{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\n Studies on CABLES1 have consistently shown that it functions as a critical negative regulator of cell proliferation and a potent tumor suppressor in a variety of tissues. In multiple cancer models—including lung, colon, ovarian, and corticotrope pituitary tumors—CABLES1 exerts its tumor‐suppressive effect by interacting with and stabilizing key cell cycle inhibitors (for example, p21) and by negatively regulating cyclin‐dependent kinases. In breast cancer cells, overexpression of CABLES1 increases the half‐life of p21 through direct complex formation and protection from proteasomal degradation, thereby inhibiting cell proliferation and inducing apoptosis."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}]}, {"type": "t", "text": " Similarly, in corticotrope tumor cells, glucocorticoid signaling upregulates CABLES1 expression; depletion of CABLES1 relieves cell cycle restraints, resulting in enhanced proliferation and constituting a mechanism that may contribute to tumor aggressiveness when inactivated."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "2"}]}, {"type": "t", "text": " In further support of its tumor‐suppressive functions, CABLES1 has been shown to mediate apoptosis by inhibiting cyclin-dependent kinase activity, a process that can be counteracted by oncogenic signaling through Akt and 14–3-3 protein recruitment."}, {"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 to its role in cancer, CABLES1 is implicated in the regulation of differentiation and survival in the female germline. Knockout studies in mice reveal that loss of CABLES1 leads to an expansion of premeiotic germ cells and an accumulation of defective oocytes, suggesting that CABLES1 normally acts to both limit germ cell proliferation and ensure oocyte quality."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "4"}]}, {"type": "t", "text": " Consistent with this, CABLES1 interacts with the transactivating form of p63 (TAp63α) to protect it from proteasomal degradation, thereby modulating the oocyte’s response to genotoxic stress."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "5"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n "}, {"type": "p", "children": [{"type": "t", "text": "\n Finally, loss of CABLES1 has been associated with enhanced β-catenin activity and increased proliferation in colon tumors, while decreased nuclear expression of CABLES1 in ovarian carcinomas further underscores its role as a tumor suppressor."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "6"}]}, {"type": "t", "text": " Moreover, the CABLES1/p21 axis has been shown to induce senescence and inhibit cell growth in endothelial cells, with similar findings being observed in hematopoietic progenitors during stress and aging."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "8"}]}, {"type": "t", "text": "\n "}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Z Shi, Z Li, Z J Li, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Cables1 controls p21/Cip1 protein stability by antagonizing proteasome subunit alpha type 3."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Oncogene (2015)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/onc.2014.171"}], "href": "https://doi.org/10.1038/onc.2014.171"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "24975575"}], "href": "https://pubmed.ncbi.nlm.nih.gov/24975575"}]}, {"type": "r", "ref": 2, "children": [{"type": "t", "text": "Audrey Roussel-Gervais, Catherine Couture, David Langlais, et al. "}, {"type": "b", "children": [{"type": "t", "text": "The Cables1 Gene in Glucocorticoid Regulation of Pituitary Corticotrope Growth and Cushing Disease."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Clin Endocrinol Metab (2016)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1210/jc.2015-3324"}], "href": "https://doi.org/10.1210/jc.2015-3324"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "26695862"}], "href": "https://pubmed.ncbi.nlm.nih.gov/26695862"}]}, {"type": "r", "ref": 3, "children": [{"type": "t", "text": "Zhi Shi, Hae Ryon Park, Yuhong Du, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Cables1 complex couples survival signaling to the cell death machinery."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cancer Res (2015)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1158/0008-5472.CAN-14-0036"}], "href": "https://doi.org/10.1158/0008-5472.CAN-14-0036"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "25361894"}], "href": "https://pubmed.ncbi.nlm.nih.gov/25361894"}]}, {"type": "r", "ref": 4, "children": [{"type": "t", "text": "Ho-Joon Lee, Hideo Sakamoto, Hongwei Luo, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Loss of CABLES1, a cyclin-dependent kinase-interacting protein that inhibits cell cycle progression, results in germline expansion at the expense of oocyte quality in adult female mice."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cell Cycle (2007)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.4161/cc.6.21.4820"}], "href": "https://doi.org/10.4161/cc.6.21.4820"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "17912041"}], "href": "https://pubmed.ncbi.nlm.nih.gov/17912041"}]}, {"type": "r", "ref": 5, "children": [{"type": "t", "text": "Ning Wang, Lankai Guo, Bo R Rueda, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Cables1 protects p63 from proteasomal degradation to ensure deletion of cells after genotoxic stress."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "EMBO Rep (2010)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/embor.2010.82"}], "href": "https://doi.org/10.1038/embor.2010.82"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "20559324"}], "href": "https://pubmed.ncbi.nlm.nih.gov/20559324"}]}, {"type": "r", "ref": 6, "children": [{"type": "t", "text": "Thomas Arnason, Maria S Pino, Omer Yilmaz, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Cables1 is a tumor suppressor gene that regulates intestinal tumor progression in Apc(Min) mice."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cancer Biol Ther (2013)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.4161/cbt.25089"}], "href": "https://doi.org/10.4161/cbt.25089"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "23792637"}], "href": "https://pubmed.ncbi.nlm.nih.gov/23792637"}]}, {"type": "r", "ref": 7, "children": [{"type": "t", "text": "Hideo Sakamoto, Anne M Friel, Antony W Wood, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Mechanisms of Cables 1 gene inactivation in human ovarian cancer development."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cancer Biol Ther (2008)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.4161/cbt.7.2.5253"}], "href": "https://doi.org/10.4161/cbt.7.2.5253"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "18059193"}], "href": "https://pubmed.ncbi.nlm.nih.gov/18059193"}]}, {"type": "r", "ref": 8, "children": [{"type": "t", "text": "Jingjin Liu, Yongshun Wang, Jinjin Cui, et al. "}, {"type": "b", "children": [{"type": "t", "text": "miR199a-3p regulates P53 by targeting CABLES1 in mouse cardiac c-kit"}, {"type": "a", "children": [{"type": "t", "text": "sup"}], "href": "sup"}, {"type": "t", "text": "+"}, {"type": "a", "children": [{"type": "t", "text": "/sup"}], "href": "/sup"}, {"type": "t", "text": " cells to promote proliferation and inhibit apoptosis through a negative feedback loop."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Stem Cell Res Ther (2017)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1186/s13287-017-0515-4"}], "href": "https://doi.org/10.1186/s13287-017-0515-4"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "28583208"}], "href": "https://pubmed.ncbi.nlm.nih.gov/28583208"}]}, {"type": "r", "ref": 9, "children": [{"type": "t", "text": "Liang He, Florian Beghi, Viviane Baral, et al. "}, {"type": "b", "children": [{"type": "t", "text": "CABLES1 Deficiency Impairs Quiescence and Stress Responses of Hematopoietic Stem Cells in Intrinsic and Extrinsic Manners."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Stem Cell Reports (2019)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.stemcr.2019.06.002"}], "href": "https://doi.org/10.1016/j.stemcr.2019.06.002"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "31327733"}], "href": "https://pubmed.ncbi.nlm.nih.gov/31327733"}]}]}]}