Cam Hakan, Griesmann Heidi, Beitzinger Michaela, Hofmann Lars, Beinoraviciute-Kellner Rasa, Sauer Markus, Hüttinger-Kirchhof Nicole, Oswald Claudia, Friedl Peter, Gattenlöhner Stefan, Burek Christof, Rosenwald Andreas, Stiewe Thorsten
Molecular Tumor Biology Group, Rudolf-Virchow-Center, DFG Research Center for Experimental Biomedicine, University of Würzburg, 97078 Würzburg, Germany.
Cancer Cell. 2006 Oct;10(4):281-93. doi: 10.1016/j.ccr.2006.08.024.
The p53 family comprises the tumor suppressor p53 and the structural homologs p63 and p73. How the three family members cooperate in tumor suppression remains unclear. Here, we report different but complementary functions of the individual members for regulating retinoblastoma protein (RB) function during myogenic differentiation. Whereas p53 transactivates the retinoblastoma gene, p63 and p73 induce the cyclin-dependent kinase inhibitor p57 to maintain RB in an active, hypophosphorylated state. DeltaNp73 inhibits these functions of the p53 family in differentiation control, prevents myogenic differentiation, and enables cooperating oncogenes to transform myoblasts to tumorigenicity. DeltaNp73 is frequently overexpressed in rhabdomyosarcoma and essential for tumor progression in vivo. These findings establish differentiation control as a key tumor suppressor activity of the p53 family.
p53家族由肿瘤抑制因子p53及其结构同源物p63和p73组成。这三个家族成员如何协同发挥肿瘤抑制作用尚不清楚。在此，我们报道了各个成员在成肌分化过程中调节视网膜母细胞瘤蛋白（RB）功能时具有不同但互补的功能。p53可反式激活视网膜母细胞瘤基因，而p63和p73则诱导细胞周期蛋白依赖性激酶抑制剂p57，以使RB维持在活性、低磷酸化状态。DeltaNp73在分化控制中抑制p53家族的这些功能可阻止成肌分化，并使协同致癌基因将成肌细胞转化为具有致瘤性。DeltaNp73在横纹肌肉瘤中经常过度表达，并且对体内肿瘤进展至关重要。这些发现确立了分化控制是p53家族关键的肿瘤抑制活性。
