Pumilio 1 Suppresses Multiple Activators of p53 to Safeguard Spermatogenesis

Abstract

During spermatogenesis, germ cells initially expand exponentially through mitoses. A majority of these cells are then eliminated through p53-mediated apoptosis to maintain germline homeostasis [ 1 Yin Y. Stahl B.C. DeWolf W.C. Morgentaler A. P53 and Fas are sequential mechanisms of testicular germ cell apoptosis. J. Androl. 2002; 23 : 64-70 PubMed Google Scholar , 2 Russell L.D. Chiarini-Garcia H. Korsmeyer S.J. Knudson C.M. Bax-dependent spermatogonia apoptosis is required for testicular development and spermatogenesis. Biol. Reprod. 2002; 66 : 950-958 Crossref PubMed Scopus (167) Google Scholar , 3 Knudson C.M. Tung K.S. Tourtellotte W.G. Brown G.A. Korsmeyer S.J. Bax-deficient mice with lymphoid hyperplasia and male germ cell death. Science. 1995; 270 : 96-99 Crossref PubMed Scopus (1255) Google Scholar , 4 Beumer T.L. Roepers-Gajadien H.L. Gademan I.S. van Buul P.P. Gil-Gomez G. Rutgers D.H. de Rooij D.G. The role of the tumor suppressor p53 in spermatogenesis. Cell Death Differ. 1998; 5 : 669-677 Crossref PubMed Scopus (169) Google Scholar ]. However, the activity of p53 must be precisely modulated, especially suppressed in postmitotic spermatogenic cells, to guarantee robustness of spermatogenesis. Currently, how the suppression is achieved is not understood. Here, we show that Pumilio 1, a posttranscriptional regulator, binds to mRNAs representing 1,527 genes, with significant enrichment for mRNAs involved in pathways regulating p53, cell cycle, and MAPK signaling. In particular, eight mRNAs encoding activators of p53 are repressed by Pumilio 1. Deleting Pumilio 1 results in strong activation of p53 and apoptosis mostly in spermatocytes, which disrupts sperm production and fertility. Removing p53 reduces apoptosis and rescues testicular hypotrophy in Pumilio 1 null mice. These results indicate that key components of the p53 pathway are coordinately regulated by Pumilio 1 at the posttranscriptional level, which may exemplify an RNA operon.