Drosophila p53 controls Notch expression and balances apoptosis and proliferation

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.

p53 Isoforms: Key Regulators of the Cell Fate Decision

“…However, its physiological activity is not limited to apoptotic pathways. Recent studies unravel the primordial roles of Drosophila p53 protein isoforms in tissue regeneration by directly controlling apoptosis-induced proliferation (AiP), compensatory proliferation (CP), cell differentiation, organ size, system growth, and cell competition (Peterson et al 2002;Jassim et al 2003;Wells et al 2006;Stieper et al 2008;Mendes et al 2009;Fan et al 2010;Mesquita et al 2010;Morata et al 2011;Wells and Johnston 2012;de la Cova et al 2014;Simó n et al 2014). This is consistent with Dmp53 being involved in life-span control (Bauer et al 2005(Bauer et al , 2010Waskar et al 2009; for review, see Martín et al 2009;Kashio et al 2014;Mollereau and Ma 2014).…”

“…However, p53-null mutation leads to complete loss of p53 protein expression and, thus, p53 activity, whereas missense mutation leads to overexpression of mutant p53 proteins that are biochemically and biologically very active as they directly interact with numerous proteins modifying, thus, gene expression and cell responses. p53-null mutation can lead to different phenotypes than missense p53 mutation as shown in Drosophila and mammalian models (Brodsky et al 2000;Ollmann et al 2000;Jassim et al 2003;Lang et al 2004;Olive et al 2004;Wells et al 2006;de la Cova et al 2014;Simó n et al 2014) The Dmp53 gene is involved in apoptosis through the Reaper-Hid-Grim cascade by directly regulating Reaper expression in response to damage (Brodsky et al 2000(Brodsky et al , 2004. However, its physiological activity is not limited to apoptotic pathways.…”

“…Thus, at the same time that the stress event eliminates a large number of cells, it also generates a stimulus to proliferation. AiP is directly controlled by Dmp53 (Wells et al 2006;Dichtel-Danjoy et al 2013;Simó n et al 2014). Both DTAp53 and DDNp53 protein isoforms were capable of activating apoptosis but they used different molecular mechanisms.…”

Programmable RNA Targeting using CasRx in Flies

“…S3 A,C). This was expected for N as there are many examples of lethal alleles for this gene [35][36][37], however mutations in y should be recessive viable with defective chitin pigmentation producing yellow cuticle phenotypes [38]. Furthermore, we were unable to obtain phenotypes in transheterozygotes (Ubiq-dCasRx/+; gRNA array /+) from our negative control crosses using all arrays tested, indicating that a catalytically active form of the ribonuclease is necessary for phenotypes to be observed (Fig.…”

Spreading the word: non-autonomous effects of apoptosis during development, regeneration and disease

“…For example, the Drosophila EGF ligand Spitz has been identified as a key signal regulating the overgrowths produced by undead cells and the tissue recovery after induction of cell death in the eye imaginal disc (Fan et al, 2014). In addition, Simon et al (2014) uncovered a role for Notch as a target of p53 involved in apoptosis-induced proliferation in Drosophila wing discs. Genes controlling apicobasal polarity and the Hippo pathway have also been implicated in the proliferative response triggered by dying cells (Grusche et al, 2011;Sun and Irvine, 2011;Warner et al, 2010;Sun and Irvine, 2013).…”