or overexpression of the Max-Planck-Institute for Biochemistry negative regulator Mdm2 (Freedman et al., 1999). For Am Klopferspitz 18a those tumors that retain functional p53 but have ampli-D 82152 Martinsried fication of Mdm2, therapeutic strategies have been Germany developed to inhibit Mdm2, whereby increased p53 2 Department of Genetics protein levels make tumor cells more susceptible to Washington University School of Medicine p53-mediated apoptosis (Chene, 2003; Lain and Lane, 4566 Scott Avenue 2003; Vassilev et al., 2004). Such a therapeutic ap-St. Louis, Missouri 63110 proach highlights the need to uncover additional path-3 Institute for Molecular Biology ways and mechanisms that negatively regulate p53 University of Zürich levels or activity. Winterthurerstrasse 190 Most studies on p53 signaling have been conducted 8057 Zürich in cell culture-based systems, and their translation into Switzerland mouse models is often hampered by the fact that some regulatory mechanisms which exist in tissues and organisms are not present in cell culture and that some Summary
p53 regulators are likely to be essential for organismal viability. C. elegans contains a primordial p53 gene, p53 is a tumor suppressor gene whose regulation is cep-1 (C. elegans p53), that is necessary for DNA damcrucial to maintaining genome stability and for the age-induced apoptosis and acts as a transcription apoptotic elimination of abnormal, potentially cancerfactor (Derry et al., 2001, Schumacher et al., 2001). The predisposing cells. C. elegans contains a primordial apparent absence of an Mdm2 homolog (WormBase p53 gene, cep-1, that acts as a transcription factor website, http://www.wormbase.org), leads to the hynecessary for DNA damage-induced apoptosis. In a pothesis that novel, possibly evolutionarily conserved genetic screen for negative regulators of CEP-1, we mechanisms for negatively regulating cep-1/p53 exist identified a mutation in GLD-1, a translational represin C. elegans. Therefore, we have taken a forward gesor implicated in multiple C. elegans germ cell fate netic approach, an unbiased genetic screen to identify decisions and related to mammalian Quaking pronegative regulators of cep-1/p53, to isolate mutants teins. CEP-1-dependent transcription of proapoptotic with increased apoptosis and upregulated p53 siggenes is upregulated in the gld-1(op236) mutant and naling. an elevation of p53-mediated germ cell apoptosis in In adult hermaphrodite worms, the germline resides response to DNA damage is observed. Further, we dein two U-shaped gonads where different germ cell monstrate that GLD-1 mediates its repressive effect types are spatially arranged in a gradient of maturation, by directly binding to the 3UTR of cep-1/p53 mRNA which includes a distal proliferative stem cell compartand repressing its translation. This study reveals that ment, entry into meiotic prophase that coincides with the regulation of cep-1/p53 translation influences the early stages of meiotic chromosome pairing (transi-DNA damage-induced apoptosis and demonstrates tion zone), and the various subsequent stages of meithe physiological importance of this mechanism. otic prophase, early and late pachytene, as well as diplotene and diakinesis that go hand in hand with oocyte Introduction growth and differentiation (Figure 5A, top panel; Hubbard and Greenstein, 2000; Seydoux and Schedl, 2001). The central role of p53 as a tumor suppressor is de-The organization of the hermaphrodite germline is remimonstrated by the fact that most human cancers niscent of mammalian male germline development and evolve ways to evade p53 tumor suppressor activity, may involve similar regulatory mechanisms (Tunquist particularly its transcriptional activation function (Roeand Maller, 2003), and pachytene cells can undergo mer, 1999; Pierotti and Dragani, 1992; Vogelstein et al., apoptotic demise that often involves p53 signaling (Cohen and Pollard, 2001; Cooke and Saunders, 2002;