Charles Stiles, Ph.D.
Professor of Neurobiology
We are currently focused on a pair of CNS-specific bHLH transcription factors known as Olig1 and Olig2. The two Olig genes map to within 40 kb of each other on human chromosome 21 within the Down syndrome critical region. During embryonic development and also in the postnatal brain, the two Olig genes are expressed in progenitor cells that give rise to oligodendrocytes and certain types of neurons (notably motor neurons). Beyond merely marking these cell types, targeted disruption of Olig1/2 in developing embryos disrupts patterning of the ventral spinal cord, ablates formation of oligodendrocytes throughout the CNS and prevents formation of motor neurons.
The two Olig proteins are similar to each other within the DNA-targeting bHLH motif. Outside the bHLH domain however, Olig1 and Olig2 are very different proteins and this is reflected in non-overlapping biological functions. Olig1 function has been shown to be essential for the repair of demyelinating lesions in murine models of multiple sclerosis. Olig2 is expressed in the stem-like cells that are found in high-grade human gliomas and is essential for tumor formation in “genetically relevant” murine models of human glioma. Current activities in the Stiles lab are aimed at defining 1) structural features of the two Olig proteins that underlie their separate biological functions, 2) genetic targets of Olig genes and 3) key co-regulator proteins. A variety of methods are used towards these ends including mass spectroscopy, ChIP/Seq and high throughput RNAi screens.
Molecular imaging of drug transit through the blood-brain barrier with MALDI mass spectrometry imaging. October 4, 2013. Scientific reports.
Genomic analysis of diffuse pediatric low-grade gliomas identifies recurrent oncogenic truncating rearrangements in the transcription factor MYBL1. April 30, 2013. Proceedings of the National Academy of Sciences of the United States of America.
Separated at birth? The functional and molecular divergence of OLIG1 and OLIG2. November 1, 2012. Nature reviews. Neuroscience.
Asleep at the switch: MEK kinases control transit to gliogenesis in developing cortex. September 20, 2012. Neuron.
Prospective, high-throughput molecular profiling of human gliomas. July 22, 2012. Journal of neuro-oncology.
Identification of molecular compartments and genetic circuitry in the developing mammalian kidney. May 1, 2012. Development (Cambridge, England).
Detection of KIAA1549-BRAF fusion transcripts in formalin-fixed paraffin-embedded pediatric low-grade gliomas. August 30, 2011. The Journal of molecular diagnostics : JMD.
Report from the fifth National Cancer Institute Mouse Models of Human Cancers Consortium Nervous System Tumors Workshop. July 1, 2011. Neuro-oncology.
Phosphorylation state of Olig2 regulates proliferation of neural progenitors. March 10, 2011. Neuron.
The central nervous system-restricted transcription factor Olig2 opposes p53 responses to genotoxic damage in neural progenitors and malignant glioma. March 8, 2011. Cancer cell.
Lonafarnib (SCH66336) improves the activity of temozolomide and radiation for orthotopic malignant gliomas. January 19, 2011. Journal of neuro-oncology.
Germline mutations in TMEM127 confer susceptibility to pheochromocytoma. February 14, 2010. Nature genetics.
Phase II study of imatinib mesylate for recurrent meningiomas (North American Brain Tumor Consortium study 01-08). December 1, 2009. Neuro-oncology.
Profiling critical cancer gene mutations in clinical tumor samples. November 18, 2009. PloS one.
A genome-wide screen for spatially restricted expression patterns identifies transcription factors that regulate glial development. September 9, 2009. The Journal of neuroscience : the official journal of the Society for Neuroscience.
Efficacy of the HSP90 inhibitor 17-AAG in human glioma cell lines and tumorigenic glioma stem cells. August 5, 2008. Neuro-oncology.
Glioma stem cells: a midterm exam. June 26, 2008. Neuron.
Molecular pathogenesis of adult brain tumors and the role of stem cells. November 1, 2007. Neurologic clinics.
"Smad"eningly erratic: target gene methylation determines whether TGFbeta promotes or suppresses malignant glioma. March 1, 2007. Developmental cell.
Olig2-regulated lineage-restricted pathway controls replication competence in neural stem cells and malignant glioma. February 15, 2007. Neuron.
Phase I/II study of imatinib mesylate for recurrent malignant gliomas: North American Brain Tumor Consortium Study 99-08. August 15, 2006. Clinical cancer research : an official journal of the American Association for Cancer Research.
The bad seed: PDGF receptors link adult neural progenitors to glioma stem cells. July 20, 2006. Neuron.
Development of NG2 neural progenitor cells requires Olig gene function. May 8, 2006. Proceedings of the National Academy of Sciences of the United States of America.
Evidence for motoneuron lineage-specific regulation of Olig2 in the vertebrate neural tube. February 8, 2006. Developmental biology.
Targeted molecular therapy of malignant gliomas. January 1, 2006. Current oncology reports.
Novel pheochromocytoma susceptibility loci identified by integrative genomics. November 1, 2005. Cancer research.
A HIF1alpha regulatory loop links hypoxia and mitochondrial signals in pheochromocytomas. July 25, 2005. PLoS genetics.
A genome-wide in situ hybridization map of RNA-binding proteins reveals anatomically restricted expression in the developing mouse brain. July 20, 2005. BMC developmental biology.
Targeted molecular therapy of malignant gliomas. May 1, 2005. Current neurology and neuroscience reports.
Distinct temporal genetic signatures of neurogenic and gliogenic cues in cortical stem cell cultures. January 1, 2005. Journal of neurobiology.
Mouse brain organization revealed through direct genome-scale TF expression analysis. December 24, 2004. Science (New York, N.Y.).
bHLH transcription factor Olig1 is required to repair demyelinated lesions in the CNS. December 17, 2004. Science (New York, N.Y.).
The oligodendroglial lineage marker OLIG2 is universally expressed in diffuse gliomas. May 1, 2004. Journal of neuropathology and experimental neurology.
Expression of the guanine nucleotide exchange factor, mr-gef, is regulated during the differentiation of specific subsets of telencephalic neurons. December 19, 2003. Brain research. Developmental brain research.
Lost in space: misregulated positional cues create tripotent neural progenitors in cell culture. October 30, 2003. Neuron.
Cross-repressive interaction of the Olig2 and Nkx2.2 transcription factors in developing neural tube associated with formation of a specific physical complex. October 22, 2003. The Journal of neuroscience : the official journal of the Society for Neuroscience.
Basic helix-loop-helix factors in cortical development. July 3, 2003. Neuron.
High-resolution imaging demonstrates dynein-based vesicular transport of activated Trk receptors. June 15, 2002. Journal of neurobiology.
Molecular mechanisms controlling cortical gliogenesis. June 1, 2002. Current opinion in neurobiology.
Common developmental requirement for Olig function indicates a motor neuron/oligodendrocyte connection. April 5, 2002. Cell.
Ectopic expression of Olig1 promotes oligodendrocyte formation and reduces neuronal survival in developing mouse cortex. October 1, 2001. Nature neuroscience.
Sonic hedgehog is required during an early phase of oligodendrocyte development in mammalian brain. October 1, 2001. Molecular and cellular neurosciences.
Olig bHLH proteins interact with homeodomain proteins to regulate cell fate acquisition in progenitors of the ventral neural tube. September 18, 2001. Current biology : CB.
Oligodendrocyte lineage genes (OLIG) as molecular markers for human glial brain tumors. August 28, 2001. Proceedings of the National Academy of Sciences of the United States of America.
Hedgehog-dependent oligodendrocyte lineage specification in the telencephalon. July 1, 2001. Development (Cambridge, England).
Oligodendrocyte development in the spinal cord and telencephalon: common themes and new perspectives. July 1, 2001. International journal of developmental neuroscience : the official journal of the International Society for Developmental Neuroscience.
Schwann cell proliferative responses to cAMP and Nf1 are mediated by cyclin D1. February 15, 2001. The Journal of neuroscience : the official journal of the Society for Neuroscience.
Intracranial inhibition of platelet-derived growth factor-mediated glioblastoma cell growth by an orally active kinase inhibitor of the 2-phenylaminopyrimidine class. September 15, 2000. Cancer research.
Growth inhibition and modulation of kinase pathways of small cell lung cancer cell lines by the novel tyrosine kinase inhibitor STI 571. July 20, 2000. Oncogene.
A developmentally regulated switch directs regenerative growth of Schwann cells through cyclin D1. May 1, 2000. Neuron.
Sonic hedgehog--regulated oligodendrocyte lineage genes encoding bHLH proteins in the mammalian central nervous system. February 1, 2000. Neuron.
Bipotent cortical progenitor cells process conflicting cues for neurons and glia in a hierarchical manner. December 1, 1999. The Journal of neuroscience : the official journal of the Society for Neuroscience.
Platelet-derived growth factor stimulation of monocyte chemoattractant protein-1 gene expression is mediated by transient activation of the phosphoinositide 3-kinase signal transduction pathway. October 22, 1999. The Journal of biological chemistry.
TrkA glycosylation regulates receptor localization and activity. May 1, 1999. Journal of neurobiology.
PTEN is inversely correlated with the cell survival factor Akt/PKB and is inactivated via multiple mechanismsin haematological malignancies. February 1, 1999. Human molecular genetics.
Activation of neurotrophin-3 receptor TrkC induces apoptosis in medulloblastomas. February 1, 1999. Cancer research.
Cancer of the central nervous system. Review of an AACR special conference in cancer research with the joint section on tumors of the AANS/CNS (San Diego, CA, June 7-11, 1997). February 20, 1998. Biochimica et biophysica acta.
Activation of ErbB2 during wallerian degeneration of sciatic nerve. November 1, 1997. The Journal of neuroscience : the official journal of the Society for Neuroscience.
Detection of activated platelet-derived growth factor receptors in human meningioma. September 15, 1997. Cancer research.
Trk receptors function as rapid retrograde signal carriers in the adult nervous system. September 15, 1997. The Journal of neuroscience : the official journal of the Society for Neuroscience.
Phosphorylation-directed antibodies in high-flux screens for compounds that modulate signal transduction. September 1, 1997. BioTechniques.
A PDGF-regulated immediate early gene response initiates neuronal differentiation in ventricular zone progenitor cells. April 1, 1997. Neuron.
Temporal and spatial specificity of PDGF alpha receptor promoter in transgenic mice. January 1, 1997. Gene expression.
Differential utilization of Trk autophosphorylation sites. August 16, 1996. The Journal of biological chemistry.
Platelet-derived growth factor induction of the immediate-early gene MCP-1 is mediated by NF-kappaB and a 90-kDa phosphoprotein coactivator. July 19, 1996. The Journal of biological chemistry.
Applications of electroporation of adherent cells in situ, on a partly conductive slide. October 1, 1995. Molecular biotechnology.
Axonal growth and fasciculation linked to differential expression of BDNF and NT3 receptors in developing cerebellar granule cells. July 1, 1995. The Journal of neuroscience : the official journal of the Society for Neuroscience.
Expression of platelet derived growth factor and platelet derived growth factor receptor mRNA in a glioblastoma from a patient with Li-Fraumeni syndrome. June 1, 1995. Journal of neurology, neurosurgery, and psychiatry.
Expression of PDGF and PDGF receptors in human astrocytoma operation specimens supports the existence of an autocrine loop. January 17, 1995. International journal of cancer. Journal international du cancer.
Transdominant negative mutations. January 1, 1995. Methods in enzymology.
A new platelet-derived growth factor-regulated genomic element which binds a serine/threonine phosphoprotein mediates induction of the slow immediate-early gene MCP-1. January 1, 1995. Molecular and cellular biology.
Electroporation of peptides into adherent cells in situ. January 1, 1995. BioTechniques.
Expression of the neurotrophin receptor TrkC is linked to a favorable outcome in medulloblastoma. December 20, 1994. Proceedings of the National Academy of Sciences of the United States of America.
Platelet-derived growth factor alpha receptor gene expression: isolation and characterization of the promoter and upstream regulatory elements. July 19, 1994. Proceedings of the National Academy of Sciences of the United States of America.
Identification of an activity that interacts with the 3'-untranslated region of c-myc mRNA and the role of its target sequence in mediating rapid mRNA degradation. February 11, 1994. The Journal of biological chemistry.
Dominant-negative mutants of platelet-derived growth factor revert the transformed phenotype of human astrocytoma cells. December 1, 1993. Molecular and cellular biology.
Regulation of platelet-derived growth factor A messenger RNA translation in differentiating F9 teratocarcinoma cells. October 1, 1993. Cell growth & differentiation : the molecular biology journal of the American Association for Cancer Research.
PDGF and its receptors in the developing rodent retina and optic nerve. June 1, 1993. Development (Cambridge, England).
The Xenopus platelet-derived growth factor alpha receptor: cDNA cloning and demonstration that mesoderm induction establishes the lineage-specific pattern of ligand and receptor gene expression. January 1, 1993. Developmental genetics.
Expression of mouse PDGF-A and PDGF alpha-receptor genes during pre- and post-implantation development: evidence for a developmental shift from an autocrine to a paracrine mode of action. December 1, 1992. Mechanisms of development.
A novel 7-nucleotide motif located in 3' untranslated sequences of the immediate-early gene set mediates platelet-derived growth factor induction of the JE gene. December 1, 1992. Molecular and cellular biology.
Synthetic phosphopeptide immunogens yield activation-specific antibodies to the c-erbB-2 receptor. November 1, 1992. Proceedings of the National Academy of Sciences of the United States of America.
Extracellular calcium mimics the actions of platelet-derived growth factor on mouse fibroblasts. March 1, 1992. Cell growth & differentiation : the molecular biology journal of the American Association for Cancer Research.
Recombinant PDGF from lower vertebrates: receptor binding and immunochemical analysis with metabolically labeled growth factor. January 1, 1992. Growth factors (Chur, Switzerland).
Human keratinocyte growth-promoting activity on the surface of fibroblasts. October 1, 1991. Journal of cellular physiology.
Platelet-derived growth factor receptor alpha-subunit gene (Pdgfra) is deleted in the mouse patch (Ph) mutation. January 1, 1991. Proceedings of the National Academy of Sciences of the United States of America.
Dominant-negative mutants of a platelet-derived growth factor gene. December 1, 1990. Genes & development.
Retinoic acid promotes transcription of the platelet-derived growth factor alpha-receptor gene. December 1, 1990. Molecular and cellular biology.
Modulation of a Mr 175,000 c-neu receptor isoform in G8/DHFR cells by serum starvation. June 25, 1990. The Journal of biological chemistry.
Selective expression of PDGF A and its receptor during early mouse embryogenesis. March 1, 1990. Developmental biology.
The beta-interferon-mediated antimitogenic state resembles the anti-viral state. January 1, 1990. Oncogene research.
A clinical virology database for a regional virology service. December 1, 1989. Journal of virological methods.
Interleukin-1 is a potent regulator of JE and KC gene expression in quiescent BALB/c fibroblasts. October 1, 1989. Journal of cellular physiology.
Environment-dependent growth inhibition of human epidermal keratinocytes by recombinant human transforming growth factor-beta. June 1, 1989. Journal of cellular physiology.
Evidence for a novel signal transduction pathway activated by platelet-derived growth factor and by double-stranded RNA. April 1, 1989. Molecular and cellular biology.
The platelet-derived growth factor-inducible KC gene encodes a secretory protein related to platelet alpha-granule proteins. March 5, 1989. The Journal of biological chemistry.
Regulation of 2',5'-oligoadenylate synthetase gene expression by interferons and platelet-derived growth factor. March 1, 1989. Molecular and cellular biology.
Serum-inducible genes. January 1, 1989. Advances in cancer research.
Labile repressors are involved in the transcriptional control of PDGF-responsive genes. January 1, 1989. Oncogene research.
Platelet-derived growth factor A chain is maternally encoded in Xenopus embryos. September 2, 1988. Science (New York, N.Y.).
Comparison of fibroblast and T-cell activation genes. September 1, 1988. Cellular immunology.
Cloning and expression of JE, a gene inducible by platelet-derived growth factor and whose product has cytokine-like properties. June 1, 1988. Proceedings of the National Academy of Sciences of the United States of America.
Growth factor superfamilies and mammalian embryogenesis. March 1, 1988. Development (Cambridge, England).
Regulation of c-myc and c-fos proto-oncogene expression by animal cell growth factors. February 1, 1988. In vitro cellular & developmental biology : journal of the Tissue Culture Association.
Platelet-derived growth factor generates at least two distinct intracellular signals that modulate gene expression. January 1, 1988. Cold Spring Harbor symposia on quantitative biology.
Molecular regulation of growth control: implications for wound healing. January 1, 1988. Progress in clinical and biological research.
A cell-cycle constraint on the regulation of gene expression by platelet-derived growth factor. November 27, 1987. Science (New York, N.Y.).
Platelet-derived growth factor-inducible genes respond differentially to at least two distinct intracellular second messengers. November 5, 1987. The Journal of biological chemistry.
Molecular cloning of gene sequences that are regulated by insulin-like growth factor I. August 15, 1987. The Journal of biological chemistry.
Regulation of c-myc and c-fos mRNA levels by polyomavirus: distinct roles for the capsid protein VP1 and the viral early proteins. March 1, 1987. Proceedings of the National Academy of Sciences of the United States of America.
Differential colony hybridization: molecular cloning from a zero data base. January 1, 1987. Methods in enzymology.
Cell cycle dependent genes inducible by different mitogens in cells from different species. June 1, 1986. Molecular and cellular biochemistry.
Platelet-derived growth factor and double-stranded ribonucleic acids stimulate expression of the same genes in 3T3 cells. December 1, 1985. Cell.
The biological role of oncogenes--insights from platelet-derived growth factor: Rhoads Memorial Award lecture. November 1, 1985. Cancer research.
The PDGF-inducible 'competence genes': intracellular mediators of the mitogenic response. January 1, 1985. Ciba Foundation symposium.
Expression of the c-fos gene and of an fos-related gene is stimulated by platelet-derived growth factor. November 30, 1984. Science (New York, N.Y.).
Autocrine control of growth? October 1, 1984. Nature.
Functional role for c-myc in mitogenic response to platelet-derived growth factor. August 1, 1984. Nature.
Regulation of cytoskeletal architecture by platelet-derived growth factor, insulin and epidermal growth factor. July 1, 1984. Experimental cell research.
Regulation of gene expression by serum and serum growth factors. January 1, 1984. Symposium on Fundamental Cancer Research.
The regulation of c-myc by growth signals. January 1, 1984. Current topics in microbiology and immunology.
Use of defined media for analysis of the action of platelet-derived growth factor on fibroblasts. January 1, 1984. Progress in clinical and biological research.
Cell-specific regulation of the c-myc gene by lymphocyte mitogens and platelet-derived growth factor. December 1, 1983. Cell.
The molecular biology of platelet-derived growth factor. July 1, 1983. Cell.
Molecular cloning of gene sequences regulated by platelet-derived growth factor. July 1, 1983. Cell.
Persistence of the mitogenic response to platelet-derived growth factor (competence) does not reflect a long-term interaction between the growth factor and the target cell. May 1, 1983. The Journal of cell biology.
Phylogenetic analysis of platelet-derived growth factor by radio-receptor assay. November 1, 1982. The Journal of cell biology.
Growth factors adherent to cell substrate are mitogenically active in situ. March 11, 1982. Nature.
Post-transcriptional control of protein synthesis in Balb/c-3T3 cells by platelet-derived growth factor and platelet-poor plasma. December 1, 1981. Journal of cellular physiology.
Cytoplasmic transfer of the mitogenic response to platelet-derived growth factor. July 1, 1981. Proceedings of the National Academy of Sciences of the United States of America.
Effect of ouabain on growth regulation by serum components in Balb/c-3T3 cells: inhibition of entry into S phase by decreased protein synthesis. December 1, 1980. Journal of cellular physiology.
Regulation of the Balb/c-3T3 cell cycle-effects of growth factors. January 1, 1980. Journal of supramolecular structure.
Roles of the T antigens in transformation by SV40. January 1, 1980. Cold Spring Harbor symposia on quantitative biology.
Initiation of cell replication by cationic polypeptide hormones. January 1, 1980. Society of General Physiologists series.
Centriole deciliation associated with the early response of 3T3 cells to growth factors but not to SV40. December 1, 1979. Cell.
Platelet-derived growth factor prevents G0 growth arrest. October 4, 1979. Nature.
The tumor promoter 12-O-tetradecanoyl-phorbol-13-acetate enhances the proliferative response of Balb/c-3T3 cells to hormonal growth factors. September 1, 1979. Journal of cellular physiology.
Platelet-derived growth factor and the regulation of the mammalian fibroblast cell cycle. August 10, 1979. Biochimica et biophysica acta.
Control of the Balb/c-3T3 cell cycle by nutrients and serum factors: analysis using platelet-derived growth factor and platelet-poor plasma. June 1, 1979. Journal of cellular physiology.
Platelet alpha granules contain a growth factor for fibroblasts. June 1, 1979. Blood.
Growth of nontumorigenic cells in Millipore diffusion chambers implanted in mice and implications for in vivo growth regulation. May 1, 1979. Cancer research.
Purification of human platelet-derived growth factor. April 1, 1979. Proceedings of the National Academy of Sciences of the United States of America.
Dual control of cell growth by somatomedins and platelet-derived growth factor. March 1, 1979. Proceedings of the National Academy of Sciences of the United States of America.
Regulation of the mammalian fibroblast cell cycle by a platelet-derived growth factor. January 1, 1979. Progress in clinical and biological research.
Transforming viruses directly reduce the cellular growth requirement for a platelet derived growth factor. December 1, 1978. Journal of cellular physiology.
An ordered sequence of events is required before BALB/c-3T3 cells become committed to DNA synthesis January 1, 1978. Proc Natl Acad Sci U S A .
Induction of DNA synthesis in BALB/c 3T3 cells by serum components: reevaluation of the commitment process. October 1, 1977. Proceedings of the National Academy of Sciences of the United States of America.
Relationship of cell growth behavior in vitro to tumorigenicity in athymic nude mice. September 1, 1976. Cancer research.
Growth control of heterologous tissue culture cells in the congenitally athymic nude mouse. April 1, 1976. Cancer research.
Growth regulation and suppression of metastasis in the congenitally athymic nude mouse. January 1, 1976. Hämatologie und Bluttransfusion.
Failure of human cells transformed by simian virus 40 to form tumors in athymic nude mice. December 1, 1975. Proceedings of the National Academy of Sciences of the United States of America.
Further evidence against post-transcriptional control of inducible tyrosine aminotransferase synthesis in cultured hepatoma cells January 1, 1973. Nat New Biol .
Degradation of messenger RNA in mammalian cells. January 1, 1972. Acta endocrinologica. Supplementum.
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