{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nRecent genetic investigations into bipolar disorder have implicated NEK4 as one of several candidate genes involved in pathways such as cell cycle regulation, neurogenesis, neuroplasticity, and neurosignaling. In a genome‐wide association study, a nonsynonymous variant in NEK4 was among those significantly associated with bipolar disorder risk, suggesting a potential contributory role in mood regulation and neuronal function."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn the context of microtubule dynamics and cancer therapy, NEK4 has been shown to control microtubule outgrowth and the proper formation of mitotic structures in response to chemotherapeutic agents. Specifically, under treatment with microtubule‐stabilizing drugs such as Taxol, NEK4 promotes microtubule outgrowth and maintains the G2–M checkpoint, whereas its deficiency disrupts these processes. This function is particularly relevant for cancers like non–small cell lung cancer, where NEK4 is located in a commonly deleted chromosomal region."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "2"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nNEK4 also plays a crucial role in ciliary function. It has been identified as a prominent component of protein complexes associated with the ciliopathy‐linked proteins RPGRIP1 and RPGRIP1L. Localizing to basal bodies and the ciliary rootlet, NEK4 is essential for proper cilium assembly, and its down‐regulation leads to significant losses in cilium formation. This insight supports the hypothesis that NEK4 is a candidate gene contributing to the spectrum of ciliopathies."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "3"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nBeyond its roles in cytoskeletal and ciliary dynamics, NEK4 has been implicated in the regulation of replicative senescence and the DNA damage response. RNA interference–mediated suppression of NEK4 in human fibroblasts delays the onset of senescence by reducing the expression of key cell cycle inhibitors such as p21. Moreover, decreased NEK4 levels impair the cell’s ability to recruit DNA repair machinery (including DNA‐PK complexes) to sites of double–stranded DNA damage, ultimately leading to reduced p53 activation and diminished H2AX phosphorylation."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "4"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn cancer biology, NEK4 has emerged as an important modulator of apoptotic and invasive pathways. In TRAIL–resistant cancer cell models, knockdown of NEK4 sensitizes cells to TRAIL–induced apoptosis by downregulating the anti–apoptotic protein survivin, while its overexpression confers resistance. Furthermore, aberrant upregulation of NEK4 has been observed in lung and colon tumors, underscoring its potential significance as a therapeutic target."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "5"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nAdditionally, NEK4 functions as a positive regulator of the epithelial–to–mesenchymal transition (EMT). Suppression of NEK4 in lung adenocarcinoma cells increases the expression of adhesion molecules such as E–cadherin and ZO1, combined with a reduction in key EMT drivers like Zeb1 and Smad transcription factors. This modulation of EMT translates into decreased migratory and invasive capabilities of tumor cells in vitro and reduced metastasis in vivo, highlighting its utility as a potential target for inhibiting lung cancer metastasis."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "6"}]}, {"type": "t", "text": ""}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Laura J Scott, Pierandrea Muglia, Xiangyang Q Kong, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Genome-wide association and meta-analysis of bipolar disorder in individuals of European ancestry."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Proc Natl Acad Sci U S A (2009)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1073/pnas.0813386106"}], "href": "https://doi.org/10.1073/pnas.0813386106"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "19416921"}], "href": "https://pubmed.ncbi.nlm.nih.gov/19416921"}]}, {"type": "r", "ref": 2, "children": [{"type": "t", "text": "Jason Doles, Michael T Hemann "}, {"type": "b", "children": [{"type": "t", "text": "Nek4 status differentially alters sensitivity to distinct microtubule poisons."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cancer Res (2010)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1158/0008-5472.CAN-09-2113"}], "href": "https://doi.org/10.1158/0008-5472.CAN-09-2113"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "20103636"}], "href": "https://pubmed.ncbi.nlm.nih.gov/20103636"}]}, {"type": "r", "ref": 3, "children": [{"type": "t", "text": "Karlien L M Coene, Dorus A Mans, Karsten Boldt, et al. "}, {"type": "b", "children": [{"type": "t", "text": "The ciliopathy-associated protein homologs RPGRIP1 and RPGRIP1L are linked to cilium integrity through interaction with Nek4 serine/threonine kinase."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Hum Mol Genet (2011)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1093/hmg/ddr280"}], "href": "https://doi.org/10.1093/hmg/ddr280"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "21685204"}], "href": "https://pubmed.ncbi.nlm.nih.gov/21685204"}]}, {"type": "r", "ref": 4, "children": [{"type": "t", "text": "Christine L Nguyen, Richard Possemato, Erica L Bauerlein, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Nek4 regulates entry into replicative senescence and the response to DNA damage in human fibroblasts."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Mol Cell Biol (2012)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1128/MCB.00436-12"}], "href": "https://doi.org/10.1128/MCB.00436-12"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "22851694"}], "href": "https://pubmed.ncbi.nlm.nih.gov/22851694"}]}, {"type": "r", "ref": 5, "children": [{"type": "t", "text": "So Jung Park, Doo Sin Jo, Se-Young Jo, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Inhibition of never in mitosis A (NIMA)-related kinase-4 reduces survivin expression and sensitizes cancer cells to TRAIL-induced cell death."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Oncotarget (2016)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.18632/oncotarget.11781"}], "href": "https://doi.org/10.18632/oncotarget.11781"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "27602754"}], "href": "https://pubmed.ncbi.nlm.nih.gov/27602754"}]}, {"type": "r", "ref": 6, "children": [{"type": "t", "text": "Nian-Hua Ding, Lu Zhang, Zhi Xiao, et al. "}, {"type": "b", "children": [{"type": "t", "text": "NEK4 kinase regulates EMT to promote lung cancer metastasis."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Cell Mol Med (2018)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1111/jcmm.13857"}], "href": "https://doi.org/10.1111/jcmm.13857"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "30247800"}], "href": "https://pubmed.ncbi.nlm.nih.gov/30247800"}]}]}]}