title: p53 inhibits angiogenesis by inducing the production of Arresten.
abstract: Several types of collagen contain cryptic antiangiogenic noncollagenous domains that are released upon proteolysis of extracellular matrix (ECM). Among those is Arresten, a collagen-derived antiangiogenic factor (CDAF) that is processed from α1 collagen IV. However, the conditions under which Arresten is released from collagen IV in vivo or whether the protein functions in tumor suppressor pathways remain unknown. Here, we show that p53 induces the expression of α1 collagen IV and release of Arresten-containing fragments from the ECM. Comparison of the transcriptional activation of COL4A1 with other CDAF-containing genes revealed that COL4A1 is a major antiangiogenic gene induced by p53 in human adenocarinoma cells. p53 directly activated transcription of the COL4A1 gene by binding to an enhancer region 26 kbp downstream of its 3' end. p53 also stabilized the expression of full-length α1 collagen IV by upregulation of α(II) prolyl-hydroxylase and increased the release of Arresten in the ECM through a matrix metalloproteinase (MMP)-dependent mechanism. The resulting upregulation of α1 collagen IV and production of Arresten by the tumor cells significantly inhibited angiogenesis and limited tumor growth in vivo. Furthermore, we show that immunostaining of Arresten correlated with p53 status in human prostate cancer specimens. Our findings, therefore, link the production of Arresten to the p53 tumor suppressor pathway and show a novel mechanism through which p53 can inhibit angiogenesis.
authors.affiliation: Goodman Cancer Research Center, Department of Biochemistry, McGill University, Montréal, Québec, Canada.
authors.forename: Sarah
authors.initials: S
authors.lastname: Assadian
authors.forename: Wissal
authors.initials: W
authors.lastname: El-Assaad
authors.forename: Xue Q D
authors.initials: XQ
authors.lastname: Wang
authors.forename: Phillipe O
authors.initials: PO
authors.lastname: Gannon
authors.forename: Véronique
authors.initials: V
authors.lastname: Barrès
authors.forename: Mathieu
authors.initials: M
authors.lastname: Latour
authors.forename: Anne-Marie
authors.initials: AM
authors.lastname: Mes-Masson
authors.forename: Fred
authors.initials: F
authors.lastname: Saad
authors.forename: Yoshikazu
authors.initials: Y
authors.lastname: Sado
authors.forename: Josée
authors.initials: J
authors.lastname: Dostie
authors.forename: Jose G
authors.initials: JG
authors.lastname: Teodoro
mesh_terms: D000230:Adenocarcinoma / Q000378:metabolism*; D020533:Angiogenesis Inhibitors / Q000235:genetics*; D000818:Animals; D045744:Cell Line, Tumor; D024141:Collagen Type IV / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D008297:Male; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D011471:Prostatic Neoplasms / Q000235:genetics*; D015533:Transcriptional Activation; D016159:Tumor Suppressor Protein p53 / Q000235:genetics*; D015854:Up-Regulation
chemical_list: D020533:Angiogenesis Inhibitors; C547475:COL4A1 protein, human; D024141:Collagen Type IV; D016159:Tumor Suppressor Protein p53