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Gene Expression and Signal Transduction

Gene Expression and Signal Transduction. Shane Burgess CVM. Why Gene Expression and Signal Transduction ?. Fundamental to all biology. A. Biological basics and paradigms B. Gene Expression C. Signaling. A. BIOLOGICAL BASICS AND PARADIGMS. Most cell biology is poorly understood.

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Gene Expression and Signal Transduction

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  1. Gene Expression and Signal Transduction Shane Burgess CVM burgess sept 2002 compubiol

  2. Why Gene Expression and Signal Transduction ? Fundamental to all biology burgess sept 2002 compubiol

  3. A. Biological basics and paradigms B. Gene Expression C. Signaling burgess sept 2002 compubiol

  4. A. BIOLOGICAL BASICS AND PARADIGMS burgess sept 2002 compubiol

  5. Most cell biology is poorly understood. Cells are complex systems in themselves but ……then add environment and a very complex web of inter-actions is created. All human cells have identical (we hope) genetic material yet, there are >200 types of cells/ human. These cells are different shapes, sizes and and carry out different functions. And ALL of these cells were developed from a single cell (from two halves of two cells if you are human). burgess sept 2002 compubiol

  6. Evolution “Nothing in Biology Makes Sense - Except in the Light of Evolution” Theodosius Dobzhansky (1900-1975) • Genetic variation leading to difference in phenotype (trait) • Pressures in environment select these and increase the frequency of the selected gene (allele) in the population • Polymorphic genes suggest high selection pressures burgess sept 2002 compubiol

  7. Key gene terms: Polymorphism: “many shapes” i.e. different versions of genes coding for the same protein in a population. The versions are called ALLELES Note on trait: Pronounced tr[=a], as in French, and still so pronounced by english speakers. burgess sept 2002 compubiol

  8. The “Molecular Arms Race” and the “Red Queen’s Hypothesis” “For an evolutionary system, continuing development is needed just in order to maintain its fitness relative to the systems it is co-evolving with ( L. van Valen, 1973).” Based on the observation, to Alice, by the Red Queen in Lewis Carroll's Through the Looking Glass that “....in this place it takes all the running you can do, to keep in the same place." burgess sept 2002 compubiol

  9. B Disease A Health Sensitive dependence on initial conditions burgess sept 2002 compubiol

  10. What are we (A) ? Proteins (amino acids) : N, H, C, O Fats: C, H, O Sugars: C, H, O Matter cannot be created or destroyed; the molecules in us could well once have been in dinosaurs or mushrooms - in fact any life form you would like to name. burgess sept 2002 compubiol

  11. What are we (B)? “Gene machines”; structures designed to pass genetic information through time. burgess sept 2002 compubiol

  12. Genotype defines phenotype …well almost…… “Central Dogma” (Francis Crick): 1 gene gives 1 mRNA gives 1 protein (predicted hundreds of thousands of genes in humans) Today 1 gene gives >1 mRNA gives >1 functional protein/mRNA species (Now estimate there are only 35 –40 K genes in human genome, but still hundreds of thousands of proteins) burgess sept 2002 compubiol

  13. Differentiation: All cells have the same genome (compliment of genes) So why do they look, and function differently ? (CLONES) burgess sept 2002 compubiol

  14. Ecosystems Communities of many interacting species (including pathogens) Interacting groups of the same species Individuals (± sexual reproduction) Organs Cells Proteins and lipids (ENZYMES) mRNA DNA (Chromosomes , Alleles) ENVIRONMENT burgess sept 2002 compubiol

  15. Death is the Default. Activation (induce cell proliferation) of any cell and it will die unless told (signaled) to do otherwise (programmed cell death). Cancer is hyper-proliferation without compensatory cell death. burgess sept 2002 compubiol

  16. Genetics and Epigenetics Genetics : the study of the heritable code of life . Only 4 letters: A, T, C, G; Which, as triplets, code for only 20 amino acids eg ATG = methionine. Epigenetics: heritable phenotypes that are not derived from the code burgess sept 2002 compubiol

  17. Structure defines function These “structures” function in interacting networks i.e. we are (structured) bags of interacting proteins that “stick” together (and come apart again) with different affinities. But the functions of these structures is not fixed, it is context dependant. burgess sept 2002 compubiol

  18. GENE EXPRESSION burgess sept 2002 compubiol

  19. The genome (the gene compliment – fixed) The transcriptome (the mRNA compliment – context dependant) The proteome (the protein compliment – context dependant) burgess sept 2002 compubiol

  20. The Code Genes: TAG CGA AGG ACG TCG GAC TCT GAC ATGGCT TCC TGC AGC CTG AGA CTG mRNA: AUGGCU UCC UGC AGC CUG AGA CUG Protein: M A S C S L R L burgess sept 2002 compubiol

  21. appliedbiosystems Genes burgess sept 2002 compubiol

  22. Gene structure Exon Intron Regulation 1 2 3 4 ORF burgess sept 2002 compubiol

  23. Transcription DNA to messenger (m)RNA burgess sept 2002 compubiol

  24. Regulation Exon Intron 1 2 3 4 Polymerase burgess sept 2002 compubiol

  25. Regulating Transcription Regulation Exon Intron 1 2 3 4 TF ± TF = transcription factor burgess sept 2002 compubiol

  26. Access (cell differentiation, structural change to DNA [epigenetic]) Regulation Exon Intron 1 2 3 4 No Transcription; gene permanently silenced. The opposite can also happen e.g. carinogens H H C TF H burgess sept 2002 compubiol

  27. Transcription Regulation Exon Intron 1 2 3 4 TF ± 1 2 3 4 burgess sept 2002 compubiol

  28. mRNA Splicing and export from nucleus The first main source of complexity. Differential splicing in different cells or in different conditions. 1 2 3 4 or 4 3 2 2 3 1 1 or etc 4 2 1 burgess sept 2002 compubiol

  29. The Transcriptome Two conditions: healthy (h) vs. poisoned (p) P > H H > P H = P burgess sept 2002 compubiol

  30. The amount of mRNA that gets to the ribosome (where translation occurs) depends not only on the amount of transcription but also on longevity. mRNA longevity can be context dependent burgess sept 2002 compubiol

  31. 4 3 2 1 Translation (making protein) 3 2 1 Exons usually encode protein domains burgess sept 2002 compubiol

  32. Functional implications of alternate splicing burgess sept 2002 compubiol

  33. Post-translational modification SH S S SH O O P P O O O O O O burgess sept 2002 compubiol

  34. SH SH S S SH SH O O P O O P O O O O Functional implications of post-translational modification burgess sept 2002 compubiol

  35. Still not done……. Protein transport to appropriate site Protein stability burgess sept 2002 compubiol

  36. The proteome • Dr Michael J Dunn Reader in Biochemistry National Heart and Lung Institute Imperial College School of Medicine Heart Science Centre Harefield Hospital Harefield Middlesex UB9 6JH burgess sept 2002 compubiol

  37. To re-emphasize, there is no linear relationship between the transcriptome and the proteome The two more often than not, do not correlate at all. burgess sept 2002 compubiol

  38. signals Michael W. KING, Ph.D Terre Haute Center for Medical Education Indiana State University Protein: signaling, structure, enzyme burgess sept 2002 compubiol

  39. Go to excell burgess sept 2002 compubiol

  40. C. Signal transduction (communication) burgess sept 2002 compubiol

  41. Environment to cells (light, sound, temperature, chemicals [toxins]) • Cells from one organism to cells of another another organism (pheromones, pollens, colors [light] and scents) • Cells from one organ to cells of another organ within an organism (endocrine) • Cells from one organ to other cells in the same organ (paracrine) • Cells to themselves (autocrine) • One organelle to another organelle within cells (trafficking) burgess sept 2002 compubiol

  42. burgess sept 2002 compubiol

  43. Intracellular: Cancer signaling networks burgess sept 2002 compubiol

  44. Wingender, E., Chen, X., Hehl, R., Karas, H., Liebich, I., Matys, V., Meinhardt, T., Prüß, M., Reuter, I. and Schacherer, F.: TRANSFAC: an integrated system for gene expression regulation Nucleic Acids Res. 28, 316-319 (2000). Steroid - direct burgess sept 2002 compubiol

  45. Wingender, E., Chen, X., Hehl, R., Karas, H., Liebich, I., Matys, V., Meinhardt, T., Prüß, M., Reuter, I. and Schacherer, F.: TRANSFAC: an integrated system for gene expression regulation Nucleic Acids Res. 28, 316-319 (2000). burgess sept 2002 compubiol

  46. Wingender, E., Chen, X., Hehl, R., Karas, H., Liebich, I., Matys, V., Meinhardt, T., Prüß, M., Reuter, I. and Schacherer, F.: TRANSFAC: an integrated system for gene expression regulation Nucleic Acids Res. 28, 316-319 (2000). burgess sept 2002 compubiol

  47. Wingender, E., Chen, X., Hehl, R., Karas, H., Liebich, I., Matys, V., Meinhardt, T., Prüß, M., Reuter, I. and Schacherer, F.: TRANSFAC: an integrated system for gene expression regulation Nucleic Acids Res. 28, 316-319 (2000). burgess sept 2002 compubiol

  48. ORI ORF burgess sept 2002 compubiol

  49. Go to word burgess sept 2002 compubiol

  50. The apex of biological cascades IFNa/b CXC IL-18 1L-1b GMCSF LPS-BP1 ES622 MBP TOLL AnnexinV (P-S) HSP C’r FcR 1.APC migration to site 2.Antigen uptake 3.Inflammation recognition APC CpG 4. Decision ICAM-1 LFA-3 CD40 CD80/86 OX40L 4-1BBL LIGHT IL-12 IL-6 MHC class I,II 5. Antigen presentation 6. Co-stimulation 7. Soluble enhancement burgess sept 2002 compubiol

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