He, S. et al. Bmi-1 over-expression in neural stem/progenitor cells increases proliferation and neurogenesis in culture but has little effect on these functions in vivo. Dev. Biol. 328, 257-272

Howard Hughes Medical Institute, Department of Internal Medicine, Center for Stem Cell Biology, University of Michigan, 5435 Life Sciences Institute, 210 Washtenaw Ave., Ann Arbor, MI 48109-2216, USA.
Developmental Biology (Impact Factor: 3.55). 02/2009; 328(2):257-72. DOI: 10.1016/j.ydbio.2009.01.020
Source: PubMed


The polycomb gene Bmi-1 is required for the self-renewal of stem cells from diverse tissues, including the central nervous system (CNS). Bmi-1 expression is elevated in most human gliomas, irrespective of grade, raising the question of whether Bmi-1 over-expression is sufficient to promote self-renewal or tumorigenesis by CNS stem/progenitor cells. To test this we generated Nestin-Bmi-1-GFP transgenic mice. Analysis of two independent lines with expression in the fetal and adult CNS demonstrated that transgenic neural stem cells formed larger colonies, more self-renewing divisions, and more neurons in culture. However, in vivo, Bmi-1 over-expression had little effect on CNS stem cell frequency, subventricular zone proliferation, olfactory bulb neurogenesis, or neurogenesis/gliogenesis during development. Bmi-1 transgenic mice were born with enlarged lateral ventricles and a minority developed idiopathic hydrocephalus as adults, but none of the transgenic mice formed detectable CNS tumors, even when aged. The more pronounced effects of Bmi-1 over-expression in culture were largely attributable to the attenuated induction of p16(Ink4a) and p19(Arf) in culture, proteins that are generally not expressed by neural stem/progenitor cells in young mice in vivo. Bmi-1 over-expression therefore has more pronounced effects in culture and does not appear to be sufficient to induce tumorigenesis in vivo.

Download full-text


Available from: Johanna Buchstaller,
    • "When the production of ROS/RNS exceeds the endogenous antioxidant buffering capacity, oxidative stress-induced cellular damage occurs. There is increasing evidence that oxidative stress level is elevated in diseases such as DMD and in normal aging (Fulle et al., 2004; Whitehead et al., 2006; Jackson, 2009; Cozzoli et al., 2011; Spassov et al., 2011). Bmi1 has an important role in mitochondrial function and redox homeostasis in thymocytes and in neurons (Liu et al., 2009; Abdouh et al., 2012); however, the mechanisms mediating this role of Bmi1 are currently unclear. "
    [Show abstract] [Hide abstract]
    ABSTRACT: The Polycomb group (PcG) protein Bmi1 is an essential epigenetic regulator of stem cell function during normal development and in adult organ systems. We show that mild up-regulation of Bmi1 expression in the adult stem cells of the skeletal muscle leads to a remarkable improvement of muscle function in a mouse model of Duchenne muscular dystrophy. The molecular mechanism underlying enhanced physiological function of Bmi1 depends on the injury context and it is mediated by metallothionein 1 (MT1)-driven modulation of resistance to oxidative stress in the satellite cell population. These results lay the basis for developing Bmi1 pharmacological activators, which either alone or in combination with MT1 agonists could be a powerful novel therapeutic approach to improve regeneration in muscle wasting conditions. © 2014 Di Foggia et al.
    Journal of Experimental Medicine 12/2014; 211(13):2617. DOI:10.1083/jcb.2075OIA222 · 12.52 Impact Factor
  • Source
    • "Bmi-1 has been reported as an oncogene that controls cell proliferation and invasion (29). Furthermore, Bmi-1 is also involved in the self-renewal of cancer stem cells, which may result in tumor initiation (30,31). In the present study, Bmi-1 was found to be significantly overexpressed in the gastric cancer tissues and cell lines compared with the adjacent normal tissues and GES-1 normal gastric epithelial cells, respectively. "
    [Show abstract] [Hide abstract]
    ABSTRACT: The aberrant expression of microRNA-183 (miRNA/miR-183) has been found to be involved in numerous tumor types. However, the role of miR-183 in gastric cancer pathology is unclear and requires investigation. In the present study, the miR-183 expression levels of gastric cancer cell lines and tissues obtained from gastric cancer patients were measured by reverse transcription quantitative polymerase chain reaction analysis. The effect of miR-183 on gastric cancer cell proliferation and invasion was evaluated using MTT, colony formation and Transwell assays. The target of miR-183 was identified and confirmed using a luciferase activity assay. The results revealed that miR-183 was significantly downregulated in gastric cancer cells compared with GES-1 normal gastric epithelial cells. In addition, miR-183 was reduced in gastric cancer tissues compared with adjacent normal tissues. The ectopic expression of miR-183 significantly inhibited gastric cancer cell proliferation, colony formation and invasion. Bmi-1 was also confirmed as a downstream target of miR-183 in the gastric cancer cells by western blot analysis and luciferase activity assays. In conclusion, miR-183 is downregulated in gastric cancer cells and tissues, and inhibits gastric cancer cell proliferation and invasion by targeting Bmi-1. Therefore, targeting miR-183 may be a potential therapeutic strategy in gastric cancer patients.
    Oncology letters 11/2014; 8(5):2345-2351. DOI:10.3892/ol.2014.2504 · 1.55 Impact Factor
  • Source
    • "However, some studies suggest that such high values of Bmi1 in several tumors are the result of other mutations: when tested in in vivo transgenic mice models (compared to in vitro models), Bmi1 was observed to have a low proliferative effect, a low effect on fetal and adult neurogenesis, and a low effect on glial differentiation. Furthermore, it did not result in an increased capacity for self-renewal and neurogenic potential [105]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Malignant brain tumors, including glioblastoma multiforme (GBM), are known for their high degree of invasiveness, aggressiveness, and lethality. These tumors are made up of heterogeneous cell populations and only a small part of these cells (known as cancer stem cells) is responsible for the initiation and recurrence of the tumor. The biology of cancer stem cells and their role in brain tumor growth and therapeutic resistance has been extensively investigated. Recent work suggests that glial tumors arise from neural stem cells that undergo a defective process of differentiation. The understanding of this process might permit the development of novel treatment strategies targeting cancer stem cells. In the present review, we address the mechanisms underlying glial tumor formation, paying special attention to cancer stem cells and the role of the microenvironment in preserving them and promoting tumor growth. Recent advancements in cancer stem cell biology, especially regarding tumor initiation and resistance to chemo- or radiotherapy, have led to the development of novel treatment strategies that focus on the niche of the stem cells that make up the tumor. Encouraging results from preclinical studies predict that these findings will be translated into the clinical field in the near future.
    03/2014; 2014:438639. DOI:10.1155/2014/438639
Show more