{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nRSL1D1 (also known as CSIG) has emerged as a multifunctional nucleolar protein that regulates key aspects of cellular proliferation and senescence. In young cells, high levels of CSIG promote cell cycle progression by repressing PTEN translation—thereby reducing p27 expression—and thus delaying replicative senescence. In colorectal cancer models, elevated RSL1D1 acts as an anti‐senescence factor by binding to the 3′ untranslated region of FTH1 mRNA to enhance its stability, maintain iron homeostasis, and prevent ferroptosis. Moreover, CSIG facilitates the myristoylation of the serine/threonine phosphatase PPM1A, enhancing its dephosphorylation of Smad2 and ultimately attenuating transforming growth factor‐β (TGF‑β) signaling."}, {"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 tumorigenesis, RSL1D1 overexpression is associated with enhanced cancer cell proliferation and aggressive behavior. In hepatocellular carcinoma, CSIG levels are markedly increased in cancerous tissues where its upregulation promotes colony formation and tumor growth by stabilizing the oncogenic c‑MYC protein. Likewise, in colorectal cancer, RSL1D1 expression is significantly elevated and correlates with increased invasion and metastasis; here, RSL1D1 inhibits autophagy by interacting with RAN, competing with Sirt7 for its deacetylation, which in turn facilitates nuclear STAT3 accumulation and activation of tumor‐promoting programs."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "4"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nUnder nucleolar stress, RSL1D1 also plays a pivotal role in modulating the p53 pathway. CSIG translocates from the nucleolus to the nucleoplasm where it interacts directly with the RING finger domain of MDM2/HDM2, leading to inhibition of their E3 ubiquitin ligase activities and consequent stabilization of p53 protein. However, in colorectal cancer cells, RSL1D1 additionally interacts with p53 in a manner that facilitates its recruitment to HDM2, thereby enhancing p53 ubiquitination. Notably, while wild‑type p53 is efficiently targeted, mutant p53 proteins (e.g., R175H and R273H) display altered binding affinities with RSL1D1, resulting in diminished regulation and contributing to their oncogenic stabilization."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "6", "end_ref": "8"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIt is noteworthy that not every study in this collection focuses on RSL1D1. One investigation, for example, analyzed PBK1’s role in upregulating urokinase-type plasminogen activator expression in lung cancer cells, thereby highlighting additional regulatory networks in cancer that are independent of RSL1D1."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "9"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Liwei Ma, Na Chang, Shuzhen Guo, et al. "}, {"type": "b", "children": [{"type": "t", "text": "CSIG inhibits PTEN translation in replicative senescence."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Mol Cell Biol (2008)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1128/MCB.00142-08"}], "href": "https://doi.org/10.1128/MCB.00142-08"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "18678645"}], "href": "https://pubmed.ncbi.nlm.nih.gov/18678645"}]}, {"type": "r", "ref": 2, "children": [{"type": "t", "text": "Feng Zhu, Nan Xie, Zhe Jiang, et al. "}, {"type": "b", "children": [{"type": "t", "text": "The Cellular Senescence-Inhibited Gene Is Essential for PPM1A Myristoylation To Modulate Transforming Growth Factor β Signaling."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Mol Cell Biol (2018)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1128/MCB.00414-18"}], "href": "https://doi.org/10.1128/MCB.00414-18"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "30201805"}], "href": "https://pubmed.ncbi.nlm.nih.gov/30201805"}]}, {"type": "r", "ref": 3, "children": [{"type": "t", "text": "Yu Jin, Lei Zhao, Shuhao Wang, et al. "}, {"type": "b", "children": [{"type": "t", "text": "RSL1D1 knockdown induces ferroptosis and mediates ferrous iron accumulation in senescent cells by inhibiting FTH1 mRNA stability."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Carcinogenesis (2023)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1093/carcin/bgad012"}], "href": "https://doi.org/10.1093/carcin/bgad012"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "36913375"}], "href": "https://pubmed.ncbi.nlm.nih.gov/36913375"}]}, {"type": "r", "ref": 4, "children": [{"type": "t", "text": "Qian Cheng, Fuwen Yuan, Fengmin Lu, et al. "}, {"type": "b", "children": [{"type": "t", "text": "CSIG promotes hepatocellular carcinoma proliferation by activating c-MYC expression."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Oncotarget (2015)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.18632/oncotarget.2900"}], "href": "https://doi.org/10.18632/oncotarget.2900"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "25749381"}], "href": "https://pubmed.ncbi.nlm.nih.gov/25749381"}]}, {"type": "r", "ref": 5, "children": [{"type": "t", "text": "Xunhua Liu, Jianxiong Chen, Xiaoli Long, et al. 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