Increased centrosome amplification in aged stem cells of the Drosophila midgut

Abstract

Age-related changes in long-lived tissue-resident stem cells may be tightly linked to aging and age-related diseases such as cancer. Centrosomes play key roles in cell proliferation, differentiation and migration. Supernumerary centrosomes are known to be an early event in tumorigenesis and senescence. However, the age-related changes of centrosome duplication in tissue-resident stem cells in vivo remain unknown. Here, using anti-γ-tubulin and anti-PH3, we analyzed mitotic intestinal stem cells with supernumerary centrosomes in the adult Drosophila midgut, which may be a versatile model system for stem cell biology. The results showed increased centrosome amplification in intestinal stem cells of aged and oxidatively stressed Drosophila midguts. Increased centrosome amplification was detected by overexpression of PVR, EGFR, and AKT in intestinal stem cells/enteroblasts, known to mimic age-related changes including hyperproliferation of intestinal stem cells and hyperplasia in the midgut. Our data show the first direct evidence for the age-related increase of centrosome amplification in intestinal stem cells and suggest that the Drosophila midgut is an excellent model for studying molecular mechanisms underlying centrosome amplification in aging adult stem cells in vivo.

Effects of a novel β–lapachone derivative on Trypanosoma cruzi : Parasite death involving apoptosis, autophagy and necrosis

“…Hydrogen peroxide (Chae et al., 2005) and ROS-mediated autophagy (Pannu et al., 2012) are associated to centrosome amplification. Oxidative stress triggers centrosome amplification in Drosophila cells (Park et al., 2014a, Park et al., 2014b) and takes part in HeLa cells centrosome organization (Bollineni et al., 2014) and human centrin 2 radiolytical oxidation causes centrosome duplication abnormalities (Blouquit et al., 2007). The kDNA alteration of R72-treated parasites maybe caused by the oxidative stress, as the ROS-producing mitochondria are also affected by naphthoquinones (reviewed in Menna-Barreto and de Castro, 2014) and lapachone was shown to affect Crithidia fasciculata kinetoplasts (Biscardi et al., 2001).…”

“…The β-lapachone-mediated ROS production in a catalase-sensitive way triggers autophagic cancer cell death (Bey et al., 2013), as well as programmed necrosis or necroptosis in a mechanism involving receptor interacting protein (RIP)1, PARP-1 and apoptosis-inducing factor (AIF; Park et al., 2014a, Park et al., 2014b). In this regard, it is noteworthy that PARP activity was reported in all T. cruzi developmental stages (Fernández Villamil et al., 2008).…”

Lesion complexity drives age related cancer susceptibility in human mammary epithelial cells

“…If proven, the fact that abnormal centrosomes can drive malignant transformation by deregulating asymmetric cell division, an integral property of stem cells, could cause a paradigm shift. Increased centrosome amplification in aged and oxidatively stressed stem cells in the drosophila mid-gut and its link to polyploidy suggests the mechanism of propagating genome instability in older cells could be by modifying stem cell division in a centrosome dependent manner [53]. …”

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“…ISCs are irregularly arrayed across the basement membrane and surrounded by ECs and visceral muscle [8]. Previous studies have revealed age-related phenotypes of ISCs; ISC hyper-proliferation, DNA damage accumulation, and increased centrosome amplification are associated with intestinal hyperplasia [12][13][14][15]. ISC homeostasis (the balance of proliferation and quiescence) has been known to be regulated by extrinsic factors such as cytokine ligands of Janus kinase (JAK)-signal transducer and activator of transcription (STAT), epidermal growth factor receptor (EGFR), and wingless signaling that are derived from niches, including EC, EB, EE, and visceral muscle [16][17][18][19][20].…”