title: 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. 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.
authors.affiliation: Yale Stem Cell Center and Department of Cell Biology, Yale School of Medicine, New Haven, CT 06519, USA.
authors.forename: Dong
authors.initials: D
authors.lastname: Chen
authors.forename: Wei
authors.initials: W
authors.lastname: Zheng
authors.forename: Aiping
authors.initials: A
authors.lastname: Lin
authors.forename: Katherine
authors.initials: K
authors.lastname: Uyhazi
authors.forename: Hongyu
authors.initials: H
authors.lastname: Zhao
authors.forename: Haifan
authors.initials: H
authors.lastname: Lin
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000502:physiology; D002453:Cell Cycle / Q000235:genetics; D005298:Fertility; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D020928:Mitogen-Activated Protein Kinases; D009845:Oligospermia; D012323:RNA Processing, Post-Transcriptional / Q000502:physiology; D012333:RNA, Messenger / Q000378:metabolism; D016601:RNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D013076:Sperm Count; D013091:Spermatogenesis / Q000502:physiology*; D013094:Spermatozoa / Q000166:cytology / Q000378:metabolism; D013737:Testis / Q000166:cytology; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*
chemical_list: D012333:RNA, Messenger; D016601:RNA-Binding Proteins; D016159:Tumor Suppressor Protein p53; D020928:Mitogen-Activated Protein Kinases