p53 inhibits angiogenesis by inducing the production of Arresten
Menée in vitro et in vivo, cette étude identifie un mécanisme par lequel p53 inhibe l'angiogenèse en induisant la production d'un facteur antiangiogénique dérivé d'un collagène (arresten)
Several types of collagen contain cryptic antiangiogenic non-collagenous domains that are released upon proteolysis of extracellular matrix (ECM). Among those is Arresten, a collagen-derived antiangiogenic factor (CDAF) that is processed from alpha 1 collagen 4. However, the conditions under which Arresten is released from collagen 4 in vivo or whether the protein functions in tumor suppressor pathways remain unknown. Here we show that p53 induces the expression of 1 collagen 4 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 26kbp downstream of its 3 prime end. p53 also stabilized the expression of full length 1 collagen 4 by upregulation of alpha (II) prolyl-hydroxylase and increased the release of Arresten in the ECM through an MMP-dependent mechanism. The resulting upregulation of alpha 1 collagen 4 and production of Arresten by the tumor cells significantly inhibited angiogenesis and limited tumor growth in vivo. Furthermore, we demonstrate 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 demonstrate a novel mechanism through which p53 can inhibit angiogenesis.