{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nCDKN2B‐encoded p15 acts as a potent cyclin‐dependent kinase inhibitor that enforces the G1/S cell‐cycle checkpoint and thereby contributes to tumor suppression. In experimental models, p15 has been shown to serve as a critical backup for other INK4 proteins, exerting strong control over CDK4/CDK6 activity. Its transcription and protein levels are tightly regulated – for example, histone demethylases (such as Jhdm1b) modulate its expression in an enzymatic activity‐dependent manner, and its potent inhibition of CDK4-mediated retinoblastoma phosphorylation marks it as one of the more effective tumor suppressors in the INK4 family."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "3"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nMultiple studies also highlight that p15 expression is dynamically regulated by non‐coding RNA mechanisms and cytokine signals. For instance, aberrant antisense transcripts can trigger p15 silencing via heterochromatin induction without immediate DNA methylation"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "4"}]}, {"type": "t", "text": ", while interferon‐β–mediated transcription—dependent on myeloid factors like ICSBP/IRF-8 and PU.1—upregulates p15 in hematopoietic cells."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "5"}]}, {"type": "t", "text": " Consistent with this, genetic inactivation or epigenetic silencing of p15 fosters preleukemic conditions in myeloproliferative models"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "6"}]}, {"type": "t", "text": ", and retroviral tagging studies further document cooperation between p15 loss and oncogenic events, although in certain models (such as in the presence of the RUNX1-ETO fusion protein) p15 inactivation alone does not fully accelerate acute leukemia."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "8"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nBeyond hematopoiesis, p15 plays multifaceted roles in non-hematopoietic tissues. In the cardiovascular system, diminished p15 expression is linked to impaired clearance of apoptotic vascular cells and an expansion of necrotic plaque cores, thereby promoting atherogenesis"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "10"}]}, {"type": "t", "text": ";"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "11"}]}, {"type": "t", "text": ";"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "12"}]}, {"type": "t", "text": ";."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "13"}]}, {"type": "t", "text": " In models of mesenchymal and neural tumors, including meningiomas and pancreatic carcinoma, loss or inactivation of p15 (often in combination with losses at the broader INK4/ARF locus) facilitates oncogenic transformation and malignant progression"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "14"}]}, {"type": "t", "text": ";"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "15"}]}, {"type": "t", "text": ";"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "16"}]}, {"type": "t", "text": ";"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "17"}]}, {"type": "t", "text": ";."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "18"}]}, {"type": "t", "text": " Moreover, in the context of adaptive immunity, p15 has been implicated in the proper differentiation and maturation of dendritic cells, linking its cell-cycle regulatory functions with the effective initiation of immune responses."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "19"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Paul Krimpenfort, Annemieke Ijpenberg, Ji-Ying Song, et al. 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"}, {"type": "b", "children": [{"type": "t", "text": "Dominant role of CDKN2B/p15INK4B of 9p21.3 tumor suppressor hub in inhibition of cell-cycle and glycolysis."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Nat Commun (2021)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/s41467-021-22327-5"}], "href": "https://doi.org/10.1038/s41467-021-22327-5"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "33824349"}], "href": "https://pubmed.ncbi.nlm.nih.gov/33824349"}]}, {"type": "r", "ref": 4, "children": [{"type": "t", "text": "Wenqiang Yu, David Gius, Patrick Onyango, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Epigenetic silencing of tumour suppressor gene p15 by its antisense RNA."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Nature (2008)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/nature06468"}], "href": "https://doi.org/10.1038/nature06468"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "18185590"}], "href": "https://pubmed.ncbi.nlm.nih.gov/18185590"}]}, {"type": "r", "ref": 5, "children": [{"type": "t", "text": "Martina Schmidt, Juraj Bies, Tomohiko Tamura, et al. "}, {"type": "b", "children": [{"type": "t", "text": "The interferon regulatory factor ICSBP/IRF-8 in combination with PU.1 up-regulates expression of tumor suppressor p15(Ink4b) in murine myeloid cells."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Blood (2004)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1182/blood-2003-01-0285"}], "href": "https://doi.org/10.1182/blood-2003-01-0285"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "14976051"}], "href": "https://pubmed.ncbi.nlm.nih.gov/14976051"}]}, {"type": "r", "ref": 6, "children": [{"type": "t", "text": "Juraj Bies, Marek Sramko, Joanna Fares, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Myeloid-specific inactivation of p15Ink4b results in monocytosis and predisposition to myeloid leukemia."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Blood (2010)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1182/blood-2009-08-238360"}], "href": "https://doi.org/10.1182/blood-2009-08-238360"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "20457873"}], "href": "https://pubmed.ncbi.nlm.nih.gov/20457873"}]}, {"type": "r", "ref": 7, "children": [{"type": "t", "text": "Linda Wolff, Matthew T Garin, Richard Koller, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Hypermethylation of the Ink4b locus in murine myeloid leukemia and increased susceptibility to leukemia in p15(Ink4b)-deficient mice."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Oncogene (2003)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/sj.onc.1207092"}], "href": "https://doi.org/10.1038/sj.onc.1207092"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "14681685"}], "href": "https://pubmed.ncbi.nlm.nih.gov/14681685"}]}, {"type": "r", "ref": 8, "children": [{"type": "t", "text": "Linda Wolff, Matthew T Garin, Richard Koller, et al. "}, {"type": "b", "children": [{"type": "t", "text": "A novel retrovirus provides the cooperating oncogenic event(s) required to demonstrate the tumor suppressor activity of p15Ink4b in myeloid cells in vivo."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Blood Cells Mol Dis (2004)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.bcmd.2003.09.006"}], "href": "https://doi.org/10.1016/j.bcmd.2003.09.006"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "14757439"}], "href": "https://pubmed.ncbi.nlm.nih.gov/14757439"}]}, {"type": "r", "ref": 9, "children": [{"type": "t", "text": "Rose M Ko, Hyung-Gyoon Kim, Linda Wolff, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Roles of p15Ink4b and p16Ink4a in myeloid differentiation and RUNX1-ETO-associated acute myeloid leukemia."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Leuk Res (2008)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.leukres.2007.10.012"}], "href": "https://doi.org/10.1016/j.leukres.2007.10.012"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "18037485"}], "href": "https://pubmed.ncbi.nlm.nih.gov/18037485"}]}, {"type": "r", "ref": 10, "children": [{"type": "t", "text": "Chinmay M Trivedi, Min Min Lu, Qiaohong Wang, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Transgenic overexpression of Hdac3 in the heart produces increased postnatal cardiac myocyte proliferation but does not induce hypertrophy."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Biol Chem (2008)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1074/jbc.M803686200"}], "href": "https://doi.org/10.1074/jbc.M803686200"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "18625706"}], "href": "https://pubmed.ncbi.nlm.nih.gov/18625706"}]}, {"type": "r", "ref": 11, "children": [{"type": "t", "text": "Kwame Osei-Sarfo, Ignacio Perez de Castro, Angel Pellicer "}, {"type": "b", "children": [{"type": "t", "text": "p15(INK4b) plays a crucial role in murine lymphoid development and tumorigenesis."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Carcinogenesis (2012)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1093/carcin/bgs003"}], "href": "https://doi.org/10.1093/carcin/bgs003"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "22227036"}], "href": "https://pubmed.ncbi.nlm.nih.gov/22227036"}]}, {"type": "r", "ref": 12, "children": [{"type": "t", "text": "M Peyre, A Stemmer-Rachamimov, E Clermont-Taranchon, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Meningioma progression in mice triggered by Nf2 and Cdkn2ab inactivation."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Oncogene (2013)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/onc.2012.436"}], "href": "https://doi.org/10.1038/onc.2012.436"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "23045274"}], "href": "https://pubmed.ncbi.nlm.nih.gov/23045274"}]}, {"type": "r", "ref": 13, "children": [{"type": "t", "text": "Yoko Kojima, Kelly Downing, Ramendra Kundu, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Cyclin-dependent kinase inhibitor 2B regulates efferocytosis and atherosclerosis."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Clin Invest (2014)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1172/JCI70391"}], "href": "https://doi.org/10.1172/JCI70391"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "24531546"}], "href": "https://pubmed.ncbi.nlm.nih.gov/24531546"}]}, {"type": "r", "ref": 14, "children": [{"type": "t", "text": "Xiao Tian, Jorge Azpurua, Zhonghe Ke, et al. "}, {"type": "b", "children": [{"type": "t", "text": "INK4 locus of the tumor-resistant rodent, the naked mole rat, expresses a functional p15/p16 hybrid isoform."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Proc Natl Acad Sci U S A (2015)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1073/pnas.1418203112"}], "href": "https://doi.org/10.1073/pnas.1418203112"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "25550505"}], "href": "https://pubmed.ncbi.nlm.nih.gov/25550505"}]}, {"type": "r", "ref": 15, "children": [{"type": "t", "text": "Vivek Nanda, Kelly P Downing, Jianqin Ye, et al. "}, {"type": "b", "children": [{"type": "t", "text": "CDKN2B Regulates TGFβ Signaling and Smooth Muscle Cell Investment of Hypoxic Neovessels."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Circ Res (2016)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1161/CIRCRESAHA.115.307906"}], "href": "https://doi.org/10.1161/CIRCRESAHA.115.307906"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "26596284"}], "href": "https://pubmed.ncbi.nlm.nih.gov/26596284"}]}, {"type": "r", "ref": 16, "children": [{"type": "t", "text": "Q Tu, J Hao, X Zhou, et al. "}, {"type": "b", "children": [{"type": "t", "text": "CDKN2B deletion is essential for pancreatic cancer development instead of unmeaningful co-deletion due to juxtaposition to CDKN2A."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Oncogene (2018)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/onc.2017.316"}], "href": "https://doi.org/10.1038/onc.2017.316"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "28892048"}], "href": "https://pubmed.ncbi.nlm.nih.gov/28892048"}]}, {"type": "r", "ref": 17, "children": [{"type": "t", "text": "Satoshi Inoue, Zhenyue Hao, Andrew J Elia, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Mule/Huwe1/Arf-BP1 suppresses Ras-driven tumorigenesis by preventing c-Myc/Miz1-mediated down-regulation of p21 and p15."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Genes Dev (2013)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1101/gad.214577.113"}], "href": "https://doi.org/10.1101/gad.214577.113"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "23699408"}], "href": "https://pubmed.ncbi.nlm.nih.gov/23699408"}]}, {"type": "r", "ref": 18, "children": [{"type": "t", "text": "C V Camacho, P K Todorova, M C Hardebeck, et al. "}, {"type": "b", "children": [{"type": "t", "text": "DNA double-strand breaks cooperate with loss of Ink4 and Arf tumor suppressors to generate glioblastomas with frequent Met amplification."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Oncogene (2015)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/onc.2014.29"}], "href": "https://doi.org/10.1038/onc.2014.29"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "24632607"}], "href": "https://pubmed.ncbi.nlm.nih.gov/24632607"}]}, {"type": "r", "ref": 19, "children": [{"type": "t", "text": "Jin-feng Tian, Pei Cao, Xiu-yuan Yu, et al. "}, {"type": "b", "children": [{"type": "t", "text": "[mRNA expression and methylation status of p15 promoter in mouse bone marrow cells exposed to 1,4-benzoquinone]."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Zhonghua Lao Dong Wei Sheng Zhi Ye Bing Za Zhi (2011)"}]}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "21619792"}], "href": "https://pubmed.ncbi.nlm.nih.gov/21619792"}]}]}]}