{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\n CACUL1, also known as CDK‐associated Cullin 1 (CAC1), is a multifunctional protein that plays key roles in regulating cell cycle progression, apoptosis, transcription, and stress responses, particularly in cancer and metabolic contexts. It enhances cell proliferation by interacting with CDK2 and promoting its kinase activity, thereby facilitating the G1/S transition; such cell cycle–promoting functions have been demonstrated in several cancer models, including gastric and colorectal cancers."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "3"}]}, {"type": "t", "text": " Moreover, CACUL1 is frequently overexpressed in diverse malignancies (gastric, colorectal, lung, and glioma), where its elevated levels are associated with enhanced tumor growth, chemoresistance, and metastatic potential."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "4", "end_ref": "7"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n \n "}, {"type": "p", "children": [{"type": "t", "text": "\n In addition to its role in promoting cell cycle progression, CACUL1 also functions as a transcriptional modulator. It directly binds to peroxisome proliferator‐activated receptor γ (PPARγ) via its CoRNR box, thereby repressing PPARγ transcriptional activity and attenuating adipocyte differentiation—a process mediated through interactions involving SIRT1 and LSD1."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "8"}]}, {"type": "t", "text": " Similarly, CACUL1 inhibits the SUMOylation of the tumor suppressor protein PML by associating with both PML and the SUMO-conjugating enzyme Ubc9, which in turn leads to reduced p53 transcriptional activity."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "9"}]}, {"type": "t", "text": " In androgen receptor–positive prostate cancer cells, CACUL1 directly associates with the androgen receptor (AR) and competes with LSD1, thereby suppressing AR transcriptional activity and influencing cell death pathways."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "10"}]}, {"type": "t", "text": " Furthermore, by binding to the Cul3-Keap1 complex, CACUL1 decreases the ubiquitination of the transcription factor Nrf2, sensitizing cells to oxidative stress through enhanced Nrf2 activation."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "11"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n \n "}, {"type": "p", "children": [{"type": "t", "text": "\n Evidence also points to a role for CACUL1 in posttranscriptional regulation via microRNAs. For instance, miR-106a* directly targets CACUL1 in esophageal carcinoma, leading to suppressed cell proliferation by modulating the CDK2 pathway."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "12"}]}, {"type": "t", "text": " In a similar vein, upregulation of circ-ERBB2 in gastric cancer can sequester miR-503, thereby relieving repression of CACUL1 and ultimately promoting tumor growth and invasion."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "13"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n \n "}, {"type": "p", "children": [{"type": "t", "text": "\n In summary, CACUL1 exerts context-dependent functions that include promoting cell cycle progression and tumor cell survival, repressing key transcriptional programs involved in differentiation and stress response, and participating in microRNA-mediated regulatory networks. These multifaceted roles render CACUL1 a potential therapeutic target in various cancers and metabolic disorders.\n "}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Ying Kong, Kejun Nan, Yuxin Yin "}, {"type": "b", "children": [{"type": "t", "text": "Identification and characterization of CAC1 as a novel CDK2-associated cullin."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cell Cycle (2009)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.4161/cc.8.21.9955"}], "href": "https://doi.org/10.4161/cc.8.21.9955"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "19829063"}], "href": "https://pubmed.ncbi.nlm.nih.gov/19829063"}]}, {"type": "r", "ref": 2, "children": [{"type": "t", "text": "Qi Zheng, Ling-Yu Zhao, Ying Kong, et al. 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