{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nWEE1 is a serine/threonine kinase that plays a critical role in regulating cell‐cycle progression by phosphorylating and inhibiting cyclin‐dependent kinases—most notably Cdc2/CDK1—in order to delay entry into mitosis. This inhibitory action is tightly controlled: for example, WEE1 is phosphorylated by key M‐phase kinases such as polo‐like kinase 1 and Cdc2 to create phospho‐degron motifs that are recognized by the SCFβ–TrCP ubiquitin ligase complex, leading to its timely degradation. In addition, oncogenic signaling pathways, including Akt, modulate WEE1’s subcellular localization, while transcription factors like KLF2 can repress its expression in certain cancers. Aberrant expression of WEE1 has also been documented in hepatocellular carcinoma and pituitary adenomas, underscoring its importance in cell‐cycle control under both physiologic and pathological conditions."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "8"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nBeyond its role in controlling the timing of mitotic entry, WEE1 is fundamental for maintaining genomic stability. Its inhibition or deregulation can lead to increased cyclin-dependent kinase activity, resulting in unscheduled replication origin firing, nucleotide pool depletion, and slower replication fork progression that culminates in DNA double-strand break formation. Moreover, WEE1 function is essential for enforcing the S-phase checkpoint and protecting stalled replication forks—in part by modulating endonucleases such as Mus81—thereby preventing catastrophic genomic instability following DNA damage."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "9", "end_ref": "13"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nThe therapeutic potential of targeting WEE1 is underscored by its dysregulation in multiple malignancies. WEE1 is frequently overexpressed or aberrantly regulated in glioblastoma, melanoma, neuroblastoma, gastric cancer, and hematologic malignancies, where it enables tumor cells to tolerate DNA damage induced by replication stress or genotoxic therapies. Inhibition of WEE1 with small-molecule inhibitors such as AZD1775 (MK-1775) can abrogate the G2/M checkpoint, force cells with damaged DNA into premature mitosis, and thereby promote mitotic catastrophe and apoptosis. Furthermore, studies have revealed that synthetic lethality can be achieved by combining WEE1 inhibitors with other agents—such as ATR or Chk1 inhibitors—and that microRNAs (for example, members of the let-7 and miR-15 families) as well as other regulatory networks can modulate WEE1 expression and influence chemoresistance. Genome-wide screens and mechanistic studies in diverse tumor models lend strong support to the concept of exploiting WEE1 as a promising target in combination therapies."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "14", "end_ref": "30"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nAdditional layers of regulation further refine WEE1 function in both normal and cancer cells. Natural compounds such as quercetin and 2‑methoxyestradiol, viral proteins (for example, HIV Vpr), and noncoding RNAs—including microRNAs like miR‑194 and miR‑128—can modulate WEE1 expression, stability, and localization. Such diverse regulatory inputs not only influence cell-cycle arrest and DNA damage responses but also impact tumor cell survival and therapeutic sensitivity, emphasizing the multifaceted nature of WEE1 regulation."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "31", "end_ref": "35"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Nobumoto Watanabe, Harumi Arai, Yoshifumi Nishihara, et al. 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"}, {"type": "b", "children": [{"type": "t", "text": "Transcriptional repression of WEE1 by Kruppel-like factor 2 is involved in DNA damage-induced apoptosis."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Oncogene (2005)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/sj.onc.1208546"}], "href": "https://doi.org/10.1038/sj.onc.1208546"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "15735666"}], "href": "https://pubmed.ncbi.nlm.nih.gov/15735666"}]}, {"type": "r", "ref": 6, "children": [{"type": "t", "text": "Henriett Butz, István Likó, Sándor Czirják, et al. 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"}, {"type": "b", "children": [{"type": "t", "text": "In silico analysis of kinase expression identifies WEE1 as a gatekeeper against mitotic catastrophe in glioblastoma."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cancer Cell (2010)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.ccr.2010.08.011"}], "href": "https://doi.org/10.1016/j.ccr.2010.08.011"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "20832752"}], "href": "https://pubmed.ncbi.nlm.nih.gov/20832752"}]}, {"type": "r", "ref": 15, "children": [{"type": "t", "text": "Sophia X Pfister, Enni Markkanen, Yanyan Jiang, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Inhibiting WEE1 Selectively Kills Histone H3K36me3-Deficient Cancers by dNTP Starvation."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cancer Cell (2015)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.ccell.2015.09.015"}], "href": "https://doi.org/10.1016/j.ccell.2015.09.015"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "26602815"}], "href": "https://pubmed.ncbi.nlm.nih.gov/26602815"}]}, {"type": "r", "ref": 16, "children": [{"type": "t", "text": "Andrea Ghelli Luserna di Rorà, Claudio Cerchione, Giovanni Martinelli, et al. 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