title: XIAP-associating factor 1, a transcriptional target of BRD7, contributes to endothelial cell senescence.
abstract: X-linked inhibitor of apoptosis (XIAP)-associated factor 1 (XAF1) is well known as an antagonist of XIAP-mediated caspase inhibition. Although XAF1 serves as a tumor-suppressor gene, the role of XAF1 in cellular senescence remains unclear. We found that XAF1 expression was increased by genotoxic agents, such as doxorubicin and ionizing radiation in pulmonary microvascular endothelial cells, consequently leading to premature senescence. Conversely, downregulation of XAF1 in premature senescent cells partially overcame endothelial cell senescence. p53 knockdown, but not p16 knockdown, abolished senescence phenotypes caused by XAF1 induction. XAF1 expression was transcriptionally regulated by Bromodomain 7 (BRD7). XAF1 induction with interferon-gamma (IFN-γ) treatment was abrogated by BRD7 knockdown, which resulted in blocking interferon-induced senescence. In lung cancer cells, XAF1 tumor suppressor activity was decreased by BRD7 knockdown, and inhibition of tumor growth by IFN-γ did not appear in BRD7-depleted xenograft tumors. These data suggest that XAF1 is involved in BRD7-associated senescence and plays an important role in the regulation of endothelial senescence through a p53-dependent pathway. Furthermore, regulation of the BRD7/XAF1 system might contribute to tissue or organismal aging and protection against cellular transformation.
authors.affiliation: Divisions of Radiation Effects, Korea Institute of Radiological and Medical Sciences, Seoul, Republic of Korea.
authors.forename: Jong-Ik
authors.initials: JI
authors.lastname: Heo
authors.affiliation: Research Center for Radiotherapy, Korea Institute of Radiological and Medical Sciences, Seoul, Republic of Korea.
authors.forename: Wonwoo
authors.initials: W
authors.lastname: Kim
authors.affiliation: Divisions of Radiation Effects, Korea Institute of Radiological and Medical Sciences, Seoul, Republic of Korea.
authors.forename: Kyu Jin
authors.initials: KJ
authors.lastname: Choi
authors.affiliation: Divisions of Radiation Effects, Korea Institute of Radiological and Medical Sciences, Seoul, Republic of Korea.
authors.forename: Sangwoo
authors.initials: S
authors.lastname: Bae
authors.affiliation: Research Center for Radiotherapy, Korea Institute of Radiological and Medical Sciences, Seoul, Republic of Korea.
authors.forename: Jae-Hoon
authors.initials: JH
authors.lastname: Jeong
authors.affiliation: Divisions of Radiation Effects, Korea Institute of Radiological and Medical Sciences, Seoul, Republic of Korea.
authors.forename: Kwang Seok
authors.initials: KS
authors.lastname: Kim
mesh_terms: D045744:Cell Line, Tumor; D016922:Cellular Senescence / Q000235:genetics*; D002868:Chromosomal Proteins, Non-Histone / Q000235:genetics* / Q000378:metabolism*; D042783:Endothelial Cells / Q000378:metabolism*; D006801:Humans; D009363:Neoplasm Proteins / Q000235:genetics*; D014162:Transfection; D051636:X-Linked Inhibitor of Apoptosis Protein / Q000235:genetics* / Q000378:metabolism*; D000092468:Bromodomain Containing Proteins
chemical_list: D002868:Chromosomal Proteins, Non-Histone; D009363:Neoplasm Proteins; D051636:X-Linked Inhibitor of Apoptosis Protein; C485694:BRD7 protein, human; D000092468:Bromodomain Containing Proteins; C496866:XIAP protein, human
keywords: BRD7; DNA damage; Gerotarget; XAF1; cellular senescence; ionizing radiation; p53