Dataset Information

Nuclear export protein CSE1L interacts with P65 and promotes NSCLC growth via NF-κB/MAPK pathway.

ABSTRACT: Non-small cell lung cancer (NSCLC) is characterized with high morbidity and mortality, mainly due to frequent recurrence and metastasis. However, the underlying molecular mechanisms of NSCLC tumorigenesis are largely unclear. Through data mining in the ONCOMINE and Gene Expression Omnibus (GEO) databases, the expression of CSE1L (chromosome segregation like 1 protein/CAS), an exportin, was identified to be significantly upregulated in NSCLC and positively associated with poor prognosis of patients. By use of in vitro and in vivo gain- and loss-of-function experiments, we found that CSE1L can promote NSCLC cell proliferation while inhibiting cell apoptosis. Through immunoprecipitation and mass spectrometry experiments, we demonstrated that CSE1L interacted with RELA (named as P65) and affected its location in the nucleus. Moreover, we found that one of the mechanisms by which CSE1L promotes proliferation and inhibits apoptosis is through activating the nuclear factor-κB (NF-κB)/mitogen-activated protein kinase (MAPK) signaling pathway. In summary, our findings indicated an oncogenic role of CSE1L in NSCLC tumorigenesis.

SUBMITTER: Lin HC

PROVIDER: S-EPMC8039531 | biostudies-literature | 2021 Jun

REPOSITORIES: biostudies-literature

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Nuclear export protein CSE1L interacts with P65 and promotes NSCLC growth via NF-κB/MAPK pathway.

Lin H C HC Li J J Cheng D D DD Zhang X X Yu T T Zhao F Y FY Geng Q Q Zhu M X MX Kong H W HW Li H H Yao M M

Molecular therapy oncolytics 20210310

Non-small cell lung cancer (NSCLC) is characterized with high morbidity and mortality, mainly due to frequent recurrence and metastasis. However, the underlying molecular mechanisms of NSCLC tumorigenesis are largely unclear. Through data mining in the ONCOMINE and Gene Expression Omnibus (GEO) databases, the expression of CSE1L (chromosome segregation like 1 protein/CAS), an exportin, was identified to be significantly upregulated in NSCLC and positively associated with poor prognosis of patien ...[more]

PMID: 33869740

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Project description:Orientia tsutsugamushi causes scrub typhus, a potentially fatal infection that threatens over one billion people. Nuclear translocation of the transcription factor, NF-κB, is the central initiating cellular event in the antimicrobial response. Here, we report that NF-κB p65 nuclear accumulation and NF-κB-dependent transcription are inhibited in O. tsutsugamushi infected HeLa cells and/or primary macrophages, even in the presence of TNFα. The bacterium modulates p65 subcellular localization by neither degrading it nor inhibiting IκBα degradation. Rather, it exploits host exportin 1 to mediate p65 nuclear export, as this phenomenon is leptomycin B-sensitive. O. tsutsugamushi antagonizes NF-κB-activated transcription even when exportin 1 is inhibited and NF-κB consequently remains in the nucleus. Two ankyrin repeat-containing effectors (Anks), Ank1 and Ank6, each of which possess a C-terminal F-box and exhibit 58.5% amino acid identity, are linked to the pathogen's ability to modulate NF-κB. When ectopically expressed, both translocate to the nucleus, abrogate NF-κB-activated transcription in an exportin 1-independent manner, and pronouncedly reduce TNFα-induced p65 nuclear levels by exportin 1-dependent means. Flag-tagged Ank 1 and Ank6 co-immunoprecipitate p65 and exportin 1. Both also bind importin β1, a host protein that is essential for the classical nuclear import pathway. Importazole, which blocks importin β1 activity, abrogates Ank1 and Ank6 nuclear translocation. The Ank1 and Ank6 regions that bind importin β1 also mediate their transport into the nucleus. Yet, these regions are distinct from those that bind p65/exportin 1. The Ank1 and Ank6 F-box and the region that lies between it and the ankyrin repeat domain are essential for blocking p65 nuclear accumulation. These data reveal a novel mechanism by which O. tsutsugamushi modulates the activity and nuclear transport of NF-κB p65 and identify the first microbial proteins that co-opt both importin β1 and exportin 1 to antagonize a critical arm of the antimicrobial response.

Dataset Information

Nuclear export protein CSE1L interacts with P65 and promotes NSCLC growth via NF-κB/MAPK pathway.

Publications

Nuclear export protein CSE1L interacts with P65 and promotes NSCLC growth via NF-κB/MAPK pathway.

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