2021 Fiscal Year Annual Research Report
Study on molecular mechanism of anti-tumor activity by splicing modulation
| Project/Area Number |
20K15420
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| Research Institution | Institute of Physical and Chemical Research |
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Principal Investigator |
ChhipiShrestha Jagat 国立研究開発法人理化学研究所, 環境資源科学研究センター, 特別研究員 (40851233)
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| Project Period (FY) |
2020-04-01 – 2022-03-31
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| Keywords | SSA / splicing modulation / cancer / translation |
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| Outline of Annual Research Achievements |
Splicing modulation by Spliceostatin A (SSA) inhibit the global translation process by mTORC1 inactivation. System-wide analysis using RNA-sequencing (transcriptome), ribosome profiling (translatome) and BONCAT mass spectrometry (Proteome)upon splicing inhibition produced the substantial number of exon-intron chimeric proteins from the retained introns which have the intrinsically disordered regions providing condensate-prone properties. The BONCAT and the biochemical experiments verified the production of aggregation-prone intron proteins causing cellular proteotoxic stress in tumor cell. Proteotoxic stress subsequently activates the JNK signaling pathway to disintegrate the mTORC1 components inactivating its kinase function to reduce the mTORC1 mediated translation initiation.
mTORC1 signaling pathway being one of the key molecular pathway upregulated in the number of cancers, and hence SSA seems to plays an important anti-tumor mechanism via mTORC1 inhibition through the proteotoxic stress from the truncated chimeric-intron proteins. The phenotype of SSA was also recapitulated by other splicing modulators such as pladienolide B and SF3B1 target knockdown of the splicing modulators.
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