{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\n BFAR (bifunctional apoptosis regulator), also known as BAR, is a multifunctional protein that plays key anti‐apoptotic and cell survival roles across diverse biological contexts. In neuronal cells, BFAR is highly expressed in the endoplasmic reticulum, where it protects against a broad range of cell death stimuli—including mitochondrial, death receptor– and ER stress–induced apoptosis—thus promoting neuronal survival."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}]}, {"type": "t", "text": " In cancer, BFAR expression is frequently dysregulated; for instance, increased BFAR levels have been observed in colorectal tumors and gingival lesions, where its overexpression among other anti‐apoptotic genes is associated with enhanced cell survival and resistance to apoptosis."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "2"}]}, {"type": "t", "text": " Moreover, studies examining the regulation of the apoptotic machinery have demonstrated that suppression of factors such as OCT4B1 leads to a marked down‐regulation of BFAR, thereby uncovering its pro‐survival role in tumor cells."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "4"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n \n "}, {"type": "p", "children": [{"type": "t", "text": "\n In the context of immune regulation and cancer immunotherapy, BFAR has emerged as a pivotal modulator of transforming growth factor–β (TGFβ) signaling. It mediates K63-linked ubiquitination of TGFβ receptor I at a specific lysine residue, an event that is critical for sustaining TGFβ signaling and promoting the differentiation of Th9 cells—an immune subset with anti-tumor activity. Down-regulation or mutation of BFAR impairs this cascade and consequently dampens Th9-mediated cancer immunotherapy."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "5"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n \n "}, {"type": "p", "children": [{"type": "t", "text": "\n BFAR also interacts with receptors such as p75NTR, and its co-expression has been shown to alter cell cycle dynamics by increasing G2/M phase accumulation in cell models."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "6"}]}, {"type": "t", "text": " In addition, rare variations in BFAR have been identified in candidate screening studies for neurodevelopmental and psychiatric disorders"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "7"}]}, {"type": "t", "text": ", while a mouse-specific BFAR variant (BFARv3) appears to participate in nuclear RNA metabolism, potentially influencing oocyte maturation and early embryonic development."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "8"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n \n "}, {"type": "p", "children": [{"type": "t", "text": "\n Finally, changes in BFAR expression have been associated with the response to therapeutic interventions; for example, in melanoma studies BFAR mRNA levels were modulated following treatments aimed at enhancing endoplasmic reticulum stress and apoptotic signaling, underscoring its potential as a therapeutic target to potentiate cell death in cancer cells."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "9"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n \n "}, {"type": "p", "children": [{"type": "t", "text": "\n In summary, BFAR exerts anti-apoptotic effects by directly inhibiting pro-apoptotic pathways and modulating key signaling processes—from sustaining TGFβ receptor activation to interacting with cell cycle regulators—which contributes to enhanced cell survival in both physiological (e.g., neuronal maintenance) and pathological contexts (such as tumor progression). These multifaceted functions make BFAR a promising target for therapeutic strategies in cancer and potentially other disorders where apoptosis regulation is perturbed.\n "}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "W Roth, P Kermer, M Krajewska, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Bifunctional apoptosis inhibitor (BAR) protects neurons from diverse cell death pathways."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cell Death Differ (2003)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/sj.cdd.4401287"}], "href": "https://doi.org/10.1038/sj.cdd.4401287"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "14502241"}], "href": "https://pubmed.ncbi.nlm.nih.gov/14502241"}]}, {"type": "r", "ref": 2, "children": [{"type": "t", "text": "Michele Bianchini, Estrella Levy, Cinzia Zucchini, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Comparative study of gene expression by cDNA microarray in human colorectal cancer tissues and normal mucosa."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Int J Oncol (2006)"}]}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "16773188"}], "href": "https://pubmed.ncbi.nlm.nih.gov/16773188"}]}, {"type": "r", "ref": 3, "children": [{"type": "t", "text": "Yang-Yang Jiang, Bin Xu, Bing Fang "}, {"type": "b", "children": [{"type": "t", "text": "[Characteristic expression of apoptotic genes in epulis]."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Shanghai Kou Qiang Yi Xue (2020)"}]}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "32524117"}], "href": "https://pubmed.ncbi.nlm.nih.gov/32524117"}]}, {"type": "r", "ref": 4, "children": [{"type": "t", "text": "Mohammad Reza Mirzaei, Ali Najafi, Mohammad Kazemi Arababadi, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Altered expression of apoptotic genes in response to OCT4B1 suppression in human tumor cell lines."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Tumour Biol (2014)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1007/s13277-014-2238-9"}], "href": "https://doi.org/10.1007/s13277-014-2238-9"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "25008565"}], "href": "https://pubmed.ncbi.nlm.nih.gov/25008565"}]}, {"type": "r", "ref": 5, "children": [{"type": "t", "text": "Siyu Pei, Mingzhu Huang, Jia Huang, et al. "}, {"type": "b", "children": [{"type": "t", "text": "BFAR coordinates TGFβ signaling to modulate Th9-mediated cancer immunotherapy."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Exp Med (2021)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1084/jem.20202144"}], "href": "https://doi.org/10.1084/jem.20202144"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "33914044"}], "href": "https://pubmed.ncbi.nlm.nih.gov/33914044"}]}, {"type": "r", "ref": 6, "children": [{"type": "t", "text": "Hongmei Li, Huili Shi, Keke Huo "}, {"type": "b", "children": [{"type": "t", "text": "p75NTR signal transduction suppressed by BFAR and p75NTR interactions."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Sci China Life Sci (2012)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1007/s11427-012-4306-y"}], "href": "https://doi.org/10.1007/s11427-012-4306-y"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "22566094"}], "href": "https://pubmed.ncbi.nlm.nih.gov/22566094"}]}, {"type": "r", "ref": 7, "children": [{"type": "t", "text": "Julio Rodríguez-López, Beatriz Sobrino, Jorge Amigo, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Identification of putative second genetic hits in schizophrenia carriers of high-risk copy number variants and resequencing in additional samples."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Eur Arch Psychiatry Clin Neurosci (2018)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1007/s00406-017-0799-5"}], "href": "https://doi.org/10.1007/s00406-017-0799-5"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "28421333"}], "href": "https://pubmed.ncbi.nlm.nih.gov/28421333"}]}, {"type": "r", "ref": 8, "children": [{"type": "t", "text": "Katarzyna Mrowiec, Marek Chadalski, Anna Paszek, et al. "}, {"type": "b", "children": [{"type": "t", "text": "The periphilin 1-like BFAR isoform 3 is highly expressed in transcriptionally silent oocytes and involved in RNA metabolism."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Biochim Biophys Acta Mol Cell Res (2021)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.bbamcr.2021.119086"}], "href": "https://doi.org/10.1016/j.bbamcr.2021.119086"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "34175335"}], "href": "https://pubmed.ncbi.nlm.nih.gov/34175335"}]}, {"type": "r", "ref": 9, "children": [{"type": "t", "text": "Ignazio Barbagallo, Rosalba Parenti, Agata Zappalà, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Combined inhibition of Hsp90 and heme oxygenase-1 induces apoptosis and endoplasmic reticulum stress in melanoma."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Acta Histochem (2015)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.acthis.2015.09.005"}], "href": "https://doi.org/10.1016/j.acthis.2015.09.005"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "26493719"}], "href": "https://pubmed.ncbi.nlm.nih.gov/26493719"}]}]}]}