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Polycomb group proteins are essential regulators of stem cell function during embryonic development and in adult tissue homeostasis. Bmi1, a key component of the Polycomb Repressive Complex 1, is highly expressed in undifferentiated neural stem cells (NSC) as well as in several human cancers including high-grade gliomas—highly aggressive brain tumors. Using a conditional gene activation approach in mice, we show that overexpression of Bmi1 induces repressive epigenetic regulation of the promoter of Survivin, a well-characterized antiapoptotic protein. This phenomenon is cell type-specific and it leads to apoptotic death of progenitor cells exclusively upon commitment toward a neuronal fate. Moreover, we show that this is triggered by increased oxidative stress-induced DNA damage. In contrast, undifferentiated NSC as well as glioma-initiating cells display an open chromatin configuration at the Survivin promoter and do not undergo apoptotic death. These findings raise the possibility that normal and neoplastic stem cells depend on the same mechanism for surviving the hyperproliferative state induced by increased Bmi1 expression.

Alterations of mitochondrial metabolism and genomic instability have been implicated in tumorigenesis in multiple tissues. High-grade glioma (HGG), one of the most lethal human neoplasms, displays genetic modifications of Krebs cycle components as well as electron transport chain (ETC) alterations. Furthermore, the p53 tumor suppressor, which has emerged as a key regulator of mitochondrial respiration at the expense of glycolysis, is genetically inactivated in a large proportion of HGG cases. Therefore, it is becoming evident that genetic modifications can affect cell metabolism in HGG; however, it is currently unclear whether mitochondrial metabolism alterations could vice versa promote genomic instability as a mechanism for neoplastic transformation. Here, we show that, in neural progenitor/stem cells (NPCs), which can act as HGG cell of origin, inhibition of mitochondrial metabolism leads to p53 genetic inactivation. Impairment of respiration via inhibition of complex I or decreased mitochondrial DNA copy number leads to p53 genetic loss and a glycolytic switch. p53 genetic inactivation in ETC-impaired neural stem cells is caused by increased reactive oxygen species and associated oxidative DNA damage. ETC-impaired cells display a marked growth advantage in the presence or absence of oncogenic RAS, and form undifferentiated tumors when transplanted into the mouse brain. Finally, p53 mutations correlated with alterations in ETC subunit composition and activity in primary glioma-initiating neural stem cells. Together, these findings provide previously unidentified insights into the relationship between mitochondria, genomic stability, and tumor suppressive control, with implications for our understanding of brain cancer pathogenesis.

Over the past decade, our understanding of apoptosis, or programmed cell death, has increased greatly, with the identification of some of the major components of the apoptotic programme and the processes regulating their activation. Although apoptosis is an intrinsic process present in all cells, it can be regulated by extrinsic factors, including hormones, growth factors, cell surface receptors, and cellular stress. The actions of both pro- and antiapoptotic factors are often affected by modulation of the phosphorylation status of key elements of the apoptotic process. This minireview will focus on the role of protein kinases in apoptosis. Apoptosis is a multistep process and protein kinases have been implicated both in the upstream induction phase of apoptosis and in the downstream execution stage, as the direct targets for caspases. Due to the space constraints of this review it is not possible to discuss all of the kinases involved in the apoptotic process and we have focused here on the role of the serine/threonine protein kinases. The kinases of this family that have been suggested to play a role in apoptosis are the mitogen-activated protein kinase (MAPK) family, specifically p42/44 ERK, p38 MAPK and c-Jun N-terminal kinase (JNK), cyclic AMP-dependent protein kinase (PKA), protein kinase B (PKB), or Akt and protein kinase C (PKC). We have also considered briefly the potential for the regulation of these kinases by tyrosine protein kinases, such as c-abl.

BACKGROUND: A key challenge in determining the cellular origin of brain tumours is the identification and selective targeting of a biological relevant stem and progenitor population. Established approaches use cre mediated recombination of tumour suppressor genes, using constitutively expressed, inducible or topically administered cre expression. We have previously induced oligoastrocytomas by intraventricular injection of adenovirus expressing cre into mice carrying combinations of multiple floxed tumour suppressor genes (PTEN, p53, Rb) (1, 2). Here we set out to develop a targeted, temporally controlled approach to recombine specific subsets of progenitors in the stem cell compartment of the SVZ, whilst preventing widespread recombination of common inducible models (GFAP-Cre (ER(T), Nestin-Cre ER(T) and similar models (3)). METHODS: We developed a novel approach of gene recombination in a specific SVZ target cell. We used GLAST cre ER(T); PTENlox/lox;p53lox/lox mice, but instead of intraperitoneally injecting Tamoxifen, which leads to a widespread recombination of CNS astrocytes, and other cells (4) we injected the active compound 4OH-Tamoxifen directly into the ventricles. RESULTS: Direct intraventricular administration of 4OH-Tamoxifen into the cerebral ventricles of GLAST-CreER(T) mice successfully recombines tumour suppressor genes in GLAST expressing SVZ B-type stem cells. Recombination occurs proportionally to the 4OH-Tamoxifen dose. Resulting brain tumours, occurring at a frequency similar to that in Adeno-cre injected controls corresponded phenotypically to gliomas with a spectrum ranging from astrocytic to oligodendroglial tumours. CONCLUSIONS: We have developed a novel method to selectively recombine genetically defined cell populations, B-type SVZ stem cells, and have successfully elicited intrinsic brain tumours. Frequency and phenotypic spectrum of these tumours is similar to that induced by intraventricular adenovirus injections. The phenotype is also similar to those achieved by systemic tamoxifen injections, which achieve higher tumour frequencies (3) albeit using different promoters. We conclude that highly selective targeting of specific SVZ stem cell population is not essential to generate an effective model system for brain tumours. This conclusion has important implications for the development of biologically relevant brain tumour models. References: 1. N. V. Henriquez et al., Cancer Res, (Jul 25, 2013).2. T. S. Jacques et al., EMBO J 29, 222 (Jan 6, 2010).3. L. M. Chow et al., Cancer Cell 19, 305 (Mar 8, 2011).4. T. Mori et al., Glia 54, 21 (Jul, 2006). SECONDARY CATEGORY: Tumor Biology.