cancer and the breakdown of gene regulatory networks 1.gene expression and transcription...
Post on 22-Dec-2015
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GENE EXPRESSION:
•GENE =SEGMENT OF DNA = BLUEPRINT FOR A
SINGLE PROTEIN
•EACH CELL CONTAINS ALL GENES !!!
•WHEN A GENE IS EXPRESSED, THE PROTEIN IT
CODES FOR IS SYNTHESIZED (AT RIBOSOMES)
•NOT ALL GENES ARE EXPRESSED IN ALL CELLS (OF A
MULTICELLULAR ORGANISM) OR AT ALL TIMES
Gene expression
(EUCARYOTIC)(EUCARYOTIC)
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DIFFERENTIATION
•DIFFERENT CELL TYPES SYNTHESIZE DIFFERENT PROTEINS•TYPICAL EUCARYOTIC CELL – ABOUT 10,000 PROTEINS•FOR THE 2000 MOST ABUNDANT (>50,000 COPIES/CELL)
FEW DIFFERENCES ARE FOUND (5 FOLD OR LESS)• A FEW % ARE CELL TYPE SPECIFIC
A PARTICULAR CELL’S EXPRESSED GENES VARY •WITH TIME•IN RESPONSE TO EXTERNAL SIGNALS•IN RESPONSE TO INTERNAL “CLOCKS”•DEPENDING ON STATE – NORMAL, STRESSED, ABNORMAL
HOW IS GENE EXPRESSION REGULATED??
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TRANSCRIPTION
Transcription
M-RNA IS PROCESSED (SPLICED)
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REGULATION AT DIFFERENT STEPS
KINDS OF REGULATION
M-RNA IS PROCESSED (SPLICED)
TRANSCRIPTIONAL CONTROL
RNA PROCESSING CONTROL
RNA TRANSPORT CONTROL
TRANSLATIONAL CONTROL
RNA DEGRADATION
PROTEIN ACTIVITY
PREVALENT (NO SYNTHESIS)
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TRANSCRIPTION – CLOSER LOOK
RNA POLYMERASE ATTACHES TO DNA, MOVES ALONG IT, OPENS DOUBLE HELIX, SYNTHESIZES MRNA.
CONTROL OF EXPRESSION BY ASSISTING OR BLOCKINGATTACHMENT OF RNA POLYMERASE TO DNA.
RNA POLYMERASE BINDS AT A SPECIFIC REGION, THEPROMOTER, AT THE START OF THE GENE, IF AN ACTIVATOR IS ATTACHED AT AN ADJACENT SPECIFIC REGULATORY BINDING SEQUENCE (OPERATOR) AND AREPRESSOR IS NOT ATTACHED TO ITS OWN OPERATOR
TRANSCIPTION activator
TRANSCRIPTION START
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6-2,6-4
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TRANSCRIPTION – CLOSER LOOK
RNA POLYMERASE ATTACHES TO DNA, MOVES ALONG IT, OPENS DOUBLE HELIX, SYNTHESIZES MRNA.
CONTROL OF EXPRESSION BY ASSISTING OR BLOCKINGATTACHMENT OF RNA POLYMERASE TO DNA.
RNA POLYMERASE DOES NOT BIND AT THEPROMOTER, AT THE START OF THE GENE, IF AREPRESSOR IS ATTACHED TO ITS OWN OPERATOR
TRANSCIPTION repressor
TRANSCRIPTIONFACTORS
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RECOGNITION OF BINDING MOTIFS IN DNA
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RECOGNITION OF BINDING MOTIFS IN DNA 2
HOMEODOMAIN
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TRYPTOPHAN REPRESSOR-SWITCH
OPERON
REGULATORY“NETWORK”
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lac OPERON – E-COLI (PROCARYOTIC)
OPERON – SET OF GENES PLACED ONE AFTER THE OTHERON DNA, TAKING PART IN ONE PROCESS (BREAKDOWN OFlactose). E-COLI PREFERS glucose – WILL PROCESS lactose ONLY UNDER ( –glucose/+ lactose ) CONDITIONS. 4-SWITCH!
Cyclic AMP CONCENTRATION WHEN +glucose allolactose CONCENTRATION WHEN +lactose
ACTIVATOR: + (ACTIVE IF COMPLEX)
--glucose/+lactose
LAC OPERON KEEP!
REPRESSOR: + (ACTIVE IF FREE)
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9 – 21 lac 4-way switch
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EUCARYOTIC – MUCH MORE COMPLEX
• RNA POLYMERASE CANNOT INITIATE TRANSCRIPTION GENERAL TRANSCRIPTION FACTORS ASSEMBLE, FORM
COMPLEX ON OPERATOR NEAR PROMOTER - ABUNDANT
EUCARYOTIC 9 – 30,31
TBP – SUBUNIT OF TFIID
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• SPECIFIC REGULATORS OF TRANSCRIPTION (ENHANCERS)
CAN ATTACH TO DNA MANY 1000 OF BP UPSTREAM,
CAN EVEN BE PLACED DOWNSTREAM FROM START SITE
VERY MINUTE AMOUNT PRESENT
• MAY NEED MORE THAN ONE TRANSCRIPTION FACTOR TO
ACTIVATE GENE
9-36,9-45
control of human beta-globin
proximity of GAL4enhances 1000 foldthe attachment of TFIIB to TFIID
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REGULATORY NETWORKS
• TRANSCRIPTION FACTORS ARE PROTEINS THAT
ACTIVATE OR REPRESS GENES’ TRANSCRIPTION INTO
PROTEINS
• PROTEINS FORM COMPLEXES THAT INDUCE /TURN OFF
/REGULATE A GENE’S TRANSCRIPTIONAL CAPACITY
COMPLEX NETWORKS OF REGULATION OF GENE
EXPRESSION EMERGE
REGULATORY NETWORKS
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HALLMARKS 1
CANCER IS CAUSED BY THE BREAKDOWN OF SEVERAL IMPORTANT NETWORKS,THAT GUARD AGAINST
UNCONTROLLED PROLIFERATION
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NORMAL CELL STATES & CELL CYCLE
Check Points (Internal and External signals)
G1 –gap, decide whether to proliferate, wait
or cross to non-dividing stage G0
S -- DNA Synthesis
G2– gap, allow DNA repair
M – Mitosis, cell division
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NORMAL ENTRY TO/EXIT FROM CELL CYCLE
Cell DivisionProliferation
Cell cycle arrest (G0) or
ProgrammedCell Death(Apoptosis)
Limited replication, senescence, crisis
Terminal differentiation
Check Point (Internal and External signals)
Growth Signals
Induced Apoptosis too many divisions
Anti Growth Signals
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Cancer Cell-HALLMARKS
Cell DivisionProliferation
Cell cycle arrest or
ProgrammedCell Death(Apoptosis)
Limited replication, senescence, crisis
Terminal differentiation
1
3 3 4
2
Defective computation at check points, or failure to interpret signals or execute instructions:1 Proliferation becomes independent of growth factors.2 Loosing responses to cell cycle inhibitory signals.3 Failure to apoptose when necessary.4 Immortalization.
series of random genetic accidents
These are the main 4 HALLMARKS OF CANCER.
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1. SELF SUFFICIENCY IN GROWTH SIGNALS
IN NORMAL CELLS, GROWTH FACTORS ARE RELEASED BY NEIGHBOR CELLS, BOUND BY GF RECEPTORS (USUALLYIN CELL MEMBRANE), WHICH GET MODIFIED AND INITIATE A CASCADE OF SIGNALING EVENTS .
1. Autonomous generation of growth factors2. Receptor overexpression or alteration3. Defective downstream processing
MUTANT Ras SEND DOWNSTREAM GROWTH SIGNALS WITHNO STIMULUS FROM UPSTREAM
What can go wrong?
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2. IGNORING ANTI-GROWTH SIGNALS
IN NORMAL CELLS, MOST ANTIGROWTH SIGNALS DIRECTING THE CELL TO G0 ARE CHANNELED THROUGH THE Rb(RETINOBLASTOMA) PROTEIN.
TERMINAL DIFFERENTIATION IS INDUCED BY FORMATION OF Myc-Max COMPLEX.
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3. EVADING APOPTOSIS
THE APOPTOTIC MACHINERY RELIES ON SENSORS (THAT DETECT INTERNAL AND EXTERNAL SIGNALS) AND EFFECTORS, THAT INDUCE AND CARRY OUT THE DEATHSENTENCE. p53 IS A CENTRAL PLAYER IN APOPTOSIS.
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4. IMMORTALIZATION
A CELL CAN UNDERGO A LIMITED NUMBER OF DIVISIONS.
THE “COUNTING DEVICE” IS A STRING OF SEVERAL 1000
REPEATS OF A 6-BP SEQUENCE ELEMENT AT THE END OF
THE CHROMOSOMES (TELOMERS). IN EACH DIVISION 50 –
100 TELOMERIC BP ARE LOST. WHEN THEY RUN OUT, THE
CHROMOSOME ENDS ARE UNPROTECTED AND FUSE,
LEADING TO CRISIS AND DEATH OF THE CELL.
CANCER CELLS ACQUIRE TELOMERE MAINTENANCE
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TWO MORE:
5. Formation of new blood vessels in the tumor (Sustained Angiogenesis) (NEEDED TO ACHIEVE LARGE SIZE)
6. Acquirement of metastatic behavior (cancer cells spread to vital organs) (CAUSE OF 90% OF CANCER RELATED DEATHS)