Data from The Codon 72 <i>TP53</i> Polymorphism Contributes to TSC Tumorigenesis through the Notch–Nodal Axis

Abstract

<div>Abstract<p>We discovered that 90.3% of patients with angiomyolipomas, lymphangioleiomyomatosis (LAM), and tuberous sclerosis complex (TSC) carry the arginine variant of codon 72 (R72) of <i>TP53</i> and that R72 increases the risk for angiomyolipoma. R72 transactivates <i>NOTCH1</i> and <i>NODAL</i> better than the proline variant of codon 72 (P72); therefore, the expression of <i>NOTCH1</i> and <i>NODAL</i> is increased in angiomyolipoma cells that carry R72. The loss of <i>Tp53</i> and <i>Tsc1</i> within nestin-expressing cells in mice resulted in the development of renal cell carcinomas (RCC) with high <i>Notch1</i> and <i>Nodal</i> expression, suggesting that similar downstream mechanisms contribute to tumorigenesis as a result of p53 loss in mice and p53 polymorphism in humans. The loss of murine <i>Tp53</i> or expression of human R72 contributes to tumorigenesis via enhancing epithelial-to-mesenchymal transition and motility of tumor cells through the Notch and Nodal pathways.</p>Implications:<p>This work revealed unexpected contributions of the p53 polymorphism to the pathogenesis of TSC and established signaling alterations caused by this polymorphism as a target for therapy. We found that the codon 72 TP53 polymorphism contributes to TSC-associated tumorigenesis via Notch and Nodal signaling.</p></div>