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Tressel S.L.,Molecular Oncology Research Institute
Methods in molecular biology (Clifton, N.J.) | Year: 2011

G protein-coupled receptors (GPCR) are a superfamily of receptors that are vital in a wide array of physiological processes. Modulation of GPCR signaling has been an intensive area of therapeutic study, mainly due to the diverse pathophysiological significance of GPCRs. Pepducins are cell-penetrating lipidated peptides designed to target the intracellular loops of the GPCR of interest. Pepducins can function as agonists or antagonists of their cognate receptor, making them highly useful compounds for the study of GPCR signaling. Pepducins have been used to control platelet-dependent hemostasis and thrombosis, tumor growth, invasion, and angiogenesis, as well as to improve sepsis outcomes in mice. Pepducins have been successfully designed against a wide variety of GPCRs including the protease-activated receptors (PAR1, 2, 4), the chemokine receptors (CXCR1, 2, 4), the sphingosine-1-phosphate receptor (S1P3), the adrenergic receptor (ADRA1B), and have the potential to help reveal the functions of intractable GPCRs. Pharmacokinetic, pharmacodynamic, and biodistribution studies have showed that pepducins are widely distributed throughout the body except the brain and possess appropriate drug-like properties for use in vivo. Here, we discuss the delivery, pharmacology, and biodistribution of pepducins, as well as the effects of pepducins in models of inflammation, cardiovascular disease, cancer, and angiogenesis. Source

Banerjee P.,Tufts University | deJesus R.,Tufts University | Gjoerup O.,Molecular Oncology Research Institute | Schaffhausen B.S.,Tufts University
PLoS Pathogens | Year: 2013

Correct repair of damaged DNA is critical for genomic integrity. Deficiencies in DNA repair are linked with human cancer. Here we report a novel mechanism by which a virus manipulates DNA damage responses. Infection with murine polyomavirus sensitizes cells to DNA damage by UV and etoposide. Polyomavirus large T antigen (LT) alone is sufficient to sensitize cells 100 fold to UV and other kinds of DNA damage. This results in activated stress responses and apoptosis. Genetic analysis shows that LT sensitizes via the binding of its origin-binding domain (OBD) to the single-stranded DNA binding protein replication protein A (RPA). Overexpression of RPA protects cells expressing OBD from damage, and knockdown of RPA mimics the LT phenotype. LT prevents recruitment of RPA to nuclear foci after DNA damage. This leads to failure to recruit repair proteins such as Rad51 or Rad9, explaining why LT prevents repair of double strand DNA breaks by homologous recombination. A targeted intervention directed at RPA based on this viral mechanism could be useful in circumventing the resistance of cancer cells to therapy. © 2013 Banerjee et al. Source

Corum D.G.,Medical University of South Carolina | Tsichlis P.N.,Molecular Oncology Research Institute | Muise-Helmericks R.C.,Medical University of South Carolina
FASEB Journal | Year: 2014

Our previous work has shown that Akt3 is required for mitochondrial biogenesis in primary human endothelial cells (ECs) and in Akt3-null mice; Akt3 affects subcellular localization of peroxisome proliferator-activated receptor γ coactivator-1 (PGC- 1α), the master regulator of mitochondrial biogenesis. The purpose of this study is to determine the mechanism by which Akt3 controls the subcellular distribution of PGC-1α and to explore the effect on mitochondrial biogenesis and turnover during angiogenesis. Here we use standard biochemical analyses and Akt3-knockdown strategies to show that Akt3 controls the stabilization of chromosome maintenance region-1 (CRM-1), the major nuclear export receptor. Site-directed mutagenesis and association analyses show that PGC-1α nuclear export is CRM-1 dependent. Akt3 knockdown and CRM-1 overexpression cause 3-fold reductions in PGC-1α target gene expression, compared to control levels. Akt3 inhibition causes autophagy, as measured by autophagosome formation, in a CRM-1-dependent, Akt1/ mTOR-independent pathway. In vivo, Akt3-null and heterozygous mice show dose-dependent decreases in angiogenesis compared to wild-type littermates (α5- and 2.5-fold decreases, respectively), as assessed by Matrigel plug assays. This correlates with an α1.5-fold decrease in mitochondrial Cox IV expression. Our studies suggest that Akt3 is a regulator of mitochondrial dynamics in the vasculature via regulation of CRM-1- dependent nuclear export. Source

Rudnick J.A.,Tufts University | Kuperwasser C.,Tufts University | Kuperwasser C.,Molecular Oncology Research Institute
Clinical and Experimental Metastasis | Year: 2012

Breast cancer is a heterogeneous, multi-factorial disease of aberrant breast development whose etiology relies upon several microenvironmental changes within the tissue. Within the last decade, it has become widely accepted that tumor cells frequently rely on signals from an activated microenvironment in order to proliferate and survive within a tissue. This activated tissue microenvironment involves the appearance of aSMA ? fibroblasts (referred to as "cancer associated fibroblasts"), the recruitment of various immune cells (macrophages, T cells, B cells, T regulatory cells), enhanced collagen I deposition, and epigenetic modifications of stromal cells. These stromal changes can predict patient survival and correlate with distinct breast tumor subtypes. Characterizing these stromal changes will facilitate their use as clinical biomarkers in breast cancer, and may facilitate their use as potential drug targets for adjuvant breast cancer therapy. © Springer Science+Business Media B.V. 2012. Source

Jun H.J.,Molecular Oncology Research Institute | Bronson R.T.,Harvard University | Charest A.,Molecular Oncology Research Institute | Charest A.,Tufts University
Stem Cells | Year: 2014

Glioblastoma multiforme (GBM) is the most lethal form of primary brain tumors, characterized by highly invasive and aggressive tumors that are resistant to all current therapeutic options. GBMs are highly heterogeneous in nature and contain a small but highly tumorigenic and selfrenewing population of stem or initiating cells (glioblastoma stem cells or GSCs). GSCs have been shown to contribute to tumor propagation and resistance to current therapeutic modalities. Recent studies of human GBMs have elucidated the genetic alterations common in these tumors, but much remains unknown about specific signaling pathways that regulate GSCs. Here we identify a distinct fraction of cells in a genetically engineered mouse model of EGFR-driven GBM that respond to anti-EGFR therapy by inducing high levels of c-MET expression. The MET-positive cells displayed clonogenic potential and long-term self-renewal ability in vitro and are capable of differentiating into multiple lineages. The MET-positive GBM cells are resistant to radiation and highly tumorigenic in vivo. Activation of MET signaling led to an increase in expression of the stemness transcriptional regulators Oct4, Nanog, and Klf4. Pharmacological inhibition of MET activity in GSCs prevented the activation of Oct4, Nanog, and Klf4 and potently abrogated stemness. Finally, the MET expressing cells were preferentially localized in perivascular regions of mouse tumors consistent with their function as GSCs. Together, our findings indicate that EGFR inhibition in GBM induces MET activation in GSCs, which is a functional requisite for GSCs activity and thus represents a promising therapeutic target. © AlphaMed Press 2013. Source

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