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Artigos de revistas sobre o tema "Nuak1"

Autor: Grafiati

Publicado: 25 de janeiro de 2025

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1

Sun, Xianglan, Ling Gao, Hung-Yu Chien, Wan-Chun Li e Jiajun Zhao. "The regulation and function of the NUAK family". Journal of Molecular Endocrinology 51, n.º 2 (19 de julho de 2013): R15—R22. http://dx.doi.org/10.1530/jme-13-0063.

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AMP-activated protein kinase (AMPK) is a critical regulator of cellular and whole-body energy homeostasis. Twelve AMPK-related kinases (ARKs; BRSK1, BRSK2, NUAK1, NUAK2, QIK, QSK, SIK, MARK1, MARK2, MARK3, MARK4, and MELK) have been identified recently. These kinases show a similar structural organization, including an N-terminal catalytic domain, followed by a ubiquitin-associated domain and a C-terminal spacer sequence, which in some cases also contains a kinase-associated domain 1. Eleven of the ARKs are phosphorylated and activated by the master upstream kinase liver kinase B1. However, most of these ARKs are largely unknown, and the NUAK family seems to have different regulations and functions. This review contains a brief discussion of the NUAK family including the specific characteristics of NUAK1 and NUAK2.

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Banerjee, Sourav, Sara J. Buhrlage, Hai-Tsang Huang, Xianming Deng, Wenjun Zhou, Jinhua Wang, Ryan Traynor, Alan R. Prescott, Dario R. Alessi e Nathanael S. Gray. "Characterization of WZ4003 and HTH-01-015 as selective inhibitors of the LKB1-tumour-suppressor-activated NUAK kinases". Biochemical Journal 457, n.º 1 (10 de dezembro de 2013): 215–25. http://dx.doi.org/10.1042/bj20131152.

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We describe the discovery of structurally diverse kinase inhibitors to dissect the physiological roles of the NUAK isoforms. We recommend use of an inhibitor-resistant NUAK1[A195T] mutant to verify that the physiological effects of these compounds is indeed mediated through inhibition of NUAKs

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3

van de Vis, Reinofke A. J., Aristidis Moustakas e Lars P. van der Heide. "NUAK1 and NUAK2 Fine-Tune TGF-β Signaling". Cancers 13, n.º 13 (5 de julho de 2021): 3377. http://dx.doi.org/10.3390/cancers13133377.

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Transforming growth factor-β (TGF-β) signaling plays a key role in governing various cellular processes, extending from cell proliferation and apoptosis to differentiation and migration. Due to this extensive involvement in the regulation of cellular function, aberrant TGF-β signaling is frequently implicated in the formation and progression of tumors. Therefore, a full understanding of the mechanisms of TGF-β signaling and its key components will provide valuable insights into how this intricate signaling cascade can shift towards a detrimental course. In this review, we discuss the interplay between TGF-β signaling and the AMP-activated protein kinase (AMPK)-related NUAK kinase family. We highlight the function and regulation of these kinases with focus on the pivotal role NUAK1 and NUAK2 play in regulating TGF-β signaling. Specifically, TGF-β induces the expression of NUAK1 and NUAK2 that regulates TGF-β signaling output in an opposite manner. Besides the focus on the TGF-β pathway, we also present a broader perspective on the expression and signaling interactions of the NUAK kinases to outline the broader functions of these protein kinases.

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4

Banerjee, Sourav, Anna Zagórska, Maria Deak, David G. Campbell, Alan R. Prescott e Dario R. Alessi. "Interplay between Polo kinase, LKB1-activated NUAK1 kinase, PP1βMYPT1 phosphatase complex and the SCFβTrCP E3 ubiquitin ligase". Biochemical Journal 461, n.º 2 (26 de junho de 2014): 233–45. http://dx.doi.org/10.1042/bj20140408.

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The present study provides insights into the biological regulation of the NUAK isoforms and highlights the remarkable interplay that exists between Polo kinase, NUAK1, PP1βMYPT1 and SCFβTrCP signalling components. It demonstrates NUAK1 inhibitors suppress cell proliferation and PLK1.

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5

Yang, Jian, Jian Lu, Ni Yin, Jingyue Sun, Jianhong Pu e Jin Zang. "miR-622 Counteracts the NUAK1-Induced Gastric Cancer Cell Proliferation and the Antioxidative Stress". Disease Markers 2022 (14 de julho de 2022): 1–21. http://dx.doi.org/10.1155/2022/9616764.

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Background. Gastric cancer (GC), a highly prevalent gastric cancer, has high-risk mortality. Thus, investigating strategies to counteract its growth is important to provide theoretical guidance for its prevention and treatment. It has been pointed out that abnormal expression of microRNAs (miRNAs) serves as noninvasive biomarkers for GC. This present study probed into the role of miR-622 and the NUAK family SNF1-like kinase 1 (NUAK1). Methods. Five mRNA datasets (GSE64916, GSE118916, GSE122401, GSE158662, and GSE159721) and one miRNA dataset (GSE128720) from the Gene Expression of Omnibus (GEO) database were used to analyze the differentially expressed miRNAs and mRNA in GC and noncancer samples. Further, western blot, real-time quantitative PCR (qRT-PCR), reactive oxygen species (ROS) assay kit experiments, and wound healing assay, together with in vivo experiments, were performed. Results. miR-622 was downregulated, and NUAK1 was upregulated in GC, and NUAK1 was a potential target of miR-622. Knocking down NUAK1 decreased GC cell proliferation and migration but increased oxidative stress in vitro and inhibited the development of tumor in vivo, while miR-622 acted to suppress the action of NUAK1 through the miR-622/NUAK1/p-protein kinase B (Akt) axis, thereby inhibiting the occurrence of GC. Conclusion. miR-622 and NUAK1 demonstrated potential for being targets and biomarkers for GC treatment.

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Ohmura, Tomomi, Go Shioi, Mariko Hirano e Shinichi Aizawa. "Neural tube defects by NUAK1 and NUAK2 double mutation". Developmental Dynamics 241, n.º 8 (22 de junho de 2012): 1350–64. http://dx.doi.org/10.1002/dvdy.23816.

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7

Yu, Yuhui, Yongsheng Wang, Xiangying Xiao, Wei Cheng, Liqiang Hu, Weiyun Yao, Zhangxuan Qian e Wei Wu. "MiR-204 inhibits hepatocellular cancer drug resistance and metastasis through targeting NUAK1". Biochemistry and Cell Biology 97, n.º 5 (outubro de 2019): 563–70. http://dx.doi.org/10.1139/bcb-2018-0354.

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Liver cancer is a leading cause of cancer-related deaths globally. Tumor response rate of liver cancer patients towards systemic chemotherapy is low and chemoresistance can easily develop. Identifying novel molecules that can repress drug resistance and metastasis of liver cancer will facilitate the development of new therapeutic strategies. The aim of this study is to determine the roles of NUAK1 and miR-204 in the drug resistance and metastasis of liver cancer and to reveal their relationship. We found that NUAK1 was increased in the tumor of primary liver cancer. Knockdown of NUAK1 significantly inhibited cell growth and migration. Moreover, NUAK1 was the direct downstream target of miR-204, and there was clinical relevance between miR-204 down-regulation and NUAK1 up-regulation in liver cancer. Furthermore, we found that miR-204 increased drug sensitivity by down-regulating NUAK1 expression. Based on these results, we identified miR-204 as a tumor suppressor by inhibiting NUAK1 expression in liver cancer, indicating both miR-204 and NUAK1 may act as promising targets for liver cancer therapy.

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8

Navarrete, Daniel J., Chi Yong Kim, Mario Gonzalez, Barbara Baro, Christian Doerig, Shao-En Ong, Martin Golkowski e Elizabeth S. Egan. "Investigating a Novel Erythrocyte Kinase and Its Impact on Plasmodium Falciparum Infection". Blood 144, Supplement 1 (5 de novembro de 2024): 2456. https://doi.org/10.1182/blood-2024-211105.

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Plasmodium falciparum has the proclivity to develop drug resistance, raising a need for novel malaria treatments. Host-directed therapeutics are emerging as a new approach to the treatment of several infectious diseases, but their potential utility in malaria infection remains largely unexplored, in part because of our limited understanding of erythrocyte host determinants of malaria infection. To begin to elucidate erythrocyte signaling pathways important for P. falciparum invasion, we performed phospho-antibody microarray experiments using cultured red blood cells (cRBCs) derived ex-vivo from hematopoietic stem cells (HSPCs), enabling the interrogation of both wildtype cells and those with deletion of a critical invasion factor, CD44. Stimulation of these cells with the P. falciparum invasion ligand EBA175 revealed altered phosphorylation of several host kinases, including NUAK1. Using immunoblotting, we confirmed that NUAK1 phosphorylation is increased in EBA175-stimulated cRBCs and in P. falciparum-infected donor RBCs. Together, these data suggest that NUAK1 plays an important role during P. falciparum infection. In other cells, NUAK1 is associated with tumor suppression, proliferation, and oxidative stress, but its function in RBCs is unknown. To determine if NUAK1 controls P. falciparum proliferation in erythrocytes, we performed parasite proliferation assays using two highly selective NUAK1 inhibitors, HTH-01-015 and WZ4003. We found that they inhibited the growth of multiple P. falciparum strains in a dose-dependent manner (IC50 <3 µM), with activity throughout the blood stage. Using egress assays and live microscopy, we found that HTH-01-015 does not inhibit merozoite egress but instead specifically blocks invasion. Importantly, discharge of the P. falciparum microneme organelles was not affected, suggesting that the observed phenotypes were due to an effect of the inhibitor on the host cell. Studies using the immortalized erythroblast cell line BEL-A revealed that the inhibitors disrupted erythroid cell growth (IC50 2.6 µM), consistent with a host cell target. To further examine specificity, we performed kinobead competition assays with HTH-01-015 and WZ4003 in human cell lysates, which identified only NUAK1 and two other human kinases as possible targets. In contrast, our kinobead experiments using P. falciparum lysates revealed that none of the 60 Plasmodium kinases interacted with the inhibitors, underscoring their selectivity for human kinases. Furthermore, we have demonstrated that treatment with HTH-01-015 inhibits phosphorylation of a well-characterized NUAK1 substrate, Myosin phosphatase target subunit 1 (MYPT1), in BEL-A cells. Since myosin is a component of the RBC cytoskeleton, it is tempting to speculate that EBA binding results in NUAK activation, which in turn triggers the mobilization of regulators of RBC cytoskeleton dynamics to promote invasion. In ongoing work to validate this hypothesis, we are using phosphoproteomics to interrogate the system-wide effect of these inhibitors on signaling networks in P. falciparum-infected RBCs, as well as genome editing to generate inhibitor-resistant cRBCs for use in P. falciparum growth assays. We propose that a better understanding of these intricate host-parasite interactions offers opportunities for more effective, resistance-refractory antimalarial therapies, highlighting the crucial role of hematological insights in advancing malaria treatment strategies.

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9

Fritz, Jamie Lee, Olga Collins, Parima Saxena, Adrian Buensuceso, Yudith Ramos Valdes, Kyle E. Francis, Kevin R. Brown et al. "A Novel Role for NUAK1 in Promoting Ovarian Cancer Metastasis through Regulation of Fibronectin Production in Spheroids". Cancers 12, n.º 5 (15 de maio de 2020): 1250. http://dx.doi.org/10.3390/cancers12051250.

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Epithelial ovarian cancer (EOC) has a unique mode of metastasis, where cells shed from the primary tumour, form aggregates called spheroids to evade anoikis, spread through the peritoneal cavity, and adhere to secondary sites. We previously showed that the master kinase Liver kinase B1 (LKB1) is required for EOC spheroid viability and metastasis. We have identified novel (nua) kinase 1 (NUAK1) as a top candidate LKB1 substrate in EOC cells and spheroids using a multiplex inhibitor beads-mass spectrometry approach. We confirmed that LKB1 maintains NUAK1 phosphorylation and promotes its stabilization. We next investigated NUAK1 function in EOC cells. Ectopic NUAK1-overexpressing EOC cell lines had increased adhesion, whereas the reverse was seen in OVCAR8-NUAK1KO cells. In fact, cells with NUAK1 loss generate spheroids with reduced integrity, leading to increased cell death after long-term culture. Following transcriptome analysis, we identified reduced enrichment for cell interaction gene expression pathways in OVCAR8-NUAK1KO spheroids. In fact, the FN1 gene, encoding fibronectin, exhibited a 745-fold decreased expression in NUAK1KO spheroids. Fibronectin expression was induced during native spheroid formation, yet this was completely lost in NUAK1KO spheroids. Co-incubation with soluble fibronectin restored the compact spheroid phenotype to OVCAR8-NUAK1KO cells. In a xenograft model of intraperitoneal metastasis, NUAK1 loss extended survival and reduced fibronectin expression in tumours. Thus, we have identified a new mechanism controlling EOC metastasis, through which LKB1-NUAK1 activity promotes spheroid formation and secondary tumours via fibronectin production.

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Al-Hakim, Abdallah K., Anna Zagorska, Louise Chapman, Maria Deak, Mark Peggie e Dario R. Alessi. "Control of AMPK-related kinases by USP9X and atypical Lys29/Lys33-linked polyubiquitin chains". Biochemical Journal 411, n.º 2 (27 de março de 2008): 249–60. http://dx.doi.org/10.1042/bj20080067.

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AMPK (AMP-activated protein kinase)-related kinases regulate cell polarity as well as proliferation and are activated by the LKB1-tumour suppressor kinase. In the present study we demonstrate that the AMPK-related kinases, NUAK1 (AMPK-related kinase 5) and MARK4 (microtubule-affinity-regulating kinase 4), are polyubiquitinated in vivo and interact with the deubiquitinating enzyme USP9X (ubiquitin specific protease-9). Knockdown of USP9X increased polyubiquitination of NUAK1 and MARK4, whereas overexpression of USP9X inhibited ubiquitination. USP9X, catalysed the removal of polyubiquitin chains from wild-type NUAK1, but not from a non-USP9X-binding mutant. Topological analysis revealed that ubiquitin monomers attached to NUAK1 and MARK4 are linked by Lys29 and/or Lys33 rather than the more common Lys48/Lys63. We find that AMPK and other AMPK-related kinases are also polyubiquitinated in cells. We identified non-USP9X-binding mutants of NUAK1 and MARK4 and find that these are hyper-ubiquitinated and not phosphorylated at their T-loop residue targeted by LKB1 when expressed in cells, suggesting that polyubiquitination may inhibit these enzymes. The results of the present study demonstrate that NUAK1 and MARK4 are substrates of USP9X and provide the first evidence that AMPK family kinases are regulated by unusual Lys29/Lys33-linked polyubiquitin chains.

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11

Windelinckx, An, Gunther De Mars, Wim Huygens, Maarten W. Peeters, Barbara Vincent, Cisca Wijmenga, Diether Lambrechts et al. "Identification and prioritization of NUAK1 and PPP1CC as positional candidate loci for skeletal muscle strength phenotypes". Physiological Genomics 43, n.º 17 (setembro de 2011): 981–92. http://dx.doi.org/10.1152/physiolgenomics.00200.2010.

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Muscle strength is an important determinant in elite sports performance as well as in the activities of daily living. Muscle metabolism also plays a role in the genesis, and therefore prevention, of common pathological conditions and chronic diseases. Even though heritability estimates between 31 and 78% suggest a significant genetic component in muscle strength, only a limited number of genes influencing muscle strength have been identified. This study aimed to identify and prioritize positional candidate genes within a skeletal muscle strength quantitative trait locus on chromosome 12q22-23 for follow-up. A two-staged gene-centered fine-mapping approach using 122 single nucleotide polymorphisms (SNPs) in stage 1 identified a familybased association ( n = 500) between several tagSNPs located in the ATPase, Ca2+ transporting, cardiac muscle, slow twitch 2 ( ATP2A2; rs3026468), the NUAK family, SNF1-like kinase, 1 ( NUAK1; rs10861553 and rs3741886), and the protein phosphatase 1, catalytic subunit, gamma isoform ( PPP1CC; rs1050587 and rs7901769) genes and knee torque production ( P values up to 0.00092). In stage 2, family-based association tests on additional putatively functional SNPs (e.g., exonic SNPs, SNPs in transcription factor binding sites or in conserved regions) in an enlarged sample ( n = 536; 464 individuals overlap with stage 1) did not identify additional associations with muscle strength characteristics. Further in-depth analyses will be necessary to elucidate the exact role of ATP2A2, PPP1CC, and NUAK1 in muscle strength and to find out which functional polymorphisms are at the base of the interindividual strength differences.

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12

Zhang, Hao-ran, Cheng-long Gao, Li-chuan Zhang, Ri-lei Yu e Cong-min Kang. "Homology modeling, virtual screening and MD simulations for the identification of NUAK1 and ULK1 potential dual inhibitors". New Journal of Chemistry 46, n.º 9 (2022): 4103–13. http://dx.doi.org/10.1039/d1nj03690d.

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13

Bernard, David, e Arnaud Augert. "NUAK1 links genomic instability and senescence". Aging 2, n.º 6 (2 de junho de 2010): 317–19. http://dx.doi.org/10.18632/aging.100153.

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14

Monteverde, T., J. Tait-Mulder, A. Hedley, J. R. Knight, O. J. Sansom e D. J. Murphy. "Calcium signalling links MYC to NUAK1". Oncogene 37, n.º 8 (6 de novembro de 2017): 982–92. http://dx.doi.org/10.1038/onc.2017.394.

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Rooney, C., W. Harrison, K. Gyuraszova e D. Murphy. "Evaluating malignant pleural mesothelioma (MPM) sensitivity to inhibition of the Hippo pathway regulators NUAK1 and NUAK2". Lung Cancer 139 (janeiro de 2020): S2. http://dx.doi.org/10.1016/s0169-5002(20)30031-3.

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Yu, Yang, Yongyan Yang, Hong Tan, Myriam Boukhali, Ashok Khatri, Yonghao Yu, Fuzhou Hua et al. "Tau Contributes to Sevoflurane-induced Neurocognitive Impairment in Neonatal Mice". Anesthesiology 133, n.º 3 (14 de julho de 2020): 595–610. http://dx.doi.org/10.1097/aln.0000000000003452.

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Background Sevoflurane anesthesia induces Tau phosphorylation and cognitive impairment in neonatal but not in adult mice. This study tested the hypothesis that differences in brain Tau amounts and in the activity of mitochondria–adenosine triphosphate (ATP)–Nuak1–Tau cascade between the neonatal and adult mice contribute to the age-dependent effects of sevoflurane on cognitive function. Methods 6- and 60-day-old mice of both sexes received anesthesia with 3% sevoflurane for 2 h daily for 3 days. Biochemical methods were used to measure amounts of Tau, phosphorylated Tau, Nuak1, ATP concentrations, and mitochondrial metabolism in the cerebral cortex and hippocampus. The Morris water maze test was used to evaluate cognitive function in the neonatal and adult mice. Results Under baseline conditions and compared with 60-day-old mice, 6-day-old mice had higher amounts of Tau (2.6 ± 0.4 [arbitrary units, mean ± SD] vs. 1.3 ± 0.2; P < 0.001), Tau oligomer (0.3 ± 0.1 vs. 0.1 ± 0.1; P = 0.008), and Nuak1 (0.9 ± 0.3 vs. 0.3 ± 0.1; P = 0.025) but lesser amounts of ATP (0.8 ± 0.1 vs. 1.5 ± 0.1; P < 0.001) and mitochondrial metabolism (74.8 ± 14.1 [pmol/min] vs. 169.6 ± 15.3; P < 0.001) in the cerebral cortex. Compared with baseline conditions, sevoflurane anesthesia induced Tau phosphorylation at its serine 202/threonine 205 residues (1.1 ± 0.4 vs. 0.2 ± 0.1; P < 0.001) in the 6-day-old mice but not in the 60-day-old mice (0.05 ± 0.04 vs. 0.03 ± 0.01; P = 0.186). The sevoflurane-induced Tau phosphorylation and cognitive impairment in the neonatal mice were both attenuated by the inhibition of Nuak1 and the treatment of vitamin K2. Conclusions Higher brain Tau concentrations and lower brain mitochondrial metabolism in neonatal compared with adult mice contribute to developmental stage–dependent cognitive dysfunction after sevoflurane anesthesia. Editor’s Perspective What We Already Know about This Topic What This Article Tells Us That Is New

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Cai, Yini, Ming Fang, GongJi Yao, Lingmin Liao e Long Huang. "Mir-556-3p Inhibits SqCLC via NUAK1". International Journal of Surgery: Oncology 7, n.º 1 (2022): 30–45. http://dx.doi.org/10.29337/ijsonco.138.

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Bekri, Abdelhamid, Marc Billaud e Jacques Thélu. "Analysis of NUAK1 and NUAK2 expression during early chick development reveals specific patterns in the developing head". International Journal of Developmental Biology 58, n.º 5 (2014): 379–84. http://dx.doi.org/10.1387/ijdb.140024jt.

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Kechagioglou, Petros, Camille Dupont, Hajime Yurugi, Ute Distler, Stefan Tenzer, Alexey Chernobrovkin, Kristina Riegel, Stephen Cosenza, Steven M. Fruchtman e Krishnaraj Rajalingam. "Narazaciclib’s kinase inhibitory activity is differentiated from approved CDK4/6 inhibitors in preclinical models." Journal of Clinical Oncology 40, n.º 16_suppl (1 de junho de 2022): e15096-e15096. http://dx.doi.org/10.1200/jco.2022.40.16_suppl.e15096.

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e15096 Background: Despite clinical benefit of CDK4/6 inhibitors in HR+Her2-mBC, patients progress. Neutropenia and diarrhea are safety concerns. Narazaciclib (ON 123300) is a multi-targeted kinase inhibitor of CDK4/6, ARK5 (NUAK1), CSF1R, and c-Kit at low nM concentrations designed to enhance efficacy and safety. Narazaciclib is in Ph I trials; NCT04739293 and CXHL1900340; in different regimens. Treatment of tumor cell lines with narazaciclib induces G1; G2 arrest and apoptosis. Mouse models suggest narazaciclib causes less neutropenia than palbociclib (palbo). Since signaling pathways are affected, we explored the activity of narazaciclib in direct comparisons with abemaciclib (abe), palbo and ribociclib (ribo) using in vitro and cell based assays. Methods: Comparison of narazaciclib’s in vitro IC50 profile to abe, palbo and ribo was studied against a panel of 370 kinases (HotSpot). Kd values were determined by KINOMEscan. Intracellular IC50 kinase values were determined by NanoBret technology. Protein specific binding of narazaciclib and palbo was investigated by Cellular Thermal Shift Assay (CETSA). To investigate narazaciclib’s effect on signaling pathways, integrative Inferred Kinase Activity (INKA) analysis was performed. Results: Narazaciclib and abe were found to be the most promiscuous in vitro kinase inhibitors and ribo the most specific. Abe and narazaciclib had similar profiles against the CDK family members. Kd values of CDK4/cyclinD1 binding show similar trends; abe (0.08 nM), narazaciclib (0.18 nM), palbo (0.75 nM) and ribo (1.3 nM). Narazaciclib and abe displayed nM activity against CDK2/cyclinA. The IC50 values against GSK3β, whose inhibition putatively causes diarrhea, was 374 nM for narazaciclib and 13 nM for abe. Although narazaciclib displayed nM IC50 values in the in vitro assays against many CDKs, narazaciclib was very specific in cellular kinase assays with highest activity against CDK4/6, CSF1R and NUAK1. CETSA-MS revealed more potential targets engaged by narazaciclib compared to palbo in both lysates and intact cells such as CHEK1, AAK1, BMP2K, GSK3α and GSK3β, but did not identify binding to NUAK1 or CSF1R. INKA analysis demonstrated that narazaciclib induced unique deregulated phosphorylation compared to palbo, including BUB1 (highly expressed in TNBC), NUAK1, CAMK2D, CDK16 and ULK1. Inhibition of autophagy, both at early and late stages, may sensitize cancer cells to narazaciclib and induce irreversible cell proliferation inhibition, providing a novel therapeutic approach. Conclusions: These studies identify important differences generated from assay models studying kinase inhibition, binding and pathway engagement and will guide future studies with narazaciclib targeting specific kinase driven tumors with the potential for improved safety. These preclinical data await confirmation from current and future clinical trials.

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Kechagioglou, Petros, Camille Dupont, Hajime Yurugi, Ute Distler, Stefan Tenzer, Alexey Chernobrovkin, Kristina Riegel, Stephen Cosenza, Steven M. Fruchtman e Krishnaraj Rajalingam. "Narazaciclib’s kinase inhibitory activity is differentiated from approved CDK4/6 inhibitors in preclinical models." Journal of Clinical Oncology 40, n.º 16_suppl (1 de junho de 2022): e15096-e15096. http://dx.doi.org/10.1200/jco.2022.40.16_suppl.e15096.

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e15096 Background: Despite clinical benefit of CDK4/6 inhibitors in HR+Her2-mBC, patients progress. Neutropenia and diarrhea are safety concerns. Narazaciclib (ON 123300) is a multi-targeted kinase inhibitor of CDK4/6, ARK5 (NUAK1), CSF1R, and c-Kit at low nM concentrations designed to enhance efficacy and safety. Narazaciclib is in Ph I trials; NCT04739293 and CXHL1900340; in different regimens. Treatment of tumor cell lines with narazaciclib induces G1; G2 arrest and apoptosis. Mouse models suggest narazaciclib causes less neutropenia than palbociclib (palbo). Since signaling pathways are affected, we explored the activity of narazaciclib in direct comparisons with abemaciclib (abe), palbo and ribociclib (ribo) using in vitro and cell based assays. Methods: Comparison of narazaciclib’s in vitro IC50 profile to abe, palbo and ribo was studied against a panel of 370 kinases (HotSpot). Kd values were determined by KINOMEscan. Intracellular IC50 kinase values were determined by NanoBret technology. Protein specific binding of narazaciclib and palbo was investigated by Cellular Thermal Shift Assay (CETSA). To investigate narazaciclib’s effect on signaling pathways, integrative Inferred Kinase Activity (INKA) analysis was performed. Results: Narazaciclib and abe were found to be the most promiscuous in vitro kinase inhibitors and ribo the most specific. Abe and narazaciclib had similar profiles against the CDK family members. Kd values of CDK4/cyclinD1 binding show similar trends; abe (0.08 nM), narazaciclib (0.18 nM), palbo (0.75 nM) and ribo (1.3 nM). Narazaciclib and abe displayed nM activity against CDK2/cyclinA. The IC50 values against GSK3β, whose inhibition putatively causes diarrhea, was 374 nM for narazaciclib and 13 nM for abe. Although narazaciclib displayed nM IC50 values in the in vitro assays against many CDKs, narazaciclib was very specific in cellular kinase assays with highest activity against CDK4/6, CSF1R and NUAK1. CETSA-MS revealed more potential targets engaged by narazaciclib compared to palbo in both lysates and intact cells such as CHEK1, AAK1, BMP2K, GSK3α and GSK3β, but did not identify binding to NUAK1 or CSF1R. INKA analysis demonstrated that narazaciclib induced unique deregulated phosphorylation compared to palbo, including BUB1 (highly expressed in TNBC), NUAK1, CAMK2D, CDK16 and ULK1. Inhibition of autophagy, both at early and late stages, may sensitize cancer cells to narazaciclib and induce irreversible cell proliferation inhibition, providing a novel therapeutic approach. Conclusions: These studies identify important differences generated from assay models studying kinase inhibition, binding and pathway engagement and will guide future studies with narazaciclib targeting specific kinase driven tumors with the potential for improved safety. These preclinical data await confirmation from current and future clinical trials.

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Seo, Myeong-Seong, Kyung Hee Jung, Kewon Kim, Ji Eun Lee, Beom Seok Han, Soyeon Ko, Jae Ho Kim, Sungwoo Hong, So Ha Lee e Soon-Sun Hong. "Discovery of a novel NUAK1 inhibitor against pancreatic cancer". Biomedicine & Pharmacotherapy 152 (agosto de 2022): 113241. http://dx.doi.org/10.1016/j.biopha.2022.113241.

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Port, Jennifer, Nathiya Muthalagu, Meera Raja, Fatih Ceteci, Tiziana Monteverde, Björn Kruspig, Ann Hedley et al. "Colorectal Tumors Require NUAK1 for Protection from Oxidative Stress". Cancer Discovery 8, n.º 5 (2 de março de 2018): 632–47. http://dx.doi.org/10.1158/2159-8290.cd-17-0533.

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Inazuka, Fumika, Naoyuki Sugiyama, Masaru Tomita, Takaya Abe, Go Shioi e Hiroyasu Esumi. "Muscle-specific Knock-out of NUAK Family SNF1-like Kinase 1 (NUAK1) Prevents High Fat Diet-induced Glucose Intolerance". Journal of Biological Chemistry 287, n.º 20 (14 de março de 2012): 16379–89. http://dx.doi.org/10.1074/jbc.m111.302687.

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Shi, L., B. Zhang, X. Sun, S. Lu, Z. Liu, Y. Liu, H. Li, L. Wang, X. Wang e C. Zhao. "MiR-204 inhibits human NSCLC metastasis through suppression of NUAK1". British Journal of Cancer 111, n.º 12 (20 de novembro de 2014): 2316–27. http://dx.doi.org/10.1038/bjc.2014.580.

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Molina, Ester, Linda Hong e Ilana Chefetz. "NUAK Kinases: Brain–Ovary Axis". Cells 10, n.º 10 (15 de outubro de 2021): 2760. http://dx.doi.org/10.3390/cells10102760.

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Liver kinase B (LKB1) and adenosine monophosphate (AMP)-activated protein kinase (AMPK) are two major kinases that regulate cellular metabolism by acting as adenosine triphosphate (ATP) sensors. During starvation conditions, LKB1 and AMPK activate different downstream pathways to increase ATP production, while decreasing ATP consumption, which abrogates cellular proliferation and cell death. Initially, LKB1 was considered to be a tumor suppressor due to its loss of expression in various tumor types. Additional studies revealed amplifications in LKB1 and AMPK kinases in several cancers, suggesting a role in tumor progression. The AMPK-related proteins were described almost 20 years ago as a group of key kinases involved in the regulation of cellular metabolism. As LKB1-downstream targets, AMPK-related proteins were also initially considered to function as tumor suppressors. However, further research demonstrated that AMPK-related kinases play a major role not only in cellular physiology but also in tumor development. Furthermore, aside from their role as regulators of metabolism, additional functions have been described for these proteins, including roles in the cell cycle, cell migration, and cell death. In this review, we aim to highlight the major role of AMPK-related proteins beyond their functions in cellular metabolism, focusing on cancer progression based on their role in cell migration, invasion, and cell survival. Additionally, we describe two main AMPK-related kinases, Novel (nua) kinase family 1 (NUAK1) and 2 (NUAK2), which have been understudied, but play a major role in cellular physiology and tumor development.

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Humbert, Nicolas, Naveenan Navaratnam, Arnaud Augert, Marco Da Costa, Sébastien Martien, Jing Wang, Dolores Martinez et al. "Regulation of ploidy and senescence by the AMPK-related kinase NUAK1". EMBO Journal 29, n.º 2 (19 de novembro de 2009): 376–86. http://dx.doi.org/10.1038/emboj.2009.342.

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Sim, Ji Hyun, Jin-Hee Kim, Min A. Seol, Sun-Kyung Lee, Bon-A. Cho, Youngho Ko, Keunhee Oh et al. "IL-7Ralow memory CD8+ T cells are clonally anergic cells and defect in aerobic glycolysis pathway (HUM4P.274)". Journal of Immunology 194, n.º 1_Supplement (1 de maio de 2015): 122.5. http://dx.doi.org/10.4049/jimmunol.194.supp.122.5.

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Abstract We have found two subsets of CD8+ T cells expressing IL-7Rahigh and IL-7Ralow with different cell survival responses to IL-7 in peripheral blood of human. Treating IL-7Rαlow memory CD8+ T cells with anti-CD3/CD28 Abs did not produce IL-2, but comparably expressed IFN-γ and TNF-a. But the mechanism for this is unknown. These cells have reduced calcium flux and subsequent inhibited nuclear translocation of NF-AT1 upon TCR stimulation as well as PMA/ionomycin treatment, suggesting that IL-7Rαlow memory CD8+ T cells also have defected in distal-TCR signaling. Importantly, this anergic status was reversed by exogenous IL-2 stimulation, clearly distinct from adaptive tolerance. When TCR stimulation on IL-7Rαlow memory CD8+ T cells exhibited markedly decreased GATA3 and c-myc expression and increased NUAK1, which are key regulators in aerobic glycolysis, compared to those of IL-7Rαhigh memory CD8+ T cells. The expression of GATA3 and c-myc in IL-7Rαlow memory CD8+ T cells were restored after IL-2 stimulation. In conclusion, we firstly show that specific subset of human CD8+ T cells, IL-7Rαlow memory CD8+ T cells, are T-cell clonally anergy in vivo. We also demonstrate that GATA3-c-myc-NUAK1 system may control the maintenance of clonally anergic IL-7Rαlow memory CD8+ T cells in vivo and provides insight into human immunology. Acknowledgement: This research was supported by National Research Foundation of Korea (2014M3A7B4052194) and by the SNUH Research Fund (34-2013-0206)

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Hou, X., J.-E. Liu, W. Liu, C.-Y. Liu, Z.-Y. Liu e Z.-Y. Sun. "A new role of NUAK1: directly phosphorylating p53 and regulating cell proliferation". Oncogene 30, n.º 26 (14 de fevereiro de 2011): 2933–42. http://dx.doi.org/10.1038/onc.2011.19.

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Palma, M., E. Riffo, V. Coliboro, J. L. Gutierrez, R. Pincheira e A. Castro. "NUAK1 directly induces Akt signaling and substrate specificity, promoting cancer cell survival". European Journal of Cancer 174 (outubro de 2022): S55. http://dx.doi.org/10.1016/s0959-8049(22)00947-9.

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Liu, Jiaoyang, Guoyan Tang, He Huang, Huan Li, Peng Zhang e Lihua Xu. "Expression level of NUAK1 in human nasopharyngeal carcinoma and its prognostic significance". European Archives of Oto-Rhino-Laryngology 275, n.º 10 (18 de agosto de 2018): 2563–73. http://dx.doi.org/10.1007/s00405-018-5095-0.

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Lasagna-Reeves, Cristian A., Maria de Haro, Shuang Hao, Jeehye Park, Maxime W. C. Rousseaux, Ismael Al-Ramahi, Paymaan Jafar-Nejad et al. "Reduction of Nuak1 Decreases Tau and Reverses Phenotypes in a Tauopathy Mouse Model". Neuron 92, n.º 2 (outubro de 2016): 407–18. http://dx.doi.org/10.1016/j.neuron.2016.09.022.

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Port, J., N. Muthalagu, M. Raja, T. Monteverde, M. Mezna, F. Ceteci, G. Murray, O. Sansom, S. Zanivan e D. Murphy. "The AMPK-related kinase NUAK1 is a target for treatment of colorectal cancer". European Journal of Cancer 61 (julho de 2016): S68. http://dx.doi.org/10.1016/s0959-8049(16)61236-4.

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Xiong, Xinkui, Daoyi Sun, Hao Chai, Wengang Shan, Yue Yu, Liyong Pu e Feng Cheng. "MiR-145 functions as a tumor suppressor targeting NUAK1 in human intrahepatic cholangiocarcinoma". Biochemical and Biophysical Research Communications 465, n.º 2 (setembro de 2015): 262–69. http://dx.doi.org/10.1016/j.bbrc.2015.08.013.

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Bell, Rachel E., Mehdi Khaled, Dvir Netanely, Steffen Schubert, Tamar Golan, Amir Buxbaum, Maja M. Janas et al. "Transcription Factor/microRNA Axis Blocks Melanoma Invasion Program by miR-211 Targeting NUAK1". Journal of Investigative Dermatology 134, n.º 2 (fevereiro de 2014): 441–51. http://dx.doi.org/10.1038/jid.2013.340.

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HUANG, XUAN, WEI LV, JIAN-HUA ZHANG e DA-LIN LU. "miR-96 functions as a tumor suppressor gene by targeting NUAK1 in pancreatic cancer". International Journal of Molecular Medicine 34, n.º 6 (19 de setembro de 2014): 1599–605. http://dx.doi.org/10.3892/ijmm.2014.1940.

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Fisher, Robert P. "Splice or Die: When MYC Is Driving, Transcription Needs NUAK1 to Avoid Fatal Pileups". Molecular Cell 77, n.º 6 (março de 2020): 1157–58. http://dx.doi.org/10.1016/j.molcel.2020.02.025.

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Chen, Meijuan, Zhina Xu, Yingyao Zhang e Xiujuan Zhang. "LINC00958 Promotes The Malignancy Of Nasopharyngeal Carcinoma By Sponging microRNA-625 And Thus Upregulating NUAK1". OncoTargets and Therapy Volume 12 (novembro de 2019): 9277–90. http://dx.doi.org/10.2147/ott.s216342.

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Chen, Peng, Kai Li, Yan Liang, Liqing Li e Xiaolin Zhu. "High NUAK1 expression correlates with poor prognosis and involved in NSCLC cells migration and invasion". Experimental Lung Research 39, n.º 1 (5 de dezembro de 2012): 9–17. http://dx.doi.org/10.3109/01902148.2012.744115.

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Courchet, Julien, Tommy L. Lewis, Sohyon Lee, Virginie Courchet, Deng-Yuan Liou, Shinichi Aizawa e Franck Polleux. "Terminal Axon Branching Is Regulated by the LKB1-NUAK1 Kinase Pathway via Presynaptic Mitochondrial Capture". Cell 153, n.º 7 (junho de 2013): 1510–25. http://dx.doi.org/10.1016/j.cell.2013.05.021.

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Thomson, David M., Marc D. H. Hansen e William W. Winder. "Regulation of the AMPK-related protein kinases by ubiquitination". Biochemical Journal 411, n.º 2 (27 de março de 2008): e9-e10. http://dx.doi.org/10.1042/bj20080459.

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How can a constitutively active ‘master’ kinase with numerous downstream targets preferentially phosphorylate one or more of these without influencing all simultaneously? How might such a system be switched off? The characterization of the role of deubiquitination in regulating the phosphorylation and activation of AMPK (AMP-activated protein kinase)-related kinases by LKB1 suggests a novel and interesting mechanism for conferring signal transduction specificity and control at the kinase substrate level. In this issue of the Biochemical Journal, Al-Hakim et al. show that the AMPK-related kinases NUAK1 (AMPK-related kinase 5) and MARK4 (microtubule-affinity-regulating kinase 4) are polyubiquitinated in vivo and that they serve as substrates of the deubiquitinating enzyme USP9X; furthermore, the first evidence is provided for regulation of AMPK-related kinase family members mediated via unusual Lys29/Lys33 polyubiquitin chains, rather than the more common Lys48/Lys63 linkages.

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Chen, Meijuan, Zhina Xu, Yingyao Zhang e Xiujuan Zhang. "LINC00958 Promotes the Malignancy of Nasopharyngeal Carcinoma by Sponging microRNA-625 and Thus Upregulating NUAK1 [Retraction]". OncoTargets and Therapy Volume 16 (maio de 2023): 329–30. http://dx.doi.org/10.2147/ott.s422927.

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42

Sejd, Josilyn, e Smita Yadav. "Abstract 2419: Elucidating the Molecular Function of the Autism-Associated Kinase NUAK1 in Neurodevelopment and Disease". Journal of Biological Chemistry 299, n.º 3 (2023): S788. http://dx.doi.org/10.1016/j.jbc.2023.104429.

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Chen, Li, Oscar GW Wong, Claire LY Cheung, Esther SY Wong, Karen KL Chan, Hextan YS Ngan, Yusanne YS Chan e Annie NY Cheung. "Abstract 3153: Regulation of ATF4-mediated stress responses by NUAK2 in ovarian cancer". Cancer Research 84, n.º 6_Supplement (22 de março de 2024): 3153. http://dx.doi.org/10.1158/1538-7445.am2024-3153.

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Abstract NUAK family kinase 2 (NUAK2) a member of the AMPK-related serine/threonine kinase family with crucial roles in various cancer cellular processes. The aim of this study was to elucidate the expression and functions of NUAK2 in ovarian cancer while investigating the underlying molecular mechanisms. Analysis of several publicly available databases suggested a significant increase in NUAK2 mRNA levels in ovarian cancer compared to normal tissue. The overexpression of NUAK2 in ovarian cancer was confirmed by immunohistochemistry of NUAK2 in our local collection of ovarian tumor tissues comprised of carcinomas of various histological types (N=88) as well as benign and borderline tumors (N=19). Intense nuclear NUAK2 immunoreactivity was observed in serous and clear-cell carcinomas. Furthermore, nuclear expression of NUAK2 was significantly correlated with higher tumor grade and poorer overall and disease-free survival. Knocking out NUAK2 in SKOV3 cells by CRISPR-Cas9 resulted in suppressed cell growth and migration. Transcriptome by RNA sequencing and pathway enrichment analysis of SKOV3 cells overexpressing NUAK2 revealed activation of activating transcription factor 4 (ATF4) -dependent unfolded protein response (UPR) in the cell. NUAK2 knockout exaggerated the reactive oxygen species level induced by the endoplasmic reticulum (ER) stress inducer tunicamycin treatment. NUAK2 upregulated ATF4 protein expression during ER stress, facilitating its translocation into the nucleus upon exposure to tunicamycin. SKOV3 with NUAK2 knockout grew significantly slower than its parental line in mice as demonstrated by in vivo imaging. Collectively, our study highlights NUAK2 as an oncogene in ovarian cancer and underscores its involvement in the UPR pathway. Citation Format: Li Chen, Oscar GW Wong, Claire LY Cheung, Esther SY Wong, Karen KL Chan, Hextan YS Ngan, Yusanne YS Chan, Annie NY Cheung. Regulation of ATF4-mediated stress responses by NUAK2 in ovarian cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 3153.

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Zhao, Ming-Ming, Lin-Yang Ge, Liang-Feng Yang, Hai-Xia Zheng, Gang Chen, Li-Zheng Wu, Shao-Ming Shi, Nan Wang e Yan-Ping Hang. "LncRNA NEAT1/miR-204/NUAK1 Axis is a Potential Therapeutic Target for Non-Small Cell Lung Cancer". Cancer Management and Research Volume 12 (dezembro de 2020): 13357–68. http://dx.doi.org/10.2147/cmar.s277524.

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Obayashi, Mariko, Maki Yoshida, Takaaki Tsunematsu, Ikuko Ogawa, Tomonori Sasahira, Hiroki Kuniyasu, Issei Imoto et al. "microRNA-203 suppresses invasion and epithelial-mesenchymal transition induction via targeting NUAK1 in head and neck cancer". Oncotarget 7, n.º 7 (22 de janeiro de 2016): 8223–39. http://dx.doi.org/10.18632/oncotarget.6972.

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Cao, Longlong, Guangtan Lin, Denghui Fan, Kai Weng, Yujing Chen, Jiabin Wang, Ping Li, Chaohui Zheng, Changming Huang e Jianwei Xie. "NUAK1 activates STAT5/GLI1/SOX2 signaling to enhance cancer cell expansion and drives chemoresistance in gastric cancer". Cell Reports 43, n.º 7 (julho de 2024): 114446. http://dx.doi.org/10.1016/j.celrep.2024.114446.

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Palma, Mario, Elizabeth N. Riffo, Tamaki Suganuma, Michael P. Washburn, Jerry L. Workman, Roxana Pincheira e Ariel F. Castro. "Identification of a nuclear localization signal and importin beta members mediating NUAK1 nuclear import inhibited by oxidative stress". Journal of Cellular Biochemistry 120, n.º 9 (15 de maio de 2019): 16088–107. http://dx.doi.org/10.1002/jcb.28890.

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Yang, Changshun, Yu Zhang, Shengtao Lin, Yi Liu e Weihua Li. "Suppressing the KIF20A/NUAK1/Nrf2/GPX4 signaling pathway induces ferroptosis and enhances the sensitivity of colorectal cancer to oxaliplatin". Aging 13, n.º 10 (26 de março de 2021): 13515–34. http://dx.doi.org/10.18632/aging.202774.

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A, Jun, Baotong Zhang, Zhiqian Zhang, Hailiang Hu e Jin-Tang Dong. "Novel Gene Signatures Predictive of Patient Recurrence-Free Survival and Castration Resistance in Prostate Cancer". Cancers 13, n.º 4 (22 de fevereiro de 2021): 917. http://dx.doi.org/10.3390/cancers13040917.

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Molecular signatures predictive of recurrence-free survival (RFS) and castration resistance are critical for treatment decision-making in prostate cancer (PCa), but the robustness of current signatures is limited. Here, we applied the Robust Rank Aggregation (RRA) method to PCa transcriptome profiles and identified 287 genes differentially expressed between localized castration-resistant PCa (CRPC) and hormone-sensitive PCa (HSPC). Least absolute shrinkage and selection operator (LASSO) and stepwise Cox regression analyses of the 287 genes developed a 6-gene signature predictive of RFS in PCa. This signature included NPEPL1, VWF, LMO7, ALDH2, NUAK1, and TPT1, and was named CRPC-derived prognosis signature (CRPCPS). Interestingly, three of these 6 genes constituted another signature capable of distinguishing CRPC from HSPC. The CRPCPS predicted RFS in 5/9 cohorts in the multivariate analysis and remained valid in patients stratified by tumor stage, Gleason score, and lymph node status. The signature also predicted overall survival and metastasis-free survival. The signature’s robustness was demonstrated by the C-index (0.55–0.74) and the calibration plot in all nine cohorts and the 3-, 5-, and 8-year area under the receiver operating characteristic curve (0.67–0.77) in three cohorts. The nomogram analyses demonstrated CRPCPS’ clinical applicability. The CRPCPS thus appears useful for RFS prediction in PCa.

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Cossa, Giacomo, Isabelle Roeschert, Florian Prinz, Apoorva Baluapuri, Raphael Silveira Vidal, Christina Schülein-Völk, Yun-Chien Chang et al. "Localized inhibition of protein phosphatase 1 by NUAK1 promotes spliceosome activity and reveals a MYC-sensitive feedback control of transcription". Molecular Cell 81, n.º 11 (junho de 2021): 2495. http://dx.doi.org/10.1016/j.molcel.2021.05.013.

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