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"Dean, D C"
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Control of glutamine metabolism by the tumor suppressor Rb
Retinoblastoma (Rb) protein is a tumor suppressor that is dysregulated in a majority of human cancers. Rb functions to inhibit cell cycle progression in part by directly disabling the E2F family of cell cycle-promoting transcription factors. Because the
de novo
synthesis of multiple glutamine-derived anabolic precursors is required for cell cycle progression, we hypothesized that Rb also may directly regulate proteins involved in glutamine metabolism. We examined glutamine metabolism in mouse embryonic fibroblasts (MEFs) isolated from mice that have triple knock-outs (TKO) of all three Rb family members (Rb-1, Rbl1 and Rbl2) and found that loss of global Rb function caused a marked increase in
13
C-glutamine uptake and incorporation into glutamate and tricarboxylic acid cycle (TCA) intermediates in part via upregulated expression of the glutamine transporter ASCT2 and the activity of glutaminase 1 (GLS1). The Rb-controlled transcription factor E2F-3 altered glutamine uptake by direct regulation of ASCT2 mRNA and protein expression, and E2F-3 was observed to associate with the ASCT2 promoter. We next examined the functional consequences of the observed increase in glutamine uptake and utilization and found that glutamine exposure potently increased oxygen consumption, whereas glutamine deprivation selectively decreased ATP concentration in the Rb TKO MEFs but not the wild-type (WT) MEFs. In addition, TKO MEFs exhibited elevated production of glutathione from exogenous glutamine and had increased expression of gamma-glutamylcysteine ligase relative to WT MEFs. Importantly, this metabolic shift towards glutamine utilization was required for the proliferation of Rb TKO MEFs but not for the proliferation of the WT MEFs. Last, addition of the TCA cycle intermediate α-ketoglutarate to the Rb TKO MEFs reversed the inhibitory effects of glutamine deprivation on ATP, GSH levels and viability. Taken together, these studies demonstrate that the Rb/E2F cascade directly regulates a major energetic and anabolic pathway that is required for neoplastic growth.
Journal Article
Mapping White Matter Microstructure in the One Month Human Brain
White matter microstructure, essential for efficient and coordinated transmission of neural communications, undergoes pronounced development during the first years of life, while deviations to this neurodevelopmental trajectory likely result in alterations of brain connectivity relevant to behavior. Hence, systematic evaluation of white matter microstructure in the normative brain is critical for a neuroscientific approach to both typical and atypical early behavioral development. However, few studies have examined the infant brain in detail, particularly in infants under 3 months of age. Here, we utilize quantitative techniques of diffusion tensor imaging and neurite orientation dispersion and density imaging to investigate neonatal white matter microstructure in 104 infants. An optimized multiple b-value diffusion protocol was developed to allow for successful acquisition during non-sedated sleep. Associations between white matter microstructure measures and gestation corrected age, regional asymmetries, infant sex, as well as newborn growth measures were assessed. Results highlight changes of white matter microstructure during the earliest periods of development and demonstrate differential timing of developing regions and regional asymmetries. Our results contribute to a growing body of research investigating the neurobiological changes associated with neurodevelopment and suggest that characteristics of white matter microstructure are already underway in the weeks immediately following birth.
Journal Article
Mechanism of active transcriptional repression by the retinoblastoma protein
THE retinoblastoma tumour-suppressor protein (Rb) belongs to a family that share a motif known as the pocket. The pocket was originally identified as the region of Rb required for binding to oncoproteins from DNA tumour viruses
1,2
, which disrupt the binding of Rb to the E2F family of cell-cycle transcription factors (referred to collectively here as E2F)
3
. Rb switches E2F sites from positive to negative elements
4
, suggesting that Rb–E2F is an active complex that blocks transcription. Here we report that Rb is selectively recruited to promoters through E2F, where it in turn inactivates surrounding transcription factors by blocking their interaction with the basal transcription complex. We suggest that this represser activity is essential for inhibiting promoters that contain enhancers in addition to E2F sites.
Journal Article
Rb function in cell-cycle regulation and apoptosis
Loss of cell-cycle control is a hallmark of neoplastic cells. One regulator of the critical G1 to S-phase transition in the cell cycle is the retinoblastoma tumour suppressor protein Rb, which interacts with the E2F family of cell-cycle transcription factors to repress gene transcription required for this transition. Through its interaction with E2F, Rb also regulates genes that control apoptosis. Here we review the roles of Rb in regulating the cell cycle and apoptosis and discuss recent results linking these Rb functions to chromatin-remodelling enzymes.
Journal Article
ZEB Represses Transcription Through Interaction with the Corepressor CtBP
ZEB is an active transcriptional repressor that regulates lymphocyte and muscle differentiation in vertebrates. Its homologue in Drosophila (zfh-1) is also essential for differentiation of somatic and cardiac muscle. Here, we demonstrate that ZEB and zfh-1 interact with the corepressor CtBP to repress transcription. ZEB and zfh-1, both contain the sequence PLDLS in the same region of the repressor domain, and we demonstrate that this sequence binds CtBP-1 and -2. In vertebrate species, ZEB contains two additional CtBP-like binding sites (variations of the PLDLS sequence) that also bind CtBP proteins and are required for full repressor activity. The three sites have an additive effect, and mutation of all three sites is necessary to abolish both binding to CtBP and repressor activity. Finally, we demonstrate that the interaction of CtBP with ZEB at the promoter is necessary for repressor activity.
Journal Article
Vascular Cell Adhesion Molecule 1: Contrasting Transcriptional Control Mechanisms in Muscle and Endothelium
Interaction between vascular cell adhesion molecule 1 (VCAM-1), which appears on the surface of endothelial cells in response to inflammation, and its integrin counter receptor, α 4β 1, on immune cells is responsible for targeting these immune cells to cytokine-stimulated endothelium. In addition to its role in the immune system, VCAM-1 is also expressed in a developmentally specific pattern on differentiating skeletal muscle, where it mediates cell-cell interactions important for myogenesis through interaction with α 4β 1. In contrast to endothelium, there is high basal expression of VCAM-1 in skeletal muscle cells and the expression is not cytokine-responsive. Here, we examine the molecular basis for these contrasting patterns of expression in muscle and endothelium, using VCAM-1 promoter constructs in a series of transfection assays. In endothelial cells, octamer binding sites act as silencers that prevent VCAM-1 expression in unstimulated cells. Tumor necrosis factor α overcomes the negative effects of these octamers and activates the promoter through two adjacent NF-κ B binding sites. In muscle cells, a position-specific enhancer located between bp -21 and -5 overrides the effect of other promoter elements, resulting in constitutive VCAM-1 expression. A nuclear protein binds the position-specific enhancer in muscle but not endothelial cells; thus the pattern of expression of this protein could control enhancer activity.
Journal Article
Differential Expression and Function of Members of the zfh-1 Family of Zinc Finger/Homeodomain Repressors
zfh-1 is a zinc finger/homeodomain transcriptional repressor in Drosophila that regulates differentiation of muscle and gonadal cells and is also expressed in the central nervous system (CNS). Binding sites for zfh-1 overlap with those for snail, and like snail, it recruits the corepressor CtBP-1. The protein ZEB-1 appears to be a vertebrate homologue of zfh-1 and is expressed in several tissues including muscle, CNS, and T lymphocytes, and during skeletal differentiation. Mutation of the ZEB-1 gene led to a severe T cell phenotype and skeletal defects but, interestingly, no defects were evident in other ZEB-1-expressing tissues. These results suggested that another ZEB-1-related factor may compensate for the loss of ZEB-1 in other tissues. Here, we characterize such a ZEB-1-related protein, which we have termed as ZEB-2. The overall organization of ZEB-2 is similar to ZEB-1 and zfh-1 and it has similar biochemical properties: it binds E boxes and interacts with CtBP-1 to repress transcription. However, there are also differences between ZEB-1 and ZEB-2, both in activity and tissue distribution. Whereas ZEB-1 and ZEB-2 overlap in skeletal muscle and CNS (providing an explanation for why mutation of ZEB-1 alone has little effect in these tissues), they show a different pattern of expression in lymphoid cells. ZEB-1, but not ZEB-2, is expressed in T cells from the thymus ZEB-2 appears to be expressed on splenic B cells. Additionally, ZEB-2 inhibits a wider spectrum of transcription factors than ZEB-1.
Journal Article
Rb-mediated chromatin structure regulation and transcriptional repression
ONCOGENE: (2001) 20, 3134-3138.
Journal Article
Retinoblastoma protein switches the E2F site from positive to negative element
ORIGINALLY E2F sites were identified as elements in the promoters of adenovirus early genes that are necessary for activation of these genes by the early protein E1a (ref. 1). E2F promoter elements have been shown to be important for transcriptional activation of several genes critical for progression through the cell cycle
2
–
4
. During the G1 phase of the cell cycle, the E2F protein forms a complex with the cell-cycle protein Rb (ref. 5) and it has been suggested that this binding of Rb to E2F inactivates E2F (
ref
. 5). Here we show that Rb-E2F is an active complex that, when bound to the E2F site, inhibits the activity of other promoter elements and thus silences transcription. We propose that the ability of this complex to inhibit transcription is integral to the function of Rb and provide evidence that E2F is a positive element in the absence of an active form of Rb. It has been shown that binding of Rb to E2F depends on the phosphorylation state of Rb (only the underphosphorylated form binds)
5
and that the phosphorylation state of Rb changes during progression through the cell cycle
6,7
. We therefore suggest that the E2F site alternates between a positive and negative element with the phosphorylation/dephosphorylation cycle of Rb. This cyclic activity may be responsible for activating and then inhibiting genes during the cell cycle.
Journal Article