN).

Selective expression of MEIS2 in MM cells but not in normal PCs, B cells or lymphoma cells further suggest MEIS2 as a druggable target in MM. In this study, we provide the first evidence that CDK4/6 inhibition reverses MEIS2 inhibition of CRBN that has a potential to enhance the clinical response to IMiD.