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Drosophila p53 controls Notch expression and balances apoptosis and proliferation

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Abstract

A balance between cell proliferation and apoptosis is important for normal development and tissue homeostasis. Under stress conditions, the conserved tumor suppressor and transcription factor Dp53 induces apoptosis to contribute to the maintenance of homeostasis. However, in some cases Dp53-induced apoptosis results in the proliferation of surrounding non-apoptotic cells. To gain insight into the Dp53 function in the control of apoptosis and proliferation, we studied the interaction between the Drosophila Dp53 and Notch genes. We present evidence that simultaneous reduction of Dp53 and Notch function synergistically increases the wing phenotype of Notch heterozygous mutant flies. Further, we found that a Notch cis-regulatory element is responsive to loss and gain of Dp53 function and that over-expression of Dp53 up-regulates Notch mRNA and protein expression. These findings suggest not only that Dp53 and Notch act together to control wing development but also indicate that Dp53 transcriptionally regulates Notch expression. Moreover, using Notch  gain and loss of function mutations we examined the relevance of Dp53 and Notch interactions in the process of Dp53-apoptosis induced proliferation. Results show that proliferation induced by Dp53 over-expression is dependent on Notch, thus identifying Notch as a new player in Dp53-induced proliferation. Interestingly, we found that Dp53-induced Notch activation and proliferation occurs even under conditions where apoptosis was inhibited. Our findings highlight the conservation between flies and vertebrates of the Dp53 and Notch cross-talk and suggest that Dp53 has a dual role regulating cell death and proliferation gene networks to control the homeostatic balance between apoptosis and proliferation.

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Acknowledgments

We thank our colleagues Sol Fereres and Carolina Simoes da Silva for fruitful discussions and Keith Harshman for carefully reading the manuscript. We thank the Consolider Drosophila facility, the Bloomington Stock Center, the TRiP at Harvard Medical School (NIH/NIGMS R01-GM084947) and the Vienna Drosophila RNAi Center for providing stocks. We also thank the Developmental Hybridoma Bank, University of Iowa, for providing antibodies and Herman Steller for the anti-DIAP1 antibody. This work was supported by grants from the Dirección General de Investigación (BFU2008-01154) to A.B, the Consolider Ingenio 2010 Program of the Ministerio de Ciencia e Innovación (CSD 2007-00008) to A.B., and by an institutional grant to the Centro de Biología Molecular Severo Ochoa from the Fundación Ramón Areces, and by an MRC programme grant to S.J.B.

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  1. Centro de Biología Molecular “Severo Ochoa”, CSIC-UAM, c) Nicolás Cabrera 1, 28049, Madrid, Spain

    Rocío Simón, Ricardo Aparicio & Ana Busturia

  2. Department of Physiology Development and Neuroscience, University of Cambridge, Downing Street, Cambridge, CB2 3DY, UK

    Ben E. Housden & Sarah Bray

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  1. Rocío Simón
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Correspondence to Ana Busturia.

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Simón, R., Aparicio, R., Housden, B.E. et al. Drosophila p53 controls Notch expression and balances apoptosis and proliferation. Apoptosis 19, 1430–1443 (2014). https://doi.org/10.1007/s10495-014-1000-5

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