Download - Gene Expression and Signal Transduction
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Gene Expression and Signal Transduction
Shane Burgess CVM
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Why Gene Expression and Signal Transduction ?
Fundamental to all biology
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A. Biological basics and paradigms
B. Gene Expression
C. Signaling
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A. BIOLOGICAL BASICS AND PARADIGMS
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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).
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“Nothing in Biology Makes Sense - Except in the Light of Evolution”
•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
Evolution
Theodosius Dobzhansky (1900-1975)
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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.
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The “Molecular Arms Race” and the “Red Queen’s Hypothesis”
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."
“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).”
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Sensitive dependence on initial conditions
Dis
ease
Health
A
B
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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.
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What are we (B)?
“Gene machines”; structures designed to pass genetic information through time.
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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)
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Differentiation:
All cells have the same genome (compliment of genes)
So why do they look, and function differently ?
(CLONES)
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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
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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.
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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
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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.
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GENE EXPRESSION
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The genome (the gene compliment – fixed)
The transcriptome (the mRNA compliment – context dependant)
The proteome (the protein compliment – context dependant)
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The Code
Genes: TAG CGA AGG ACG TCG GAC TCT GAC ATG GCT TCC TGC AGC CTG AGA CTG
Protein: M A S C S L R L
mRNA: AUG GCU UCC UGC AGC CUG AGA CUG
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appliedbiosystems
Genes
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1 2 3 4
Regulation
ORF
Exon IntronGene structure
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Transcription
DNA to messenger (m)RNA
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1 2 3 4
Regulation Exon Intron
Polymerase
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1 2 3 4
Regulation Exon Intron
TF
±
Regulating Transcription
TF = transcription factor
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Access (cell differentiation, structural change to DNA [epigenetic])
1 2 3 4
Regulation Exon Intron
TF
C HH
H
No Transcription; gene permanently silenced. The opposite can also happen e.g. carinogens
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1 2 3 4
Regulation Exon Intron
TF
±
Transcription
1 2 3 4
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mRNA Splicing and export from nucleus
The first main source of complexity.Differential splicing in different cells or indifferent conditions.
1 2 3 4
1 2 3 4 or 1 2 3
or1 2 4 etc
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The TranscriptomeTwo conditions: healthy (h) vs. poisoned (p)
P > H H > P H = P
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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
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Translation (making protein)1
23
4
12
3
Exons usually encode protein domains
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Functional implications of alternate splicing
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Post-translational modification
O
O
O
P O
SH
SH
O
O
O
P O
SS
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Functional implications of post-translational modification
SH
SH
O
O
O
P O
SS
O
O
O
P O
SH
SH
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Still not done…….
Protein transport to appropriate site
Protein stability
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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
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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.
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Michael W. KING, Ph.DTerre Haute Center for Medical EducationIndiana State University
signals
Protein: signaling, structure, enzyme
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Go to excell
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C. Signal transduction (communication)
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•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)
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Intracellular: Cancer signaling networks
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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 regulationNucleic Acids Res. 28, 316-319 (2000).
Steroid - direct
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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 regulationNucleic Acids Res. 28, 316-319 (2000).
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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 regulationNucleic Acids Res. 28, 316-319 (2000).
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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 regulationNucleic Acids Res. 28, 316-319 (2000).
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ORF
ORI
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Go to word
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APC
1.APC migration to site 2.Antigen uptake 3.Inflammation recognition
5. Antigen presentation 6. Co-stimulation7. Soluble enhancement
4. Decision
AnnexinV (P-S)HSPC’rFcR
LPS-BP1
ES622
MBPTOLL
IFN/CXCIL-181L-1GMCSF
CpG
MHC class I,II CD40CD80/86OX40L4-1BBLLIGHT
IL-12IL-6
ICAM-1LFA-3
The apex of biological cascades
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T“HELPER”
HVEM
CD28 CTLA-4
ICOS
TCRCD4
CD154
OX40
B7-H1L
APC
LIGHT
CD80/86
ICOS-L
MHC II
CD40
OX40L
B7-H1
T“KILLER”
IL-2IL-2
CD80/86
MHC I
4-1BBL
CD28CTLA-4
TCRCD8
4-1BB
IL-12
The apex of biological cascades
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TAPC
CD28
CD40 CD154
CD80
CD4/ 8
On/OFF switches:Antigen recognition with out co-stimulation causes anergy (tolerance, “ignorance)
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Gene Expression and Signaling (or life): a summary.A finite set of relatively simple self replicating error prone instructions, which create a finite (but much greater and more complicated) set of structures, which interact in context-dependant networks to create an infinitely variable diversity of forms based on a standard design, which is affected by, and can in turn affect, its environment.