{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\n Deleted in azoospermia‐associated protein 2 (DAZAP2) has emerged as a multifunctional adaptor protein implicated in diverse cellular processes. In human embryonic stem cells, DAZAP2 is one of several bone morphogenetic protein (BMP) inhibitors that is repressed by members of the miR‐302/367 cluster, thereby enhancing BMP signaling and contributing to the maintenance of pluripotency and proper differentiation."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}]}, {"type": "t", "text": " In spermatogonia exposed to the cyclic heptapeptide toxin microcystin‐LR, DAZAP2 is a direct target of miR‐96; modulation of miR‐96 levels alters DAZAP2 expression and impacts cell viability under cytotoxic stress."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "2"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n "}, {"type": "p", "children": [{"type": "t", "text": "\n In the immune system, DAZAP2 interacts with the interleukin‐17 receptor IL17RB. This association, mediated by two SH2‐binding domains and mapped to a discrete region within the receptor’s cytoplasmic tail, is regulated by ligand (IL17E) stimulation, which promotes DAZAP2’s cytoplasmic accumulation and subsequent recruitment of the E3 ubiquitin ligase Smurf2 for its proteasome‐dependent degradation. Such regulated turnover appears crucial for proper IL17RB signaling."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "3"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n "}, {"type": "p", "children": [{"type": "t", "text": "\n In addition, DAZAP2 functions as a modulator of canonical Wnt signaling by directly binding to TCF/LEF family transcription factors—most notably TCF‐4—thereby influencing their DNA-binding affinity and the expression of Wnt target genes."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "4"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n "}, {"type": "p", "children": [{"type": "t", "text": "\n DAZAP2 also plays a pivotal role in the cellular DNA damage response. Under unstressed conditions, DAZAP2 promotes polyubiquitination and degradation of HIPK2 via cooperation with SIAH1. However, upon DNA damage, HIPK2 phosphorylates DAZAP2, shifting its localization to the nucleus where it interacts with p53 and modulates a subset of its target genes. This switch functions to shape the p53 response and ultimately influences cancer cell chemosensitivity."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "5"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n "}, {"type": "p", "children": [{"type": "t", "text": "\n Finally, analyses in multiple myeloma have revealed that DAZAP2 is frequently downregulated, an effect attributed in part to promoter hypermethylation and silencing of transcription factor binding sites. This epigenetic suppression of DAZAP2 not only distinguishes myeloma cells from their normal counterparts but also implicates its loss in the pathogenesis of the disease."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "6", "end_ref": "8"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n "}, {"type": "p", "children": [{"type": "t", "text": "\n Moreover, emerging evidence from studies in human pluripotent stem cells suggests that DAZAP2 is a relevant downstream target of the miR‐302 cluster, thereby influencing both cell proliferation and neural differentiation."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "9"}]}, {"type": "t", "text": " Collectively, these findings highlight DAZAP2 as a key adaptor protein that integrates signals from developmental, stress‐response, immune, and oncogenic pathways.\n "}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Inna Lipchina, Yechiel Elkabetz, Markus Hafner, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Genome-wide identification of microRNA targets in human ES cells reveals a role for miR-302 in modulating BMP response."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Genes Dev (2011)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1101/gad.17221311"}], "href": "https://doi.org/10.1101/gad.17221311"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "22012620"}], "href": "https://pubmed.ncbi.nlm.nih.gov/22012620"}]}, {"type": "r", "ref": 2, "children": [{"type": "t", "text": "Yuan Zhou, Zou Xiang, Dongmei Li, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Regulation of microcystin-LR-induced toxicity in mouse spermatogonia by miR-96."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Environ Sci Technol (2014)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1021/es500152m"}], "href": "https://doi.org/10.1021/es500152m"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "24803159"}], "href": "https://pubmed.ncbi.nlm.nih.gov/24803159"}]}, {"type": "r", "ref": 3, "children": [{"type": "t", "text": "Anna Popova, Julia Kzhyshkowska, Dinara Nurgazieva, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Smurf2 regulates IL17RB by proteasomal degradation of its novel binding partner DAZAP2."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Immunobiology (2012)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.imbio.2011.10.004"}], "href": "https://doi.org/10.1016/j.imbio.2011.10.004"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "22070932"}], "href": "https://pubmed.ncbi.nlm.nih.gov/22070932"}]}, {"type": "r", "ref": 4, "children": [{"type": "t", "text": "Jan Lukas, Petr Mazna, Tomas Valenta, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Dazap2 modulates transcription driven by the Wnt effector TCF-4."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Nucleic Acids Res (2009)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1093/nar/gkp179"}], "href": "https://doi.org/10.1093/nar/gkp179"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "19304756"}], "href": "https://pubmed.ncbi.nlm.nih.gov/19304756"}]}, {"type": "r", "ref": 5, "children": [{"type": "t", "text": "Magdalena C Liebl, Jutta Moehlenbrink, Huong Becker, et al. "}, {"type": "b", "children": [{"type": "t", "text": "DAZAP2 acts as specifier of the p53 response to DNA damage."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Nucleic Acids Res (2021)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1093/nar/gkab084"}], "href": "https://doi.org/10.1093/nar/gkab084"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "33591310"}], "href": "https://pubmed.ncbi.nlm.nih.gov/33591310"}]}, {"type": "r", "ref": 6, "children": [{"type": "t", "text": "Yi-wu Shi, Rong Shen, Wei Ren, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Molecular features and expression of DAZAP2 in human multiple myeloma."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Chin Med J (Engl) (2007)"}]}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "17935665"}], "href": "https://pubmed.ncbi.nlm.nih.gov/17935665"}]}, {"type": "r", "ref": 7, "children": [{"type": "t", "text": "Sai-Qun Luo, Jing-Ping Hu, Qiang Qu, et al. "}, {"type": "b", "children": [{"type": "t", "text": "The effects of promoter methylation on downregulation of DAZAP2 in multiple myeloma cell lines."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "PLoS One (2012)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1371/journal.pone.0040475"}], "href": "https://doi.org/10.1371/journal.pone.0040475"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "22792345"}], "href": "https://pubmed.ncbi.nlm.nih.gov/22792345"}]}, {"type": "r", "ref": 8, "children": [{"type": "t", "text": "Jiang Li, Wei-Xin Hu, Sai-Qun Luo, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Promoter methylation induced epigenetic silencing of DAZAP2, a downstream effector of p38/MAPK pathway, in multiple myeloma cells."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cell Signal (2019)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.cellsig.2019.04.012"}], "href": "https://doi.org/10.1016/j.cellsig.2019.04.012"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "31034872"}], "href": "https://pubmed.ncbi.nlm.nih.gov/31034872"}]}, {"type": "r", "ref": 9, "children": [{"type": "t", "text": "Tohru Sugawara, Takumi Miura, Tomoyuki Kawasaki, et al. "}, {"type": "b", "children": [{"type": "t", "text": "The hsa-miR-302 cluster controls ectodermal differentiation of human pluripotent stem cell via repression of "}, {"type": "a", "children": [{"type": "t", "text": "i"}], "href": "i"}, {"type": "t", "text": "DAZAP2"}, {"type": "a", "children": [{"type": "t", "text": "/i"}], "href": "/i"}, {"type": "t", "text": "."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Regen Ther (2020)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.reth.2020.03.011"}], "href": "https://doi.org/10.1016/j.reth.2020.03.011"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "32490061"}], "href": "https://pubmed.ncbi.nlm.nih.gov/32490061"}]}]}]}