{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nRSK4 (encoded by RPS6KA6), an X‐linked serine/threonine kinase belonging to the p90 ribosomal S6 kinase family, displays several unconventional features that distinguish it from its paralogues. Biochemical and functional studies have shown that RSK4 is constitutively active under conditions of growth factor deprivation and can promote cellular growth arrest and senescence through signals mediated by p21. These observations support its putative tumor‐suppressive role and its involvement in regulating stress‐ and oncogene‐induced senescence in normal cells."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "3"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn addition to its role in cell cycle regulation and senescence, RSK4 has been implicated in modulating the response of cancer cells to therapeutic inhibition and stress. Forced overexpression of RSK4 was found to sustain proliferation when cells were exposed to PI3K/mTOR inhibitors, in part by attenuating apoptosis and upregulating protein translation. Similarly, in esophageal squamous cell carcinoma, RSK4 expression promoted cancer stem cell properties and conferred radioresistance by phosphorylating key substrates such as GSK‑3β and activating β‐catenin signaling. Moreover, evidence in breast and kidney cancer models indicates that the expression level of RSK4 influences sensitivity to cytotoxic agents like doxorubicin and multi‐targeted kinase inhibitors such as Sunitinib, and its tumor‐suppressive effects have been further substantiated in endometrial cancer."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "4", "end_ref": "8"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nChanges in RSK4 expression also appear to be linked to epigenetic regulation and may contribute to tumor progression. Downregulation through promoter hypermethylation has been observed in a variety of malignancies—including colon, breast, ovarian, papillary thyroid carcinoma, and possibly colorectal cancer—wherein reduced RSK4 expression correlates with advanced disease stage and poorer clinical outcomes. In breast cancer, for example, diminished RSK4 levels (and concomitant changes in related molecules such as cyclin D1, CXCR4, and E‑cadherin) have been associated with increased cell proliferation and invasion. Similar patterns of reduced expression have been documented in other tumors, with differential RSK4 methylation reflecting the influence of hormonal status and signaling inputs (such as estrogen receptor activity) on its transcription."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "9", "end_ref": "22"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nBeyond its established roles in cancer biology, genetic studies and clinical association analyses suggest that RSK4 may have broader biological implications. A SNP located in a conserved region near RPS6KA6 was associated with slower disease progression in HIV‐1–infected females, indicating a potential link to immune response regulation. Furthermore, mutational analyses in autism spectrum disorders and studies on endothelial progenitor cell senescence in diabetes hint at pleiotropic functions of this kinase in neurodevelopment and vascular biology."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "23", "end_ref": "25"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Bettina A Dümmler, Camilla Hauge, Joachim Silber, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Functional characterization of human RSK4, a new 90-kDa ribosomal S6 kinase, reveals constitutive activation in most cell types."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Biol Chem (2005)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1074/jbc.M408194200"}], "href": "https://doi.org/10.1074/jbc.M408194200"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "15632195"}], "href": "https://pubmed.ncbi.nlm.nih.gov/15632195"}]}, {"type": "r", "ref": 2, "children": [{"type": "t", "text": "Laura López-Vicente, Gemma Armengol, Berta Pons, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Regulation of replicative and stress-induced senescence by RSK4, which is down-regulated in human tumors."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Clin Cancer Res (2009)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1158/1078-0432.CCR-08-3159"}], "href": "https://doi.org/10.1158/1078-0432.CCR-08-3159"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "19584160"}], "href": "https://pubmed.ncbi.nlm.nih.gov/19584160"}]}, {"type": "r", "ref": 3, "children": [{"type": "t", "text": "Laura López-Vicente, Berta Pons, Laura Coch, et al. "}, {"type": "b", "children": [{"type": "t", "text": "RSK4 inhibition results in bypass of stress-induced and oncogene-induced senescence."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Carcinogenesis (2011)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1093/carcin/bgr003"}], "href": "https://doi.org/10.1093/carcin/bgr003"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "21239520"}], "href": "https://pubmed.ncbi.nlm.nih.gov/21239520"}]}, {"type": "r", "ref": 4, "children": [{"type": "t", "text": "Violeta Serra, Pieter J A Eichhorn, Celina García-García, et al. "}, {"type": "b", "children": [{"type": "t", "text": "RSK3/4 mediate resistance to PI3K pathway inhibitors in breast cancer."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Clin Invest (2013)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1172/JCI66343"}], "href": "https://doi.org/10.1172/JCI66343"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "23635776"}], "href": "https://pubmed.ncbi.nlm.nih.gov/23635776"}]}, {"type": "r", "ref": 5, "children": [{"type": "t", "text": "Claus Bender, Axel Ullrich "}, {"type": "b", "children": [{"type": "t", "text": "PRKX, TTBK2 and RSK4 expression causes Sunitinib resistance in kidney carcinoma- and melanoma-cell lines."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Int J Cancer (2012)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1002/ijc.26486"}], "href": "https://doi.org/10.1002/ijc.26486"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "22020623"}], "href": "https://pubmed.ncbi.nlm.nih.gov/22020623"}]}, {"type": "r", "ref": 6, "children": [{"type": "t", "text": "Ming-Yang Li, Lin-Ni Fan, Dong-Hui Han, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Ribosomal S6 protein kinase 4 promotes radioresistance in esophageal squamous cell carcinoma."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Clin Invest (2020)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1172/JCI134930"}], "href": "https://doi.org/10.1172/JCI134930"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "32396532"}], "href": "https://pubmed.ncbi.nlm.nih.gov/32396532"}]}, {"type": "r", "ref": 7, "children": [{"type": "t", "text": "Yan Mei, Xiaoming Liao, Lingyu Zhu, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Overexpression of RSK4 reverses doxorubicin resistance in human breast cancer cells via PI3K/AKT signalling pathway."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Biochem (2020)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1093/jb/mvaa009"}], "href": "https://doi.org/10.1093/jb/mvaa009"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "31960922"}], "href": "https://pubmed.ncbi.nlm.nih.gov/31960922"}]}, {"type": "r", "ref": 8, "children": [{"type": "t", "text": "Summer B Dewdney, B J Rimel, Premal H Thaker, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Aberrant methylation of the X-linked ribosomal S6 kinase RPS6KA6 (RSK4) in endometrial cancers."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Clin Cancer Res (2011)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1158/1078-0432.CCR-10-2668"}], "href": "https://doi.org/10.1158/1078-0432.CCR-10-2668"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "21372219"}], "href": "https://pubmed.ncbi.nlm.nih.gov/21372219"}]}, {"type": "r", "ref": 9, "children": [{"type": "t", "text": "M E LLeonart, F Vidal, D Gallardo, et al. "}, {"type": "b", "children": [{"type": "t", "text": "New p53 related genes in human tumors: significant downregulation in colon and lung carcinomas."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Oncol Rep (2006)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.3892/or.16.3.603"}], "href": "https://doi.org/10.3892/or.16.3.603"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "16865262"}], "href": "https://pubmed.ncbi.nlm.nih.gov/16865262"}]}, {"type": "r", "ref": 10, "children": [{"type": "t", "text": "Archana Thakur, Km Wahidur Rahman, Jack Wu, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Aberrant expression of X-linked genes RbAp46, Rsk4, and Cldn2 in breast cancer."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Mol Cancer Res (2007)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1158/1541-7786.MCR-06-0071"}], "href": "https://doi.org/10.1158/1541-7786.MCR-06-0071"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "17314274"}], "href": "https://pubmed.ncbi.nlm.nih.gov/17314274"}]}, {"type": "r", "ref": 11, "children": [{"type": "t", "text": "Jun Cai, Hong Ma, Fang Huang, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Low expression of RSK4 predicts poor prognosis in patients with colorectal cancer."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Int J Clin Exp Pathol (2014)"}]}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "25197367"}], "href": "https://pubmed.ncbi.nlm.nih.gov/25197367"}]}, {"type": "r", "ref": 12, "children": [{"type": "t", "text": "Fabian Arechavaleta-Velasco, Moises Zeferino-Toquero, Isaias Estrada-Moscoso, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Ribosomal S6 kinase 4 (RSK4) expression in ovarian tumors and its regulation by antineoplastic drugs in ovarian cancer cell lines."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Med Oncol (2016)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1007/s12032-015-0724-6"}], "href": "https://doi.org/10.1007/s12032-015-0724-6"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "26732474"}], "href": "https://pubmed.ncbi.nlm.nih.gov/26732474"}]}, {"type": "r", "ref": 13, "children": [{"type": "t", "text": "Jia Zhu, Qiu-Yun Li, Jian-Lun Liu, et al. "}, {"type": "b", "children": [{"type": "t", "text": "RSK4 knockdown promotes proliferation, migration and metastasis of human breast adenocarcinoma cells."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Oncol Rep (2015)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.3892/or.2015.4291"}], "href": "https://doi.org/10.3892/or.2015.4291"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "26397146"}], "href": "https://pubmed.ncbi.nlm.nih.gov/26397146"}]}, {"type": "r", "ref": 14, "children": [{"type": "t", "text": "Qingqing Ye, Xuan Wang, Min Jin, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Effect of RSK4 on biological characteristics of colorectal cancer."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "World J Surg Oncol (2018)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1186/s12957-018-1474-7"}], "href": "https://doi.org/10.1186/s12957-018-1474-7"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "30579335"}], "href": "https://pubmed.ncbi.nlm.nih.gov/30579335"}]}, {"type": "r", "ref": 15, "children": [{"type": "t", "text": "Qiuyun Li, Yi Jiang, Wei Wei, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Frequent epigenetic inactivation of RSK4 by promoter methylation in cancerous and non-cancerous tissues of breast cancer."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Med Oncol (2014)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1007/s12032-013-0793-3"}], "href": "https://doi.org/10.1007/s12032-013-0793-3"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "24338215"}], "href": "https://pubmed.ncbi.nlm.nih.gov/24338215"}]}, {"type": "r", "ref": 16, "children": [{"type": "t", "text": "Yi Jiang, Xinqing Ye, Yinan Ji, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Aberrant expression of RSK4 in breast cancer and its role in the regulation of tumorigenicity."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Int J Mol Med (2017)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.3892/ijmm.2017.3069"}], "href": "https://doi.org/10.3892/ijmm.2017.3069"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "28731146"}], "href": "https://pubmed.ncbi.nlm.nih.gov/28731146"}]}, {"type": "r", "ref": 17, "children": [{"type": "t", "text": "Hong Huo, Xinqing Ye, Honghe Yang, et al. "}, {"type": "b", "children": [{"type": "t", "text": "RSK4 inhibits breast cancer cell proliferation and invasion in vitro, and is correlated with estrogen receptor upregulation in breast cancer."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Oncol Rep (2019)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.3892/or.2019.7328"}], "href": "https://doi.org/10.3892/or.2019.7328"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "31545499"}], "href": "https://pubmed.ncbi.nlm.nih.gov/31545499"}]}, {"type": "r", "ref": 18, "children": [{"type": "t", "text": "Yanan Yin, Kui Che, Jianxia Hu, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Hypermethylation of the RSK4 promoter associated with BRAF V600E promotes papillary thyroid carcinoma."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Int J Oncol (2020)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.3892/ijo.2020.4999"}], "href": "https://doi.org/10.3892/ijo.2020.4999"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "32319586"}], "href": "https://pubmed.ncbi.nlm.nih.gov/32319586"}]}, {"type": "r", "ref": 19, "children": [{"type": "t", "text": "Ligang Chen, Tianqi Xu, Qingge Jia, et al. "}, {"type": "b", "children": [{"type": "t", "text": "RSK4: a new prognostic factor in glioma."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Pathol Res Pract (2020)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.prp.2020.153020"}], "href": "https://doi.org/10.1016/j.prp.2020.153020"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "32703488"}], "href": "https://pubmed.ncbi.nlm.nih.gov/32703488"}]}, {"type": "r", "ref": 20, "children": [{"type": "t", "text": "Jing Ma, Kaijing Wang, Jia Chai, et al. "}, {"type": "b", "children": [{"type": "t", "text": "High RSK4 expression constitutes a predictor of poor prognosis for patients with clear cell renal carcinoma."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Pathol Res Pract (2021)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.prp.2021.153642"}], "href": "https://doi.org/10.1016/j.prp.2021.153642"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "34649054"}], "href": "https://pubmed.ncbi.nlm.nih.gov/34649054"}]}, {"type": "r", "ref": 21, "children": [{"type": "t", "text": "Jian-lun Liu, Hua-wei Yang, Zu-shun Chen, et al. "}, {"type": "b", "children": [{"type": "t", "text": "[Abnormal expression of RSK-4 and its clinical significance in breast cancer]."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Zhonghua Zhong Liu Za Zhi (2011)"}]}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "21875487"}], "href": "https://pubmed.ncbi.nlm.nih.gov/21875487"}]}, {"type": "r", "ref": 22, "children": [{"type": "t", "text": "Fabian Arechavaleta-Velasco, Pablo Dominguez-Lopez, Ernesto Acosta-Jimenez, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Ribosomal S6 kinase 4 (RSK4) tumor suppressor gene promoter methylation status in ovarian cancer."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Mol Biol Rep (2023)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1007/s11033-023-08609-9"}], "href": "https://doi.org/10.1007/s11033-023-08609-9"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "37402066"}], "href": "https://pubmed.ncbi.nlm.nih.gov/37402066"}]}, {"type": "r", "ref": 23, "children": [{"type": "t", "text": "Roman A Siddiqui, Ulrike Sauermann, Janine Altmüller, et al. "}, {"type": "b", "children": [{"type": "t", "text": "X chromosomal variation is associated with slow progression to AIDS in HIV-1-infected women."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Am J Hum Genet (2009)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.ajhg.2009.07.013"}], "href": "https://doi.org/10.1016/j.ajhg.2009.07.013"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "19679225"}], "href": "https://pubmed.ncbi.nlm.nih.gov/19679225"}]}, {"type": "r", "ref": 24, "children": [{"type": "t", "text": "Katri Kantojärvi, Ilona Kotala, Karola Rehnström, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Fine mapping of Xq11.1-q21.33 and mutation screening of RPS6KA6, ZNF711, ACSL4, DLG3, and IL1RAPL2 for autism spectrum disorders (ASD)."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Autism Res (2011)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1002/aur.187"}], "href": "https://doi.org/10.1002/aur.187"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "21384559"}], "href": "https://pubmed.ncbi.nlm.nih.gov/21384559"}]}, {"type": "r", "ref": 25, "children": [{"type": "t", "text": "Zhiyong Yin, Linni Fan, Gaosheng Huang, et al. "}, {"type": "b", "children": [{"type": "t", "text": "The possible role of ribosomal protein S6 kinase 4 in the senescence of endothelial progenitor cells in diabetes mellitus."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cardiovasc Diabetol (2012)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1186/1475-2840-11-12"}], "href": "https://doi.org/10.1186/1475-2840-11-12"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "22297070"}], "href": "https://pubmed.ncbi.nlm.nih.gov/22297070"}]}]}]}