{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\n Cytokine‐like protein 1 (CYTL1) is a secreted, multifunctional protein originally identified in CD34+ progenitor cells that has emerged as an important regulator in several biological systems. In the musculoskeletal system, CYTL1 is highly expressed by chondrocytes and during cartilage formation, where it promotes chondrogenesis by stimulating Sox9 transcriptional activity and enhancing the expression of key cartilage matrix components (such as type II collagen) without influencing later hypertrophic maturation. Moreover, knockout studies indicate that although CYTL1 is not essential for cartilage or bone development, its presence is critical for maintaining cartilage homeostasis and protecting against osteoarthritis‐associated degeneration (for example, [1,2,14])."}]}, {"type": "t", "text": "\n \n "}, {"type": "p", "children": [{"type": "t", "text": "\n In addition to its chondroregulatory functions, CYTL1 appears to possess chemokine‐like properties. Structural modeling and biochemical studies strongly suggest that it adopts an IL8‐like fold similar to that of CCL2, enabling it to signal via the CCR2 receptor. Consistent with this, CYTL1 exhibits chemotactic activity toward monocytes and neutrophils, promoting receptor internalization and activation of downstream signaling pathways (such as ERK and Akt), which in turn enhance phagocytosis, reactive oxygen species production, and cellular migration ([3,9,13]). \n "}]}, {"type": "t", "text": "\n \n "}, {"type": "p", "children": [{"type": "t", "text": "\n Beyond its roles in cartilage and immune cell recruitment, CYTL1 exerts proangiogenic effects by enhancing endothelial cell sprouting and supporting functional vessel formation independent of VEGF‐A, suggesting potential applications in tissue regeneration and ischemic disease ([5]). Furthermore, in the heart, CYTL1 is upregulated in failing myocardium where it contributes to cardiac fibrosis by triggering endothelial–mesenchymal transition and fibroblast activation through TGF‑β–SMAD signaling, pointing to a deleterious role in adverse cardiac remodeling ([6]). \n "}]}, {"type": "t", "text": "\n \n "}, {"type": "p", "children": [{"type": "t", "text": "\n In the hematologic and cancer fields, CYTL1 has been implicated in promoting the survival of leukemic monocytes in chronic myelomonocytic leukemia via an autocrine mechanism that activates ERK through CCR2, and intracellular forms of CYTL1 can modulate metabolic reprogramming in breast cancer cells by stabilizing mitochondrial complex components, thereby inhibiting glycolytic switching and reducing malignancy ([7,8]). In neuroblastoma cells, elevated CYTL1 expression appears to support tumor cell proliferation, migration, and invasion ([4]).\n "}]}, {"type": "t", "text": "\n \n "}, {"type": "p", "children": [{"type": "t", "text": "\n Finally, CYTL1 is expressed in the endometrium in an ovarian hormone–dependent manner, where it enhances endometrial cell proliferation, secretion of factors such as leukemia inhibitory factor (LIF) and HB‑EGF, and cell adhesion properties—functions that may be important for successful embryo implantation ([11]). Together with the observation that genetic variations in the CYTL1 locus are associated with alcohol consumption behavior, these studies underscore the pleiotropic nature of CYTL1 and its diverse roles in development, inflammation, tissue homeostasis, and disease ([15]).\n "}]}, {"type": "t", "text": "\n \n "}, {"type": "p", "children": [{"type": "t", "text": "\n Collectively, these findings highlight CYTL1 as a cytokine‐like factor with overlapping chemokine activity that modulates cellular differentiation, inflammatory cell recruitment, angiogenesis, fibrotic remodeling, tumor biology, and reproductive physiology ([1,2,3,4,5,6,7,8,9,10,11,12,13,14,15]).\n "}]}, {"type": "t", "text": "\n \n <!-- Hyperlinked citations -->\n "}, {"type": "p", "children": [{"type": "t", "text": "\n [1]"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}]}, {"type": "t", "text": ", \n [2]"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "2"}]}, {"type": "t", "text": ", \n [3]"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "3"}]}, {"type": "t", "text": ", \n [4]"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "4"}]}, {"type": "t", "text": ", \n [5]"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "5"}]}, {"type": "t", "text": ", \n [6]"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "6"}]}, {"type": "t", "text": ", \n [7]"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "7"}]}, {"type": "t", "text": ", \n [8]"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "8"}]}, {"type": "t", "text": ", \n [9]"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "9"}]}, {"type": "t", "text": ", \n [10]"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "10"}]}, {"type": "t", "text": ", \n [11]"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "11"}]}, {"type": "t", "text": ", \n [12]"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "12"}]}, {"type": "t", "text": ", \n [13]"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "13"}]}, {"type": "t", "text": ", \n [14]"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "14"}]}, {"type": "t", "text": ", \n [15]."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "15"}]}, {"type": "t", "text": ""}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Jae-Sung Kim, Zae Young Ryoo, Jang-Soo Chun "}, {"type": "b", "children": [{"type": "t", "text": "Cytokine-like 1 (Cytl1) regulates the chondrogenesis of mesenchymal cells."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Biol Chem (2007)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1074/jbc.M700965200"}], "href": "https://doi.org/10.1074/jbc.M700965200"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "17644814"}], "href": "https://pubmed.ncbi.nlm.nih.gov/17644814"}]}, {"type": "r", "ref": 2, "children": [{"type": "t", "text": "Jimin Jeon, Hwanhee Oh, Gyusuk Lee, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Cytokine-like 1 knock-out mice (Cytl1-/-) show normal cartilage and bone development but exhibit augmented osteoarthritic cartilage destruction."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Biol Chem (2011)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1074/jbc.M111.218065"}], "href": "https://doi.org/10.1074/jbc.M111.218065"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "21652695"}], "href": "https://pubmed.ncbi.nlm.nih.gov/21652695"}]}, {"type": "r", "ref": 3, "children": [{"type": "t", "text": "Xiaolin Wang, Ting Li, Wenyan Wang, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Cytokine-like 1 Chemoattracts Monocytes/Macrophages via CCR2."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Immunol (2016)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.4049/jimmunol.1501908"}], "href": "https://doi.org/10.4049/jimmunol.1501908"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "27084102"}], "href": "https://pubmed.ncbi.nlm.nih.gov/27084102"}]}, {"type": "r", "ref": 4, "children": [{"type": "t", "text": "Mingjie Wen, Huanmin Wang, Xulong Zhang, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Cytokine-like 1 is involved in the growth and metastasis of neuroblastoma cells."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Int J Oncol (2012)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.3892/ijo.2012.1552"}], "href": "https://doi.org/10.3892/ijo.2012.1552"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "22797702"}], "href": "https://pubmed.ncbi.nlm.nih.gov/22797702"}]}, {"type": "r", "ref": 5, "children": [{"type": "t", "text": "Doris Schneller, Renate Hofer-Warbinek, Caterina Sturtzel, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Cytokine-Like 1 Is a Novel Proangiogenic Factor Secreted by and Mediating Functions of Endothelial Progenitor Cells."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Circ Res (2019)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1161/CIRCRESAHA.118.313645"}], "href": "https://doi.org/10.1161/CIRCRESAHA.118.313645"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "30582450"}], "href": "https://pubmed.ncbi.nlm.nih.gov/30582450"}]}, {"type": "r", "ref": 6, "children": [{"type": "t", "text": "Jooyeon Kim, Jihwa Kim, Seung Hee Lee, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Cytokine-Like 1 Regulates Cardiac Fibrosis via Modulation of TGF-β Signaling."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "PLoS One (2016)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1371/journal.pone.0166480"}], "href": "https://doi.org/10.1371/journal.pone.0166480"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "27835665"}], "href": "https://pubmed.ncbi.nlm.nih.gov/27835665"}]}, {"type": "r", "ref": 7, "children": [{"type": "t", "text": "Margaux Sevin, Franck Debeurme, Lucie Laplane, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Cytokine-like protein 1-induced survival of monocytes suggests a combined strategy targeting MCL1 and MAPK in CMML."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Blood (2021)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1182/blood.2020008729"}], "href": "https://doi.org/10.1182/blood.2020008729"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "33690800"}], "href": "https://pubmed.ncbi.nlm.nih.gov/33690800"}]}, {"type": "r", "ref": 8, "children": [{"type": "t", "text": "Wenwen Xue, Xin Li, Wuhao Li, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Intracellular CYTL1, a novel tumor suppressor, stabilizes NDUFV1 to inhibit metabolic reprogramming in breast cancer."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Signal Transduct Target Ther (2022)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/s41392-021-00856-1"}], "href": "https://doi.org/10.1038/s41392-021-00856-1"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "35115484"}], "href": "https://pubmed.ncbi.nlm.nih.gov/35115484"}]}, {"type": "r", "ref": 9, "children": [{"type": "t", "text": "Aurelie Tomczak, M Teresa Pisabarro "}, {"type": "b", "children": [{"type": "t", "text": "Identification of CCR2-binding features in Cytl1 by a CCL2-like chemokine model."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Proteins (2011)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1002/prot.22963"}], "href": "https://doi.org/10.1002/prot.22963"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "21322034"}], "href": "https://pubmed.ncbi.nlm.nih.gov/21322034"}]}, {"type": "r", "ref": 10, "children": [{"type": "t", "text": "Connie Chao, Barbara Joyce-Shaikh, Jeff Grein, et al. "}, {"type": "b", "children": [{"type": "t", "text": "C17 prevents inflammatory arthritis and associated joint destruction in mice."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "PLoS One (2011)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1371/journal.pone.0022256"}], "href": "https://doi.org/10.1371/journal.pone.0022256"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "21799806"}], "href": "https://pubmed.ncbi.nlm.nih.gov/21799806"}]}, {"type": "r", "ref": 11, "children": [{"type": "t", "text": "Zhichao Ai, Wei Jing, Li Fang "}, {"type": "b", "children": [{"type": "t", "text": "Cytokine-Like Protein 1(Cytl1): A Potential Molecular Mediator in Embryo Implantation."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "PLoS One (2016)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1371/journal.pone.0147424"}], "href": "https://doi.org/10.1371/journal.pone.0147424"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "26800213"}], "href": "https://pubmed.ncbi.nlm.nih.gov/26800213"}]}, {"type": "r", "ref": 12, "children": [{"type": "t", "text": "Aurelie Tomczak, Kavita Singh, Apostolos G Gittis, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Biochemical and biophysical characterization of cytokine-like protein 1 (CYTL1)."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cytokine (2017)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.cyto.2017.04.023"}], "href": "https://doi.org/10.1016/j.cyto.2017.04.023"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "28478073"}], "href": "https://pubmed.ncbi.nlm.nih.gov/28478073"}]}, {"type": "r", "ref": 13, "children": [{"type": "t", "text": "Haiyan Xue, Shu Li, Xiujuan Zhao, et al. "}, {"type": "b", "children": [{"type": "t", "text": "CYTL1 Promotes the Activation of Neutrophils in a Sepsis Model."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Inflammation (2020)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1007/s10753-019-01116-9"}], "href": "https://doi.org/10.1007/s10753-019-01116-9"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "31823178"}], "href": "https://pubmed.ncbi.nlm.nih.gov/31823178"}]}, {"type": "r", "ref": 14, "children": [{"type": "t", "text": "Weicong Zhu, Xiaohong Yang, Shaojie Liu, et al. "}, {"type": "b", "children": [{"type": "t", "text": "The involvement of cytokine-like 1 (Cytl1) in chondrogenesis and cartilage metabolism."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Biochem Biophys Res Commun (2020)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.bbrc.2020.06.069"}], "href": "https://doi.org/10.1016/j.bbrc.2020.06.069"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "32736681"}], "href": "https://pubmed.ncbi.nlm.nih.gov/32736681"}]}, {"type": "r", "ref": 15, "children": [{"type": "t", "text": "Xiang-ding Chen, Dong-hai Xiong, Tie-lin Yang, et al. "}, {"type": "b", "children": [{"type": "t", "text": "ANKRD7 and CYTL1 are novel risk genes for alcohol drinking behavior."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Chin Med J (Engl) (2012)"}]}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "22613542"}], "href": "https://pubmed.ncbi.nlm.nih.gov/22613542"}]}]}]}