dp53 Restrains Ectopic Neural Stem Cell Formation in the Drosophila Brain in a Non-Apoptotic Mechanism Involving Archipelago and Cyclin E

Abstract

Accumulating evidence suggests that tumor-initiating stem cells or cancer stem cells (CSCs) possibly originating from normal stem cells may be the root cause of certain malignancies. How stem cell homeostasis is impaired in tumor tissues is not well understood, although certain tumor suppressors have been implicated. In this study, we use the Drosophila neural stem cells (NSCs) called neuroblasts as a model to study this process. Loss-of-function of Numb, a key cell fate determinant with well-conserved mammalian counterparts, leads to the formation of ectopic neuroblasts and a tumor phenotype in the larval brain. Overexpression of the Drosophila tumor suppressor p53 (dp53) was able to suppress ectopic neuroblast formation caused by numb loss-of-function. This occurred in a non-apoptotic manner and was independent of Dacapo, the fly counterpart of the well-characterized mammalian p53 target p21 involved in cellular senescence. The observation that dp53 affected Edu incorporation into neuroblasts led us to test the hypothesis that dp53 acts through regulation of factors involved in cell cycle progression. Our results show that the inhibitory effect of dp53 on ectopic neuroblast formation was mediated largely through its regulation of Cyclin E (Cyc E). Overexpression of Cyc E was able to abrogate dp53′s ability to rescue numb loss-of-function phenotypes. Increasing Cyc E levels by attenuating Archipelago (Ago), a recently identified transcriptional target of dp53 and a negative regulator of Cyc E, had similar effects. Conversely, reducing Cyc E activity by overexpressing Ago blocked ectopic neuroblast formation in numb mutant. Our results reveal an intimate connection between cell cycle progression and NSC self-renewal vs. differentiation control, and indicate that p53-mediated regulation of ectopic NSC self-renewal through the Ago/Cyc E axis becomes particularly important when NSC homeostasis is perturbed as in numb loss-of-function condition. This has important clinical implications.

A novel Fizzy/Cdc20-dependent mechanism suppresses necrosis in neural stem cells

“…A previous study showed that overexpression of p53 can suppress the supernumerary neuroblast phenotype induced by loss of numb function in the absence of caspase activation (Ouyang et al, 2011). This study also showed that co-expression of Cyclin E can abolish the suppressive effect of the overexpression of p53 on the supernumerary neuroblast phenotype in numb mutant clones.…”

“…Brain neuroblasts appear incapable of undergoing apoptosis during larval development as the Polycomb proteins actively silence the apoptotic genes (Bello et al, 2007;Siegrist et al, 2010). Consistently, overexpression of p53 reduces the total number of larval brain neuroblasts in the absence of caspase activation (Ouyang et al, 2011). Thus, fly larval brain neuroblasts provide a unique system for discovering genes that elicit an alternative cell death modality in a stem cell type that is apoptosis deficient.…”

The function of Drosophila p53 isoforms in apoptosis

“…The p53B isoform may also participate in other processes that Drosophila p53 has been implicated in, which include the culling of primordial germ cells, meiotic checkpoints, DNA repair, stem cell divisions, and tissue regeneration. 41,[60][61][62][63][64][65][66][67][68][69] Our results indicate that p53A and p53B localize to nuclear bodies and physically associate, an interaction that is likely direct through the conserved p53 oligomerization domain. Therefore, p53 tetramers may be heterogeneous and have different ratios of p53A and p53B subunits.…”

Stem Cells and Asymmetric Cell Division

“…Other well-characterized human tumour suppressors, such as the kinase Lkb1 , whose loss-of-function phenotype results in Peutz-Jeghers syndrome, and p53, regulate cell polarity in worms, fl ies and humans and might be involved in asymmetric cell division as well (Marignani 2005 ;Cicalese et al 2009 ;Ouyang et al 2011b ). Thus, similar to the situation in Drosophila , asymmetric cell division in mammals appears to be involved in the regulation of stem and progenitor cell self-renewal, and the regulation of cell cycle progression and growth control.…”