{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nPAX4 is widely recognized as a pivotal transcription factor governing pancreatic islet development by promoting β‐cell lineage commitment, differentiation, proliferation, and survival. Loss‐of‐function mutations (for example, R121W and other missense variants) impair its repressor activity and DNA binding, thereby reducing the formation and functional competency of insulin‐producing β‐cells and predisposing carriers to various forms of diabetes—including maturity‐onset diabetes of the young (MODY), type 2 diabetes, and ketosis‐prone diabetes. Moreover, PAX4 is critical during embryogenesis, where it represses alternate endocrine fates to secure the β‐cell identity, as evidenced by both genetic mutation analyses and promoter studies in human and rodent models."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "9"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn addition to its role in determining cell fate, PAX4 expression is finely regulated by external signaling molecules and intrinsic transcriptional networks. Activin A, for instance, enhances PAX4 gene transcription via E‐box–binding factors (E47/E12), and modulation of its promoter by repressor complexes (including those involving neuron‐restrictive silencer elements) further refines its expression. Notably, the PAX4 protein itself exhibits non–cell autonomous functions by virtue of a protein transduction domain that enables its uptake and anti–apoptotic actions in target cells. These regulatory mechanisms and differential activities—exemplified by ethnic and species differences in binding affinities—underscore the complexity of PAX4 regulation in pancreatic and extra–pancreatic contexts."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "10", "end_ref": "14"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nBeyond its classical role in islet biology, emerging evidence indicates that aberrant PAX4 expression or genetic variation contributes to disease susceptibility and progression in diverse tissues. In the endocrine pancreas, genetic polymorphisms and mutations in PAX4 have been linked not only to various diabetic phenotypes (including gestational diabetes and altered therapeutic responses) but also to differences in β‐cell function and longevity. In parallel, dysregulated PAX4 activity has been implicated in cancer, acting context–dependently as either an oncogene or tumor suppressor—for example, its overexpression in gastric cancer cells enhances migration and invasion via miRNA regulatory networks, while in melanoma its reduced expression appears to inhibit tumor growth. Together with data from recent large–scale genetic and functional studies, these findings underscore the multifaceted role of PAX4 as a key modulator of cell differentiation, survival, and disease risk."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "15", "end_ref": "29"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Y Shimajiri, T Sanke, H Furuta, et al. 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