{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nPTGES3, also known as p23, is an essential Hsp90 co‐chaperone that modulates the conformational dynamics and ATPase cycle of the Hsp90 machinery. Structural and biochemical studies have revealed that PTGES3 promotes the proper folding and activation of many client proteins by stabilizing specific, nucleotide‐bound conformations and by assisting in the assembly (and disassembly) of multicomponent transcriptional regulatory complexes – a function that is particularly evident in steroid receptor systems such as the glucocorticoid receptor. These investigations demonstrate that PTGES3 is critical for maintaining a client‐ready, Hsp90 “closed” state that enables hormone‐dependent as well as hormone‐independent receptor maturation and signaling."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "6"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn addition to its central role in modulating Hsp90’s chaperoning activity, PTGES3 regulates the stability and subcellular localization of key regulatory proteins. It is indispensable for the proper assembly and nuclear import of hTERT within the telomerase complex, and it influences other signaling routes by promoting the recruitment of factors such as prolyl hydroxylase (involved in hypoxia‐inducible factor regulation) as well as by directly interacting with transcription factors like p53. PTGES3’s activity is also modulated during cellular stress; for example, caspase‐mediated cleavage of PTGES3 under endoplasmic reticulum stress alters its function and can lead to enhanced ubiquitination and degradation of client proteins. Furthermore, PTGES3 helps to protect proteins such as the aryl hydrocarbon receptor from autophagy‐mediated degradation, thereby contributing to their steady‐state levels."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "7", "end_ref": "15"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nThe multifaceted functions of PTGES3 have significant implications in pathophysiological settings, particularly in cancer. Aberrant expression or activity of PTGES3 has been linked to enhanced receptor‐mediated gene transcription, increased cell invasion, and chemoresistance in malignancies such as breast, prostate, and lung adenocarcinomas. Notably, small molecules – including celastrol and natural compounds identified in green tea – can disrupt PTGES3 function and its interplay with the Hsp90 machinery, suggesting that targeting PTGES3 may offer new avenues for therapeutic intervention. In addition, PTGES3 has been shown to influence the oligomerization state of Hsp90 and to coordinate multiple stress‐response pathways, rendering it a promising candidate both as a prognostic biomarker and as a secondary target in combination therapies."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "16", "end_ref": "22"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Brian C Freeman, Keith R Yamamoto "}, {"type": "b", "children": [{"type": "t", "text": "Disassembly of transcriptional regulatory complexes by molecular chaperones."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Science (2002)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1126/science.1073051"}], "href": "https://doi.org/10.1126/science.1073051"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "12077419"}], "href": "https://pubmed.ncbi.nlm.nih.gov/12077419"}]}, {"type": "r", "ref": 2, "children": [{"type": "t", "text": "Yoshihiro Morishima, Kimon C Kanelakis, Patrick J M Murphy, et al. 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