p63 is a cereblon substrate involved in thalidomide teratogenicity

Asatsuma‐Okumura, Tomoko; Ando, Hideki; Simone, Marco De; Yamamoto, Junichi; Satō, Tomomi; Shimizu, Nobuyuki; Asakawa, Kazuhide; Yamaguchi, Yuki; Ito, Takumi; Guerrini, Luisa; Handa, Hiroshi

doi:10.1038/s41589-019-0366-7

Cited by 102 publications

(84 citation statements)

References 49 publications

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“…Although SALL1, SALL2, and SALL3 are predicted to bind to the pomalidomide-CRBN complex via docking simulations 48 , neither SALL1, SALL2, nor SALL3 are degraded in the presence of thalidomide, lenalidomide, or pomalidomide in human embryonic stem cells 11 , suggesting that SALL1, SALL2, and SALL3 are not neosubstrates of CRBN in the presence of thalidomide or IMiDs. Additionally, p63 has been identified as a putative neosubstrate of CRBN in the presence of thalidomide and a molecular mediator of thalidomide teratogenicity whose degradation can be induced by thalidomide in adult human epithelial cells 50 . TP63 was not expressed in hiPSCs here ( Supplementary Table 4) in agreement with Asatsuma-Okumura et al 50 .…”

Section: Discussionmentioning

confidence: 99%

“…Additionally, p63 has been identified as a putative neosubstrate of CRBN in the presence of thalidomide and a molecular mediator of thalidomide teratogenicity whose degradation can be induced by thalidomide in adult human epithelial cells 50 . TP63 was not expressed in hiPSCs here ( Supplementary Table 4) in agreement with Asatsuma-Okumura et al 50 . Thus, although p63 may be a putative CRBN neosubstrate in the presence of thalidomide and may play a role in thalidomide teratogenicity, p63 is unlikely a mediator of thalidomide-, lenalidomide-, and pomalidomide-mediated disruption of LPM differentiation.…”

Section: Discussionmentioning

confidence: 99%

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Thalidomide Inhibits Human iPSC Mesendoderm Differentiation by Modulating CRBN-dependent Degradation of SALL4

Belair¹,

Lü²,

Waller³

et al. 2020

Sci Rep

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exposure to thalidomide during a critical window of development results in limb defects in humans and non-human primates while mice and rats are refractory to these effects. Thalidomide-induced teratogenicity is dependent on its binding to cereblon (CRBN), the substrate receptor of the Cul4A-DDB1-CRBN-RBX1 E3 ubiquitin ligase complex. Thalidomide binding to CRBN elicits subsequent ubiquitination and proteasomal degradation of CRBN neosubstrates including SALL4, a transcription factor of which polymorphisms phenocopy thalidomide-induced limb defects in humans. Herein, thalidomide-induced degradation of SALL4 was examined in human induced pluripotent stem cells (hiPSCs) that were differentiated either to lateral plate mesoderm (LPM)-like cells, the developmental ontology of the limb bud, or definitive endoderm. Thalidomide and its immunomodulatory drug (iMiD) analogs, lenalidomide, and pomalidomide, dose-dependently inhibited hipSc mesendoderm differentiation. Thalidomide-and IMiD-induced SALL4 degradation can be abrogated by CRBN V388I mutation or SALL4 G416A mutation in hiPSCs. Genetically modified hiPSCs expressing CRBN E377V/ V388I mutant or SALL4 G416A mutant were insensitive to the inhibitory effects of thalidomide, lenalidomide, and pomalidomide on LPM differentiation while retaining sensitivity to another known limb teratogen, all-trans retinoic acid (atRA). Finally, disruption of LPM differentiation by atRA or thalidomide perturbed subsequent chondrogenic differentiation in vitro. the data here show that thalidomide, lenalidomide, and pomalidomide affect stem cell mesendoderm differentiation through CRBN-mediated degradation of SALL4 and highlight the utility of the LPM differentiation model for studying the teratogenicity of new cRBn modulating agents.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Thalidomide Inhibits Human iPSC Mesendoderm Differentiation by Modulating CRBN-dependent Degradation of SALL4

Belair¹,

Lü²,

Waller³

et al. 2020

Sci Rep

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“…In addition, we showed that spatial overlap between CRBN and its substrates is important for efficient degradation of the substrates and for the efficacy of CRBN modulators. To date, over a dozen proteins including Ikaros, Aiolos, GSPT1, CK1α, glutamine synthetase, MEIS2, KCNMA1/SLO1, CLC1, and AMPKα have been identified as substrates for CRBN 3,[11][12][13][14][15][16][24][25][26][27][28] . The subcellular localizations of these factors differ: the transcription factors Ikaros, Aiolos, and MEIS2 are localized to the nucleus, whereas GSPT1, CK1α, and glutamine synthetase reside in the cytoplasm.…”

Section: Discussionmentioning

confidence: 99%

“…On the other hand, CC-885 induces degradation of the translation factor GSPT1, thereby eliciting broad-spectrum growth inhibition against a variety of cancer cell lines 3 . Moreover, thalidomide-induced degradation of the transcription factors p63 and SALL4 has been implicated in embryopathy [13][14][15] . Thus, each CRBN modulator acts as a molecular "glue" that mediates the interaction between CRBN and specific substrates 16 .…”

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confidence: 99%

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

Tateno

Iida

Fujii

et al. 2020

Sci Rep

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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 CRL4 cRBn . To search for novel factors involved in the anti-cancer activity of pomalidomide, we performed a genomewide 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 CRL4 cRBn 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.

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“…For example, the identification of SALL4 has remained elusive for many years until the correct biological system expressing that protein was utilized. Additionally, optimal cellular systems must be chosen for profiling against other reported off targets of CRBN warheads, such as IKZF1 and IKZF3 as mentioned earlier(Donovan et al, 2018;Matyskiela et al, 2018) as well as p63(Asatsuma- Okumura et al, 2019).Following identification of off-target proteins that are degraded by the PROTAC, it is necessary to investigate the safety risks of these undesired effects through understanding the function of the degraded proteins and the physiological consequences of reducing their levels in different tissues. This can be a formidable task, especially when the function of the degraded protein has not been characterized.…”

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confidence: 99%

Proteolysis‐targeting chimeras in drug development: A safety perspective

Moreau

Coen

Zhang

et al. 2020

British J Pharmacology

114

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Proteolysis‐targeting chimeras are a new drug modality that exploits the endogenous ubiquitin proteasome system to degrade a protein of interest for therapeutic benefit. As the first‐generation of proteolysis‐targeting chimeras have now entered clinical trials for oncology indications, it is timely to consider the theoretical safety risks inherent with this modality which include off‐target degradation, intracellular accumulation of natural substrates for the E3 ligases used in the ubiquitin proteasome system, proteasome saturation by ubiquitinated proteins, and liabilities associated with the “hook effect” of proteolysis‐targeting chimeras This review describes in vitro and non‐clinical in vivo data that provide mechanistic insight of these safety risks and approaches being used to mitigate these risks in the next generation of proteolysis‐targeting chimera molecules to extend therapeutic applications beyond life‐threatening diseases.

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p63 is a cereblon substrate involved in thalidomide teratogenicity

Cited by 102 publications

References 49 publications

Thalidomide Inhibits Human iPSC Mesendoderm Differentiation by Modulating CRBN-dependent Degradation of SALL4

Thalidomide Inhibits Human iPSC Mesendoderm Differentiation by Modulating CRBN-dependent Degradation of SALL4

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

Proteolysis‐targeting chimeras in drug development: A safety perspective

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