Unfavorable neuroblastoma prognostic factor <scp>NLRR</scp>2 inhibits cell differentiation by transcriptional induction through <scp>JNK</scp> pathway

Sheikh, Afzal; Takatori, Atsushi; Hossain, Shamim; Hasan, Md. Kamrul; Tagawa, Masatoshi; Nagase, Hiroki; Nakagawara, Akira

doi:10.1111/cas.13003

Cited by 15 publications

(15 citation statements)

References 37 publications

(97 reference statements)

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“…A few of our KO lines target genes having human orthologs that share a GWAS BMI cluster with other genes linked to obesity. Genes for the kinase Dgkg 188 and the neuronal membrane protein Lrrn2 189 have no publicly available KO data or published links to obesity despite having increased body fat in our HTS ( Table 7 ). DGKG and ETV5 (ETS variant transcription factor 5) are the only genes sharing a BMI cluster on human chromosome 3, while LRRN2 and MDM4 (MDM4 regulator of p53) are the only genes sharing a BMI cluster on human chromosome 1 ( Table 8 ); the low body fat observed in Etv5 KO mice 190 and Mdmx KO mice 191 suggests that one or both genes in each of these two BMI clusters may contribute to the GWAS signal.…”

Section: Resultsmentioning

confidence: 99%

High-Throughput Screening of Mouse Gene Knockouts Identifies Established and Novel High Body Fat Phenotypes

Powell¹,

Revelli²,

Doree³

et al. 2021

DMSO

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Purpose Obesity is a major public health problem. Understanding which genes contribute to obesity may better predict individual risk and allow development of new therapies. Because obesity of a mouse gene knockout (KO) line predicts an association of the orthologous human gene with obesity, we reviewed data from the Lexicon Genome5000 TM high throughput phenotypic screen (HTS) of mouse gene KOs to identify KO lines with high body fat. Materials and Methods KO lines were generated using homologous recombination or gene trapping technologies. HTS body composition analyses were performed on adult wild-type and homozygous KO littermate mice from 3758 druggable mouse genes having a human ortholog. Body composition was measured by either DXA or QMR on chow-fed cohorts from all 3758 KO lines and was measured by QMR on independent high fat diet-fed cohorts from 2488 of these KO lines. Where possible, comparisons were made to HTS data from the International Mouse Phenotyping Consortium (IMPC). Results Body fat data are presented for 75 KO lines. Of 46 KO lines where independent external published and/or IMPC KO lines are reported as obese, 43 had increased body fat. For the remaining 29 novel high body fat KO lines, Ksr2 and G2e3 are supported by data from additional independent KO cohorts, 6 ( Asnsd1, Srpk2, Dpp8, Cxxc4, Tenm3 and Kiss1 ) are supported by data from additional internal cohorts, and the remaining 21 including Tle4, Ak5, Ntm, Tusc3, Ankk1, Mfap3l, Prok2 and Prokr2 were studied with HTS cohorts only. Conclusion These data support the finding of high body fat in 43 independent external published and/or IMPC KO lines. A novel obese phenotype was identified in 29 additional KO lines, with 27 still lacking the external confirmation now provided for Ksr2 and G2e3 KO mice. Undoubtedly, many mammalian obesity genes remain to be identified and characterized.

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Section: Resultsmentioning

confidence: 99%

High-Throughput Screening of Mouse Gene Knockouts Identifies Established and Novel High Body Fat Phenotypes

Powell¹,

Revelli²,

Doree³

et al. 2021

DMSO

View full text Add to dashboard Cite

show abstract

“…Activation of JNK, one of the MAPK members, contributes to apoptosis and tumor progression in conjunction with a variety of stimuli, indicating the contradictory functions of JNK [42][43][44]. Several papers suggested a critical role of JNK activation in malignancy and the poor prognosis of cancer patients [45,46]. The differential roles of JNK activation in MTA-induced anticancer effects were previously reported.…”

Section: Discussionmentioning

confidence: 93%

Activation of PERK Contributes to Apoptosis and G2/M Arrest by Microtubule Disruptors in Human Colorectal Carcinoma Cells

Chien

Jargalsaikhan

et al. 2019

Cancers

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Microtubule-targeting agents (MTAs) are widely used in cancer chemotherapy, but the therapeutic responses significantly vary among different tumor types. Protein kinase RNA-like endoplasmic reticular (ER) kinase (PERK) is an ER stress kinase, and the role of PERK in the anticancer effects of MTAs is still undefined. In the present study, taxol (TAX) and nocodazole (NOC) significantly induced apoptosis with increased expression of phosphorylated PERK (pPERK; Tyr980) in four human colon cancer cell lines, including HCT-15, COLO205, HT-20, and LOVO cells. Induction of G2/M arrest by TAX and NOC with increases in phosphorylated Cdc25C and cyclin B1 protein were observed in human colon cancer cells. Application of the c-Jun N-terminal kinase (JNK) inhibitors SP600125 (SP) and JNK inhibitor V (JNKI) significantly reduced TAX- and NOC-induced apoptosis and G2/M arrest of human colon cancer cells. Interestingly, TAX- and NOC-induced pPERK (Tyr980) protein expression was inhibited by adding the JNK inhibitors, SP and JNKI, and application of the PERK inhibitor GSK2606414 (GSK) significantly reduced apoptosis and G2/M arrest by TAX and NOC, with decreased pPERK (Tyr980) and pJNK, phosphorylated Cdc25C, and Cyc B1 protein expressions in human colon cancer cells. Decreased viability by TAX and NOC was inhibited by knockdown of PERK using PERK siRNA in COLO205 and HCT-15 cells. Disruption of the mitochondrial membrane potential and an increase in B-cell lymphoma-2 (Bcl-2) protein phosphorylation (pBcl-2; Ser70) by TAX and NOC were prevented by adding the PERK inhibitor GSK and JNK inhibitor SP and JNKI. A cross-activation of JNK and PERK by TAX and NOC leading to anti-CRC actions including apoptosis and G2/M arrest was first demonstrated herein.

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“…The role of the PI3K/mTOR/Akt pathway in neuroblastoma pathogenesis has been well established, 47 and early-phase clinical trials evaluating the efficacy of inhibitors of PI3K/mTOR/Akt signalling have demonstrated efficacy in children with neuroblastoma. 48 – 52 The role of signalling through the Fos/Jun pathway in neuroblastoma pathogenesis is less well understood, although recent studies have identified a role for Jun kinase (JNK) signalling in neuroblastoma differentiation, 53 and computational models of neuroblastoma demonstrated an association between JNK signalling and patient survival. 54 The efficacy of inhibition of these pathways in other adult and paediatric cancer models has not previously been reported, and the specific roles of these pathways in the responses of neuroblastoma cells to regorafenib are unknown.…”

Section: Discussionmentioning

confidence: 99%

Regorafenib is effective against neuroblastoma in vitro and in vivo and inhibits the RAS/MAPK, PI3K/Akt/mTOR and Fos/Jun pathways

et al. 2020

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Background Regorafenib is an inhibitor of multiple kinases with aberrant expression and activity in neuroblastoma tumours that have potential roles in neuroblastoma pathogenesis. Methods We evaluated neuroblastoma cells treated with regorafenib for cell viability and confluence, and analysed treated cells for apoptosis and cell cycle progression. We evaluated the efficacy of regorafenib in vivo using an orthotopic xenograft model. We evaluated regorafenib-mediated inhibition of kinase targets and performed reverse-phase protein array (RPPA) analysis of neuroblastoma cells treated with regorafenib. Lastly, we evaluated the efficacy and effects of the combination of regorafenib and 13-cis-retinoic acid on intracellular signalling. Results Regorafenib treatment resulted in reduced neuroblastoma cell viability and confluence, with both induction of apoptosis and of cell cycle arrest. Regorafenib treatment inhibits known receptor tyrosine kinase targets RET and PDGFRβ and intracellular signalling through the RAS/MAPK, PI3K/Akt/mTOR and Fos/Jun pathways. Regorafenib is effective against neuroblastoma tumours in vivo, and the combination of regorafenib and 13-cis-retinoic acid demonstrates enhanced efficacy compared with regorafenib alone. Conclusions The effects of regorafenib on multiple intracellular signalling pathways and the potential additional efficacy when combined with 13-cis-retinoic acid represent opportunities to develop treatment regimens incorporating regorafenib for children with neuroblastoma.

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Unfavorable neuroblastoma prognostic factor NLRR2 inhibits cell differentiation by transcriptional induction through JNK pathway

Cited by 15 publications

References 37 publications

High-Throughput Screening of Mouse Gene Knockouts Identifies Established and Novel High Body Fat Phenotypes

High-Throughput Screening of Mouse Gene Knockouts Identifies Established and Novel High Body Fat Phenotypes

Activation of PERK Contributes to Apoptosis and G2/M Arrest by Microtubule Disruptors in Human Colorectal Carcinoma Cells

Regorafenib is effective against neuroblastoma in vitro and in vivo and inhibits the RAS/MAPK, PI3K/Akt/mTOR and Fos/Jun pathways

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