{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\n CCDC134 is emerging as a multifunctional protein with both secretory and nuclear roles that impact a variety of biological processes. In several studies, CCDC134 has been identified as a secreted molecule that can inhibit mitogen‐activated protein kinase (MAPK) signaling pathways—specifically, the Erk1/2 and JNK cascades. Loss‐of‐function mutations in CCDC134, which result in increased Erk1/2 phosphorylation, have been implicated in severe forms of osteogenesis imperfecta, suggesting that proper regulation of MAPK signaling is critical for normal bone formation and mineralization."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "3"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n \n "}, {"type": "p", "children": [{"type": "t", "text": "\n In parallel, CCDC134 has been shown to function as an immune cytokine. Its secreted form appears to promote CD8⁺ T‐cell activation, proliferation, and cytotoxic function via the JAK3–STAT5 pathway, thereby contributing to potent antitumor effects."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "4", "end_ref": "6"}]}, {"type": "t", "text": " In contrast, in some cancer types such as gastric and breast cancer, reduced expression of CCDC134 has been associated with enhanced tumor cell migration and invasion, correlating with poorer patient survival."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "7"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n \n "}, {"type": "p", "children": [{"type": "t", "text": "\n Beyond its extracellular actions, nuclear CCDC134 has been found to interact with the transcriptional adaptor hADA2a within the PCAF complex. This association enhances hADA2a stability and promotes PCAF-dependent acetylation of p53 at lysine 320, thereby enhancing p53 stability, facilitating cell cycle arrest, and promoting apoptosis in response to DNA damage."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "9"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n \n "}, {"type": "p", "children": [{"type": "t", "text": "\n In addition to its roles in MAPK regulation, immune modulation, and transcriptional control, CCDC134 is also involved in developmental processes. For instance, it is highly expressed in Purkinje cells and contributes to proper cerebellar morphogenesis and function, with its deficiency leading to impaired dendritic growth, defective granule cell development, and consequent motor deficits."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "10"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n \n "}, {"type": "p", "children": [{"type": "t", "text": "\n Finally, CCDC134 has been implicated in genetic studies exploring diverse pathological conditions. Genome-wide analyses have identified variants and altered expression levels of CCDC134 as potential risk factors in Alzheimer’s disease"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "11"}]}, {"type": "t", "text": "and schizophrenia"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "12"}]}, {"type": "t", "text": ", further underscoring its pleiotropic contributions to human pathophysiology.\n "}]}, {"type": "t", "text": "\n \n "}, {"type": "p", "children": [{"type": "t", "text": "\n In summary, the available evidence indicates that CCDC134 functions as a MAPK pathway inhibitor that is crucial for normal bone formation and neurodevelopment, acts as a secreted immune cytokine enhancing CD8⁺ T-cell antitumor responses, and modulates transcriptional responses through its interaction with histone acetyltransferase complexes. These diverse roles make CCDC134 a promising candidate for further investigation as a biomarker and therapeutic target in diseases ranging from osteogenesis imperfecta and cancer to neurodevelopmental and neurodegenerative disorders."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}, {"type": "fg_f", "ref": "7"}, {"type": "fg_f", "ref": "2"}, {"type": "fg_f", "ref": "9"}, {"type": "fg_f", "ref": "4"}, {"type": "fg_f", "ref": "3"}, {"type": "fg_f", "ref": "10"}, {"type": "fg_f", "ref": "6"}, {"type": "fg_f", "ref": "11"}, {"type": "fg_f", "ref": "8"}, {"type": "fg_f", "ref": "12"}]}, {"type": "t", "text": "\n "}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Johanne Dubail, Perrine Brunelle, Geneviève Baujat, et al. 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