{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nAMBRA1, the autophagy‐ and beclin‑1 regulator 1, emerges from these studies as a master modulator of autophagy that is essential for embryonic development and neural differentiation. It controls autophagosome formation and clearance, thereby maintaining cellular homeostasis during conditions as diverse as nutrient starvation, neuronal differentiation and stress. Deficiencies in AMBRA1 lead to impaired autophagy during early embryogenesis, resulting in neural tube defects, aberrant accumulation of misfolded proteins, and disruptions in neuronal differentiation and survival. Furthermore, altered AMBRA1 expression in the brain is linked to neurodevelopmental abnormalities, including autism‑like behaviors and imbalances in excitatory/inhibitory neurotransmission."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "7"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nBeyond its developmental roles, AMBRA1 exerts pivotal control over cell proliferation by modulating key cell‐cycle regulators. Acting as a scaffold, it facilitates the dephosphorylation and proteasomal degradation of proto‑oncogenic cyclin D, thereby linking autophagy with mTOR and cell‐cycle signalling. AMBRA1 coordinates the timely onset and termination of autophagy through dynamic associations with different Cullin E3 ligases, and its loss leads to the stabilization of D‑type cyclins, hyperphosphorylation of RB, and enhanced proliferation. Moreover, AMBRA1’s interactions extend to mitochondrial quality control, where it ensures proper mitophagy, and its deficiency can reduce cellular sensitivity to CDK4/6 inhibitors by rerouting cyclin complexes."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "8", "end_ref": "19"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nAdditional evidence indicates that AMBRA1 functions as a tumor suppressor and immunomodulatory factor, influencing cancer progression and response to therapy. Loss or mutation of AMBRA1 enhances focal adhesion kinase and Src signaling to promote invasion and metastasis, while also impairing mitochondrial autophagy in muscle and altering inflammatory responses in disorders such as inflammatory bowel disease. These studies underscore that AMBRA1’s regulation of autophagy intersects with diverse cellular pathways—from coordinating membrane recycling and cytoskeletal dynamics to modulating the response to immunotherapies—thereby making it a potential target for treating a spectrum of conditions ranging from melanoma to chronic inflammatory disorders."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "20", "end_ref": "24"}]}, {"type": "t", "text": ""}]}]}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Gian Maria Fimia, Anastassia Stoykova, Alessandra Romagnoli, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Ambra1 regulates autophagy and development of the nervous system."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Nature (2007)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/nature05925"}], "href": "https://doi.org/10.1038/nature05925"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "17589504"}], "href": "https://pubmed.ncbi.nlm.nih.gov/17589504"}]}, {"type": "r", "ref": 2, "children": [{"type": "t", "text": "Cindy Van Humbeeck, Tom Cornelissen, Hilde Hofkens, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Parkin interacts with Ambra1 to induce mitophagy."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Neurosci (2011)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1523/JNEUROSCI.1917-11.2011"}], "href": "https://doi.org/10.1523/JNEUROSCI.1917-11.2011"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "21753002"}], "href": "https://pubmed.ncbi.nlm.nih.gov/21753002"}]}, {"type": "r", "ref": 3, "children": [{"type": "t", "text": "Patricia Vázquez, Ana I Arroba, Francesco Cecconi, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Atg5 and Ambra1 differentially modulate neurogenesis in neural stem cells."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Autophagy (2012)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.4161/auto.8.2.18535"}], "href": "https://doi.org/10.4161/auto.8.2.18535"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "22240590"}], "href": "https://pubmed.ncbi.nlm.nih.gov/22240590"}]}, {"type": "r", "ref": 4, "children": [{"type": "t", "text": "Charlotte Steenblock, Tobias Heckel, Cornelia Czupalla, et al. "}, {"type": "b", "children": [{"type": "t", "text": "The Cdc42 guanine nucleotide exchange factor FGD6 coordinates cell polarity and endosomal membrane recycling in osteoclasts."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Biol Chem (2014)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1074/jbc.M113.504894"}], "href": "https://doi.org/10.1074/jbc.M113.504894"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "24821726"}], "href": "https://pubmed.ncbi.nlm.nih.gov/24821726"}]}, {"type": "r", "ref": 5, "children": [{"type": "t", "text": "Christina Schoenherr, Adam Byron, Emma Sandilands, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Ambra1 spatially regulates Src activity and Src/FAK-mediated cancer cell invasion via trafficking networks."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Elife (2017)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.7554/eLife.23172"}], "href": "https://doi.org/10.7554/eLife.23172"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "28362576"}], "href": "https://pubmed.ncbi.nlm.nih.gov/28362576"}]}, {"type": "r", "ref": 6, "children": [{"type": "t", "text": "M Mitjans, M Begemann, A Ju, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Sexual dimorphism of AMBRA1-related autistic features in human and mouse."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Transl Psychiatry (2017)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/tp.2017.213"}], "href": "https://doi.org/10.1038/tp.2017.213"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "28994820"}], "href": "https://pubmed.ncbi.nlm.nih.gov/28994820"}]}, {"type": "r", "ref": 7, "children": [{"type": "t", "text": "Annalisa Nobili, Paraskevi Krashia, Alberto Cordella, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Ambra1 Shapes Hippocampal Inhibition/Excitation Balance: Role in Neurodevelopmental Disorders."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Mol Neurobiol (2018)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1007/s12035-018-0911-5"}], "href": "https://doi.org/10.1007/s12035-018-0911-5"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "29488136"}], "href": "https://pubmed.ncbi.nlm.nih.gov/29488136"}]}, {"type": "r", "ref": 8, "children": [{"type": "t", "text": "Valentina Cianfanelli, Claudia Fuoco, Mar Lorente, et al. "}, {"type": "b", "children": [{"type": "t", "text": "AMBRA1 links autophagy to cell proliferation and tumorigenesis by promoting c-Myc dephosphorylation and degradation."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Nat Cell Biol (2015)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/ncb3072"}], "href": "https://doi.org/10.1038/ncb3072"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "25438055"}], "href": "https://pubmed.ncbi.nlm.nih.gov/25438055"}]}, {"type": "r", "ref": 9, "children": [{"type": "t", "text": "Manuela Antonioli, Federica Albiero, Francesca Nazio, et al. "}, {"type": "b", "children": [{"type": "t", "text": "AMBRA1 interplay with cullin E3 ubiquitin ligases regulates autophagy dynamics."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Dev Cell (2014)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.devcel.2014.11.013"}], "href": "https://doi.org/10.1016/j.devcel.2014.11.013"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "25499913"}], "href": "https://pubmed.ncbi.nlm.nih.gov/25499913"}]}, {"type": "r", "ref": 10, "children": [{"type": "t", "text": "Christopher C Pan, Sanjay Kumar, Nirav Shah, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Endoglin Regulation of Smad2 Function Mediates Beclin1 Expression and Endothelial Autophagy."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Biol Chem (2015)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1074/jbc.M114.630178"}], "href": "https://doi.org/10.1074/jbc.M114.630178"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "25931117"}], "href": "https://pubmed.ncbi.nlm.nih.gov/25931117"}]}, {"type": "r", "ref": 11, "children": [{"type": "t", "text": "Jiejun Zhu, Xu Chen, Yun Song, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Deficit of RACK1 contributes to the spatial memory impairment via upregulating BECLIN1 to induce autophagy."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Life Sci (2016)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.lfs.2016.02.014"}], "href": "https://doi.org/10.1016/j.lfs.2016.02.014"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "26930371"}], "href": "https://pubmed.ncbi.nlm.nih.gov/26930371"}]}, {"type": "r", "ref": 12, "children": [{"type": "t", "text": "Yasuo Miki, Kunikazu Tanji, Fumiaki Mori, et al. "}, {"type": "b", "children": [{"type": "t", "text": "AMBRA1, a novel α-synuclein-binding protein, is implicated in the pathogenesis of multiple system atrophy."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Brain Pathol (2018)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1111/bpa.12461"}], "href": "https://doi.org/10.1111/bpa.12461"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "27875637"}], "href": "https://pubmed.ncbi.nlm.nih.gov/27875637"}]}, {"type": "r", "ref": 13, "children": [{"type": "t", "text": "Jianliang Chen, Yue Yu, Shu Li, et al. "}, {"type": "b", "children": [{"type": "t", "text": "MicroRNA-30a ameliorates hepatic fibrosis by inhibiting Beclin1-mediated autophagy."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Cell Mol Med (2017)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1111/jcmm.13278"}], "href": "https://doi.org/10.1111/jcmm.13278"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "28766848"}], "href": "https://pubmed.ncbi.nlm.nih.gov/28766848"}]}, {"type": "r", "ref": 14, "children": [{"type": "t", "text": "Hisako Akatsuka, Shuhei Kuga, Kaori Masuhara, et al. "}, {"type": "b", "children": [{"type": "t", "text": "AMBRA1 is involved in T cell receptor-mediated metabolic reprogramming through an ATG7-independent pathway."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Biochem Biophys Res Commun (2017)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.bbrc.2017.08.019"}], "href": "https://doi.org/10.1016/j.bbrc.2017.08.019"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "28789945"}], "href": "https://pubmed.ncbi.nlm.nih.gov/28789945"}]}, {"type": "r", "ref": 15, "children": [{"type": "t", "text": "Shu-Jie Zhao, Fan-Qi Kong, Wei Cai, et al. "}, {"type": "b", "children": [{"type": "t", "text": "GIT1 contributes to autophagy in osteoclast through disruption of the binding of Beclin1 and Bcl2 under starvation condition."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cell Death Dis (2018)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/s41419-018-1256-8"}], "href": "https://doi.org/10.1038/s41419-018-1256-8"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "30546041"}], "href": "https://pubmed.ncbi.nlm.nih.gov/30546041"}]}, {"type": "r", "ref": 16, "children": [{"type": "t", "text": "Xianju Bi, Yanhui Xu, Tong Li, et al. "}, {"type": "b", "children": [{"type": "t", "text": "RNA Targets Ribogenesis Factor WDR43 to Chromatin for Transcription and Pluripotency Control."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Mol Cell (2019)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.molcel.2019.05.007"}], "href": "https://doi.org/10.1016/j.molcel.2019.05.007"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "31128943"}], "href": "https://pubmed.ncbi.nlm.nih.gov/31128943"}]}, {"type": "r", "ref": 17, "children": [{"type": "t", "text": "Emiliano Maiani, Giacomo Milletti, Francesca Nazio, et al. "}, {"type": "b", "children": [{"type": "t", "text": "AMBRA1 regulates cyclin D to guard S-phase entry and genomic integrity."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Nature (2021)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/s41586-021-03422-5"}], "href": "https://doi.org/10.1038/s41586-021-03422-5"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "33854232"}], "href": "https://pubmed.ncbi.nlm.nih.gov/33854232"}]}, {"type": "r", "ref": 18, "children": [{"type": "t", "text": "Daniele Simoneschi, Gergely Rona, Nan Zhou, et al. "}, {"type": "b", "children": [{"type": "t", "text": "CRL4"}, {"type": "a", "children": [{"type": "t", "text": "sup"}], "href": "sup"}, {"type": "t", "text": "AMBRA1"}, {"type": "a", "children": [{"type": "t", "text": "/sup"}], "href": "/sup"}, {"type": "t", "text": " is a master regulator of D-type cyclins."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Nature (2021)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/s41586-021-03445-y"}], "href": "https://doi.org/10.1038/s41586-021-03445-y"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "33854235"}], "href": "https://pubmed.ncbi.nlm.nih.gov/33854235"}]}, {"type": "r", "ref": 19, "children": [{"type": "t", "text": "Andrea C Chaikovsky, Chuan Li, Edwin E Jeng, et al. "}, {"type": "b", "children": [{"type": "t", "text": "The AMBRA1 E3 ligase adaptor regulates the stability of cyclin D."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Nature (2021)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/s41586-021-03474-7"}], "href": "https://doi.org/10.1038/s41586-021-03474-7"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "33854239"}], "href": "https://pubmed.ncbi.nlm.nih.gov/33854239"}]}, {"type": "r", "ref": 20, "children": [{"type": "t", "text": "Gu Lijie, Zhang Yueyue, Zhu Nan, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Mitsugumin 53 promotes mitochondrial autophagy through regulating Ambra1 expression in C2C12 myoblast cells."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cell Biol Int (2019)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1002/cbin.11097"}], "href": "https://doi.org/10.1002/cbin.11097"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "30614598"}], "href": "https://pubmed.ncbi.nlm.nih.gov/30614598"}]}, {"type": "r", "ref": 21, "children": [{"type": "t", "text": "Lisa Gambarotto, Samuele Metti, Martina Chrisam, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Ambra1 deficiency impairs mitophagy in skeletal muscle."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Cachexia Sarcopenia Muscle (2022)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1002/jcsm.13010"}], "href": "https://doi.org/10.1002/jcsm.13010"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "35593053"}], "href": "https://pubmed.ncbi.nlm.nih.gov/35593053"}]}, {"type": "r", "ref": 22, "children": [{"type": "t", "text": "Ignacio Ramírez-Pardo, Beatriz Villarejo-Zori, Juan Ignacio Jiménez-Loygorri, et al. "}, {"type": "b", "children": [{"type": "a", "children": [{"type": "t", "text": "i"}], "href": "i"}, {"type": "t", "text": "Ambra1"}, {"type": "a", "children": [{"type": "t", "text": "/i"}], "href": "/i"}, {"type": "t", "text": " haploinsufficiency in CD1 mice results in metabolic alterations and exacerbates age-associated retinal degeneration."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Autophagy (2023)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1080/15548627.2022.2103307"}], "href": "https://doi.org/10.1080/15548627.2022.2103307"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "35875981"}], "href": "https://pubmed.ncbi.nlm.nih.gov/35875981"}]}, {"type": "r", "ref": 23, "children": [{"type": "t", "text": "Alex Frias, Luca Di Leo, Asier Antoranz, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Ambra1 modulates the tumor immune microenvironment and response to PD-1 blockade in melanoma."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Immunother Cancer (2023)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1136/jitc-2022-006389"}], "href": "https://doi.org/10.1136/jitc-2022-006389"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "36868570"}], "href": "https://pubmed.ncbi.nlm.nih.gov/36868570"}]}, {"type": "r", "ref": 24, "children": [{"type": "t", "text": "Weimin Xu, Zhebin Hua, Yaosheng Wang, et al. "}, {"type": "b", "children": [{"type": "t", "text": "AMBRA1 promotes intestinal inflammation by antagonizing PP4R1/PP4c mediated IKK dephosphorylation in an autophagy-independent manner."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cell Death Differ (2024)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/s41418-024-01275-9"}], "href": "https://doi.org/10.1038/s41418-024-01275-9"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "38424148"}], "href": "https://pubmed.ncbi.nlm.nih.gov/38424148"}]}]}]}